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Captopril


Class: Angiotensin-Converting Enzyme Inhibitors
VA Class: CV800
CAS Number: 62571-86-2
Brands: Capoten, Capozide

May cause fetal and neonatal morbidity and mortality if used during pregnancy.401 402 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

If pregnancy is detected, discontinue captopril as soon as possible.115 402

Introduction

Sulfhydryl ACE inhibitor.1 3 4 5

Uses for Captopril Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).100 115 215 259 316 317

One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, high coronary disease risk, diabetes mellitus, chronic renal failure, and/or cerebrovascular disease.382

Can be used as monotherapy for initial management of uncomplicated hypertension;115 however, thiazide diuretics are preferred by JNC 7.382

Nephropathy

Stabilization or improvement of effective renal blood flow and glomerular filtration rate and reduction of proteinuria in hypertensive115 141 142 143 174 187 188 189 281 323 or normotensive115 162 patients with moderately impaired renal function,141 143 174 323 moderate to severe renal disease,141 323 or diabetic nephropathy.141 142 143 187 188 189 268 334

CHF

Management of symptomatic CHF, usually in conjunction with cardiac glycosides, diuretics, and ?-adrenergic blocking agents.115 210 246 247 248 249 250 252 253 254 256 257 292 304 319 320 321 333 377

Left Ventricular Dysfunction after AMI

Treatment of clinically stable patients with left ventricular dysfunction (ejection fraction ?40%) to improve survival following MI and to reduce the incidence of overt heart failure and subsequent hospitalizations for CHF.115 319 321 374

Captopril Dosage and Administration Administration Oral Administration

Administer orally 1 hour before meals to maximize absorption.115

Dosage Pediatric Patients Hypertension Oral

Dosage has been reduced in proportion to body weight; titrate carefully.115 Some experts recommend an initial dosage of 0.9–1.5 mg/kg daily (given as 0.3–0.5 mg/kg 3 times daily).398 Increase dosage as necessary to a maximum of 6 mg/kg daily.398

Adults Hypertension Oral

Initially, 25 mg 2 or 3 times daily.115 316 382 If BP is not adequately controlled after 1–2 weeks, increase dosage to 50 mg 2 or 3 times daily.115

Lower initial dosages (e.g., 6.25 mg twice daily to 12.5 mg 3 times daily) may be effective in some patients, particularly those already receiving a diuretic.a (See Hypotension under Cautions.)

Usual dosage: Manufacturers recommend 25–150 mg 2 or 3 times daily (usually not necessary to exceed 450 mg daily).115 316 JNC 7 recommends 25–100 mg daily given in 2 divided doses; JNC 7 recommends adding another drug, if needed, rather than continuing to increase dosage.382

If combination therapy is initiated with captopril/hydrochlorothiazide fixed-combination preparation, captopril 25 mg and hydrochlorothiazide 15 mg daily initially;102 259 adjust dosage (generally at 6-week intervals) by administering each drug separately or by advancing the fixed-combination preparation.102 259

Hypertensive Crises Oral

25 mg 2 or 3 times daily, initiated promptly under close supervision with frequent monitoring of BP.115 May continue previous diuretic therapy, but discontinue other hypotensive agents.115 May increase dosage at intervals of ?24 hours under continuous supervision until optimum BP response is attained or 450 mg daily is given.115 Adjunctive therapy with other hypotensive agents may be necessary.a

Acute therapy (e.g., 12.5–25 mg, repeated once or twice if necessary at intervals of 30–60 minutes or longer) has been effective231 232 236 259 in adults with hypertensive urgencies†231 232 259 and emergencies†.233 234 235 236 237 238 259 310

Nephropathy Diabetic Nephropathy Oral

25 mg 3 times daily.115 262

CHF Oral

Manufacturers recommend initial dosage of 25 mg 3 times daily;115 in patients with normal or low BP who may be volume- and/or salt-depleted, initial dosage of 6.25 or 12.5 mg 3 times daily.115 Increase dosage gradually to 50 mg 3 times daily; delay further dosage increases for ?2 weeks to assess response.115

Some clinicians recommend initial dosage of 6.25 or 12.5 mg 3 times daily, with gradual titration over several weeks to 50 mg 3 times daily, regardless of BP, salt/volume status, or concomitant diuretic therapy.321 333 377 Generally titrate dosage to prespecified target (i.e., ?150 mg daily) or highest tolerated dosage rather than according to response.333 377

Left Ventricular Dysfunction after AMI Oral

Manufacturers recommend initiation of therapy ?3 days post-MI with single dose of 6.25 mg, followed by 12.5 mg 3 times daily.115 Increase dosage over next several days to 25 mg 3 times daily and then over next several weeks (as tolerated) to 50 mg 3 times daily.115

Some clinicians recommend initiation of therapy <24 hours post-MI with initial dose of 6.25 mg, followed by 12.5 mg 2 hours later, 25 mg 10–12 hours later, and then 50 mg twice daily as tolerated.319 Recommended maintenance dosage: 50 mg 3 times daily.115

Prescribing Limits Pediatric Patients Hypertension Oral

Maximum 6 mg/kg daily.398

Adults Hypertension Oral

Maximum 450 mg daily.115

Dosage of captopril/hydrochlorothiazide fixed-combination generally should not exceed captopril 150 mg and hydrochlorothiazide 50 mg daily.102

CHF Oral

Maximum dosage recommended by manufacturer and some experts is 450 mg daily.115 333 Other experts suggest maximum dosage of 50 mg 3 times daily.377

Special Populations Renal Impairment

Manufacturers recommend initial dosage of <75 mg daily; increase dosage in small increments at 1- to 2-week intervals.115 After desired therapeutic effect has been attained, slowly reduce dosage to minimum effective level.115

Patients with Clcr 10–50 mL/minute: 75% of usual captopril dosage or administration of usual dose every 12–18 hours suggested by some clinicians.211

Clcr <10 mL/minute: 50% of usual dosage or administration of usual dose every 24 hours suggested by some clinicians.211

Patients undergoing hemodialysis may require supplemental dose after dialysis.211

Fixed-combination captopril/hydrochlorothiazide tablets usually are not recommended for patients with severe renal impairment.102

Geriatric Patients Hypertension

Usual adult dosages generally have been used; dosages of 6.25–12.5 mg 1–4 times daily used occasionally.175

Volume-and/or Salt-Depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy under close medical supervision using lower initial dosage.115 116 148 153 (See Dosage: CHF, under Dosage and Administration.)

Cautions for Captopril Contraindications

Known hypersensitivity (e.g. history of angioedema) to captopril or another ACE inhibitor.115 147 325 326 333

Warnings/Precautions Warnings Hematologic Effects

Possible neutropenia or agranulocytosis; risk of neutropenia appears to depend principally on degree of renal impairment and presence of collagen vascular disease (e.g., systemic lupus erythematosus, scleroderma).115

Use with caution and only after careful risk/benefit assessment in patients with collagen vascular disease or those taking drugs known to affect leukocytes or immune response.115

If used in patients with renal impairment, determine complete and differential leukocyte counts prior to initiation of therapy, at about 2-week intervals for the first 3 months of therapy, and periodically thereafter.115 Discontinue therapy if confirmed neutrophil count is <1000/mm3.115

Proteinuria

Proteinuria possible, particularly in patients with prior renal disease and/or those receiving relatively high dosages (>150 mg daily).115 Usually occurs by the 8th month of treatment1 3 46 and subsides or clears within 6 months whether or not therapy is continued;115 however, may persist in some patients.a

Hypotension

Possible excessive hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics or undergoing dialysis, patients with severe CHF).1 5 17 23 25 31 66 85 115 116 148 154 156

Hypotension may occur in patients undergoing surgery or during anesthesia with agents that produce hypotension; recommended treatment is fluid volume expansion.115

Transient hypotension is not a contraindication to additional doses; may reinstate therapy cautiously after BP is stabilized (e.g., with volume expansion).115

To minimize potential for hypotension, consider recent antihypertensive therapy, extent of BP elevation, sodium intake, fluid status, and other clinical conditions.a (See Special Populations under Dosage and Administration.) Discontinue other antihypertensive therapy, if possible, 1 week before initiating captopril, except in patients with severe hypertension.115 a Withholding diuretic therapy and/or increasing sodium intake approximately 3–7 days prior to initiation of captopril may minimize potential for severe hypotension.115 116 148 153

Initiate therapy in patients with CHF under close medical supervision; monitor closely for first 2 weeks following initiation of captopril or any increase in captopril or diuretic dosage.115

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.102 115 239 240 241 402 (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.402

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.401 402

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.402 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.239

Hepatic Effects

Clinical syndrome that usually is manifested initially by cholestatic jaundice and may progress to fulminant hepatic necrosis (occasionally fatal) reported rarely with ACE inhibitors.102 115 370

If jaundice or marked elevation of liver enzymes occurs, discontinue drug and monitor patient.115

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible; if associated with laryngeal edema, may be fatal.115 333 Immediate medical intervention (e.g., epinephrine) for involvement of tongue, glottis, or larynx.115 Intestinal angioedema possible; consider in differential diagnosis of patients who develop abdominal pain.115

Anaphylactoid reactions reported in patients receiving ACE inhibitors while undergoing LDL apheresis with dextran sulfate absorption115 275 276 277 or following initiation of hemodialysis that utilized high-flux membrane.102 115 242 243 244

Life-threatening anaphylactoid reactions reported in at least 2 patients receiving ACE inhibitors while undergoing desensitization treatment with hymenoptera venom.102 155 278

Not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitors.a

General Precautions Renal Effects

Transient increases in BUN and Scr possible, especially in patients with preexisting renal impairment, sodium depletion, or hypovolemia; patients with renovascular hypertension, particularly those with bilateral renal-artery stenosis or those with renal-artery stenosis in a solitary kidney;5 86 115 117 122 123 124 207 208 209 333 372 or patients with chronic or severe hypertension in whom the glomerular filtration rate may decrease transiently.1 115

Possible increases in BUN and Scr in patients with CHF;115 206 333 rapidity of onset and magnitude may depend in part on degree of sodium depletion.148 156 206 372

Closely monitor renal function following initiation of therapy in such patients.86 87 115 117 122 123 124 333 372 Some patients may require dosage reduction or discontinuance of ACE inhibitor or diuretic and/or adequate sodium repletion.115 156 206 207 209

Hyperkalemia

Possible hyperkalemia,5 7 38 69 70 85 115 122 125 126 162 163 164 177 especially in patients with impaired renal function, CHF, or diabetes mellitus and those receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).38 85 115 125 126 148 162 163 164 333 372 (See Interactions.)

Monitor serum potassium concentration carefully in these patients.126 162 163

Cough

Persistent and nonproductive cough; resolves after drug discontinuance.102 115 333

Valvular Stenosis

Possible risk of decreased coronary perfusion in patients with aortic stenosis when treated with captopril.a 115

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.102

Specific Populations Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).115 (See Fetal/Neonatal Morbidity and Mortality under Cautions and see Boxed Warning.)

Lactation

Distributed into milk.115 Discontinue nursing or the drug.115

Pediatric Use

Safety and efficacy not established; however, captopril has been used in children.115 Manufacturer states that captopril should be used only when other measures for controlling BP have not been effective.115

Possible excessive, prolonged, and unpredictable decreases in BP and associated complications (e.g., oliguria, seizures) in infants.115

Renal Impairment

Systemic exposure to captopril may be increased.115 (See Special Populations under Pharmacokinetics.) Initial dosage adjustment recommended in patients with severe renal impairment.115 (See Renal Impairment under Dosage and Administration.)

Deterioration of renal function may occur.115 211 Possible increased risk of neutropenia/agranulocytosis,115 proteinuria,115 and hyperkalemia.115 (See Warnings and General Precautions under Cautions.)

Use of captopril/hydrochlorothiazide fixed combination usually is not recommended in patients with severe renal impairment.102

Blacks

BP reduction may be smaller in black patients compared with nonblack patients;115 139 177 178 179 180 181 351 however, no apparent population difference during combined therapy with ACE inhibitor and thiazide diuretic.179 193 194 217 218 219 316 Use in combination with a diuretic.179 193 194 217 218 219 316

Higher incidence of angioedema reported with ACE inhibitors in blacks compared with other races.102 115 325 326 327 351 379 380

Common Adverse Effects

Rash, pruritus, cough, dysgeusia, proteinuria, tachycardia, chest pain, palpitations.115

Interactions for Captopril Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Adrenergic neuron blocking agents (guanethidine)

Possible increased hypotensive effect115

Use with caution115

Antacids

Decreased rate and extent of captopril absorption197 201

Clinical importance is uncertain197 201

Antidiabetic agents, oral

Possible hypoglycemia in diabetic patients101

Consider risk of hypoglycemia if used concomitantly101

Allopurinol

Pharmacokinetic interaction unlikely115

?-adrenergic blocking agents

Increased (but less than additive) hypotensive effect115

Cimetidine

Neuropathy reporteda

Further documentation of interaction necessarya

Digoxin

Possible increased serum digoxin concentrations in patients with CHF198 199 200

Monitor serum digoxin concentration;198 200 reduction of digoxin dosage not required upon initiation of captopril198

Diuretics

Possible additive hypotensive effectsa

Pharmacokinetic interaction with furosemide unlikely115

Adjust dosage carefullya (see Dosage under Dosage and Administration)

Diuretics, potassium-sparing (amiloride, spironolactone, triamterene)

Possible hyperkalemia, especially in patients with renal impairment162 329 331 335

Use cautiously and only if hypokalemia is documented; monitor serum potassium carefully;85 115 125 126 148 162 163 164 discontinue or reduce dosage of potassium-sparing diuretic as necessary85 126 148 162 163

Insulin

Possible hypoglycemia in diabetic patients101

Consider risk of hypoglycemia101

Lithium

Possible increased serum lithium concentrations, particularly in patients receiving concomitant diuretic therapy115

Use with caution; monitor serum lithium concentrations frequently115

NSAIAs

Possible decreased antihypertensive response to captopril;283 284 285 286 287 288 289 290 333 364 potential for acute reduction of renal function;285 291 possible attenuation of hemodynamic actions of ACE inhibitors in patients with CHF333 364

Monitor BP carefully and be alert for evidence of impaired renal function;285 if interaction is suspected, discontinue NSAIA or modify captopril dosage or use another hypotensive agent285 286

Potassium supplements or potassium-containing salt substitutes

Possible hyperkalemia, especially in patients with renal impairment162

Use cautiously and only if hypokalemia is documented; monitor serum potassium carefully;85 115 125 126 148 162 163 164 discontinue or reduce dosage of potassium supplement as necessary85 126 148 162 163

Probenecid

Possible increased blood concentrations of captopril and its metabolites203 204 205 213

Test for urine acetone

Possible false-positive results with sodium nitroprusside reagent54 115

Vasodilating agents (e.g., hydralazine, nitrates, prazosin)

Possible increased hypotensive effect115

If possible, discontinue vasodilating agent before starting captopril; if vasodilating agent is resumed during captopril therapy, administer with caution and possibly at a lower dosage115

Captopril Pharmacokinetics Absorption Bioavailability

Rapidly absorbed following oral administration in fasting individuals,19 20 84 115 with peak blood concentration attained in 1 hour.19 Approximately 60–75% of an oral dose is absorbed.19 20 84 115

Onset

Hypotensive effect may be apparent within 15 minutes5 6 16 23 and usually is maximal in 1–2 hours after a single oral dose.1 3 10 15 16 17 21 24 29 Several weeks of therapy may be required before full effect on BP is achieved.1 3 5 16 21 28

Duration

Duration of action generally is 2–6 hours but appears to increase with increasing doses.a

Food

Food may decrease absorption of captopril by up to 25–40%;1 3 115 191 195 196 197 202 effect may not be clinically important.191 192 195

Distribution Extent

Appears to be rapidly distributed into most body tissues, except CNS.1 5

Crosses the placenta and is distributed into milk.115

Plasma Protein Binding

25–30%1 3 22 (mainly albumin).3

Elimination Metabolism

About half the absorbed dose is rapidly metabolized.3 5 19 Captopril and its metabolites may undergo reversible interconversions.3

Elimination Route

Excreted in urine (95%) as unchanged drug (40–50%) and metabolites.3 19 20 22 115

Half-life

<2 hours.115

Special Populations

Elimination half-life is about 20–40 hours in patients with Clcr <20 mL/minute 3 and up to 6.5 days in anuric patients.5 22

Stability Storage Oral Tablets

Tight containers at ?30°C.115

Tablets (Captopril and Hydrochlorothiazide)

Tight containers at ?30°C.102

ActionsActions

Suppresses the renin-angiotensin-aldosterone system.1

Advice to Patients

Risk of angioedema, anaphylactoid reactions, or other sensitivity reactions.115 Importance of reporting sensitivity reactions (e.g., edema of face, eyes, lips, tongue, or extremities; hoarseness; swallowing or breathing with difficulty) immediately to clinician and of discontinuing the drug.115

Importance of reporting signs of infection (e.g., sore throat, fever).115

Risk of hypotension.115 Importance of informing clinicians promptly if lightheadedness or fainting occurs.115

Importance of adequate fluid intake; risk of volume depletion with excessive perspiration, dehydration, vomiting, or diarrhea.115

Importance of not discontinuing or interrupting therapy unless instructed by a clinician.115

Risks of use during pregnancy.115 401 402 (See Boxed Warning.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium) as well as any concomitant illnesses.115

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.115

Importance of taking 1 hour before meals.115

Importance of advising patients of other important precautionary information.115 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Captopril

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

12.5 mg*

Capoten (scored)

Par

25 mg*

Capoten (scored)

Par

50 mg*

Capoten (scored)

Par

100 mg*

Capoten (scored)

Par

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Captopril and Hydrochlorothiazide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg Captopril and Hydrochlorothiazide 15 mg*

Capozide (scored)

Par

Captopril and Hydrochlorothiazide Tablets

Endo, Mylan, Sandoz, Teva

25 mg Captopril and Hydrochlorothiazide 25 mg*

Capozide (scored)

Par

Captopril and Hydrochlorothiazide Tablets

Endo, Mylan, Sandoz, Teva

50 mg Captopril and Hydrochlorothiazide 15 mg*

Capozide (scored)

Par

Captopril and Hydrochlorothiazide Tablets

Endo, Mylan, Sandoz, Teva

50 mg Captopril and Hydrochlorothiazide 25 mg*

Capozide (scored)

Par

Captopril and Hydrochlorothiazide Tablets

Endo, Mylan, Sandoz, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Capozide 50-25MG Tablets (PAR): 30/$95.99 or 90/$269.98

Captopril 100MG Tablets (WEST-WARD): 90/$19.99 or 180/$29.97

Captopril 12.5MG Tablets (WEST-WARD): 100/$12.99 or 200/$18.98

Captopril 25MG Tablets (TEVA PHARMACEUTICALS USA): 90/$13.99 or 180/$26.99

Captopril 50MG Tablets (WEST-WARD): 100/$16.99 or 200/$22.97

Captopril-Hydrochlorothiazide 25-15MG Tablets (MYLAN): 90/$47.99 or 270/$114.97

Captopril-Hydrochlorothiazide 25-25MG Tablets (MYLAN): 90/$44.99 or 270/$125.99

Captopril-Hydrochlorothiazide 50-15MG Tablets (TEVA PHARMACEUTICALS USA): 60/$53.99 or 180/$154.98

Captopril-Hydrochlorothiazide 50-25MG Tablets (MYLAN): 60/$53.99 or 180/$154.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. ER Squibb & Sons, Inc. Capoten prescribing information. Princeton, NJ; 1981 Mar.

3. ER Squibb & Sons, Inc. Capoten (captopril) monograph. Princeton, NJ; 1981 Apr.

4. Atkinson AB, Robertson JIS. Captopril in the treatment of clinical hypertension and cardiac failure. Lancet. 1979; 2:836-9. [IDIS 102581] [PubMed 90928]

5. Heel RC, Brogden RN, Speight TM et al. Captopril: a preliminary review of its pharmacological properties and therapeutic efficacy. Drugs. 1980; 20:409-52. [IDIS 134943] [PubMed 7009133]

6. Ferguson RK, Turini GA, Brunner HR et al. A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet. 1977; 1:775-8. [IDIS 78256] [PubMed 66571]

7. Gavras H, Brunner HR, Turini GA et al. Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ 14225 in man. N Engl J Med. 1978; 298:991-5. [IDIS 80115] [PubMed 205788]

8. Larochelle P, Genest J, Kuchel O et al. Effect of captopril (SQ 14225) on blood pressure, plasma renin activity and angiotensin I converting enzyme activity. Can Med Assoc J. 1979; 121:309-16. [IDIS 100999] [PubMed 223756]

9. Swartz S, Williams GH, Hollenberg NK et al. Increase in prostaglandins during converting enzyme inhibition. Clin Sci. 1980; 59(Suppl):133-5S.

10. Brunner HR, Gavras H, Waeber B et al. Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann Intern Med. 1979; 90:19-23. [IDIS 96700] [PubMed 217289]

11. Johnston CI, Millar JA, McGrath BP et al. Long-term effects of captopril (SQ 14225) on blood-pressure and hormone levels in essential hypertension. Lancet. 1979; 2:493-6. [IDIS 103099] [PubMed 90216]

12. McCaa CS, Langford HG, Cushman WC et al. Response of arterial blood pressure, plasma renin activity and aldosterone concentration to long-term administration of captopril to patients with severe, treatment-resistant malignant hypertension. Clin Sci. 1979; 57(Suppl):371-3S.

13. Fagard R, Amery A, Reybrouck T et al. Acute and chronic systemic and pulmonary hemodynamic effects of angiotensin converting enzyme inhibition with captopril in hypertensive patients. Am J Cardiol. 1980; 46:295-300. [IDIS 122485] [PubMed 6250392]

14. Maruyama A, Ogihara T, Naka T et al. Long-term effects of captopril in hypertension. Clin Pharmacol Ther. 1980; 28:316-23. [IDIS 123828] [PubMed 6996895]

15. Mimran A, Brunner HR, Turini GA et al. Effect of captopril on renal vascular tone in patients with essential hypertension. Clin Sci. 1979; 57(Suppl):421-3S. [IDIS 109948] [PubMed 519950]

16. Case DB, Atlas SA, Laragh JH et al. Clinical experience with blockade of the renin-angiotensin-aldosterone system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in hypertensive patients. Prog Cardiovasc Dis. 1978; 21:195-206. [PubMed 214819]

17. Morganti A, Pickering TG, Lopez-Ovejero JA et al. Endocrine and cardiovascular influences of converting enzyme inhibition with SQ 14225 in hypertensive patients in the supine position and during head-up tilt before and after sodium depletion. J Clin Endocrinol Metab. 1980; 50:748-54. [IDIS 124889] [PubMed 6245101]

19. Kripalani KJ, McKinstry DN, Singhvi SM et al. Disposition of captopril in normal subjects. Clin Pharmacol Ther. 1980; 27:636-41. [IDIS 113124] [PubMed 6989546]

20. McKinstry DN, Kripalani KJ, Migdalof BH et al. The effe


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Navane


Generic Name: Thiothixene
Class: Thioxanthenes
VA Class: CN709
Chemical Name: N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthene-2-sulfonamide
Molecular Formula: C23H29N3O2S2
CAS Number: 5591-45-7

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

[Posted 06/16/2008] FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. Antipsychotics are not indicated for the treatment of dementia-related psychosis. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a BOXED WARNING and the WARNINGS section. For more information visit the FDA website at: , and .

Introduction

Thioxanthene-derivative, conventional (prototypical, first-generation) antipsychotic agent; structurally and pharmacologically related to chlorprothixene (no longer commercially available in the US) and trifluoperazine.a b c d e g u

Uses for Navane Psychotic Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Symptomatic management of psychotic disorders (i.e., schizophrenia).a b c d u

Has been used in the management of refractory or treatment-resistant schizophrenia.c

Mental Retardation

Efficacy not established for the management of behavioral complications in patients with mental retardation.a b c u

Navane Dosage and Administration General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Adjust dosage carefully according to individual requirements and response; use the lowest possible effective dosage.a b c u

Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued.a b u w (See Tardive Dyskinesia under Cautions.)

For symptomatic relief of psychotic disorders, initial therapeutic response to antipsychotic therapy usually occurs within 2–4 weeks and optimum therapeutic response occurs within 6 months or longer.d w

Administration Oral Administration

Thiothixene is administered orally once daily or in divided doses 2 or 3 times daily.a b c k t u Thiothixene hydrochloride has been given orally and parenterally, but no longer is commercially available in the US.a c h v

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Pediatric Patients Psychotic Disorders Oral

Children ?12 years of age: Initially, 2 mg 3 times daily for mild to moderate psychotic disorders; may gradually increase dosage, if necessary, up to 15 mg daily.a b c u

For more severe psychotic disorders in children ?12 years of age: Initially, 5 mg twice daily; may then increase dosage until satisfactory response obtained.a b c u

Optimal maintenance dosage usually 20–30 mg daily; may be increased up to 60 mg daily, if necessary; once-daily administration may be adequate.a b c k u

Daily dosages >60 mg rarely provide additional therapeutic effect.a b c u

Adults Psychotic Disorders Oral

For mild to moderate psychotic disorders: Initially, 2 mg 3 times daily; may gradually increase dosage, if necessary, up to 15 mg daily.a b c u

For more severe psychotic disorders: Initially, 5 mg twice daily; may then increase dosage until satisfactory response obtained.a b c u

Optimal maintenance dosage usually 20–30 mg daily; may be increased up to 60 mg daily, if necessary; once-daily administration may be adequate.a b c k u

Daily dosages >60 mg rarely provide additional therapeutic effect.a b c u

Prescribing Limits Pediatric Patients Psychotic Disorders Oral

Children ?12 years of age: Maximum 60 mg daily.a b c u

Adults Psychotic Disorders

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Oral

Maximum 60 mg daily.a b c u

Special Populations Geriatric Patients

No specific dosage recommendations for geriatric patients, but generally select dosage at the lower end of recommended range; increase dosage more gradually and monitor closely.a b d h u w (See Geriatric Use under Cautions and see Special Populations under Pharmacokinetics.)

Cautions for Navane Contraindications

Circulatory collapse.a b c u

Comatose states or CNS depression from any cause.a b c u (See Specific Drugs and Laboratory Tests under Interactions.)

Blood dyscrasias.a b c u

Known hypersensitivity to thiothixene.a b c u Not known if cross-sensitivity exists between thioxanthenes and phenothiazines; consider possibility that cross-sensitivity may occur.a b c u

Warnings/Precautions Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Shares the toxic potentials of other antipsychotic agents (e.g., phenothiazines); observe the usual precautions associated with therapy with these agents.a b c u

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients receiving antipsychotic agents, including thiothixene.a b c d u w Consider reducing thiothixene dosage or discontinuing drug and switching to a second-generation (atypical) antipsychotic agent.a b c d u w

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported with antipsychotic agents, including thiothixene.a b c u w

CNS Depression

May impair mental and/or physical abilities, especially during the first few days of therapy; use caution with activities requiring alertness (e.g., operating vehicles or machinery).a b u

Response to CNS depressants and alcohol may be potentiated.a b u (See Specific Drugs and Laboratory Tests under Interactions.)

Sensitivity Reactions Hypersensitivity and Cross-sensitivity

Possible sensitivity reactions reported with thiothixene (e.g., rash, pruritus, urticaria, anaphylactoid reactions) and related drugs (e.g., agranulocytosis, pancytopenia, thrombocytopenic purpura, jaundice, biliary stasis).a b c u w

Not known if cross-sensitivity exists between thioxanthenes and phenothiazines; consider possibility that cross-sensitivity may occur.a b u

Photosensitivity

Photosensitivity may occur; avoid excessive exposure to sunlight during therapy.a b u w

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Seizures

Possible risk of seizures; may lower seizure threshold.a b c u Use with extreme caution in patients with a history of seizures or during alcohol withdrawal.a b c u (See Specific Drugs and Laboratory Tests under Interactions.)

Cardiovascular Effects

Possible hypotension, tachycardia, nonspecific ECG changes, dizziness, and/or syncope; use with caution in patients with cardiovascular disease.a b c u

If severe hypotension occurs, administer norepinephrine or phenylephrine; epinephrine or dopamine should not be used.a b c u w (See Specific Drugs and Laboratory Tests under Interactions.)

Anticholinergic Effects

Possible anticholinergic effects (e.g., dry mouth, blurred vision, constipation, increased perspiration, urinary retention, impotence).a b c u

Use with caution in patients with glaucoma or prostatic hypertrophy.c (See Specific Drugs and Laboratory Tests under Interactions.)

Ocular Effects

Pigmentary retinopathy and lenticular pigmentation reported with prolonged therapy with antipsychotic agents, including thiothixene.a b c u Observe carefully.a b c u

Prolactin Secretion

Elevated prolactin concentrations reported; elevation persists during chronic administration.a b c u w

Clinical significance unknown; consider that approximately one-third of human breast cancers are prolactin dependent when prescribing thiothixene in patients with previously detected breast cancer.a b c u w

Galactorrhea, amenorrhea, gynecomastia, and impotence reported.a b c u w

Regulation of Body Temperature

Use with caution in patients exposed to extreme heat or cold.a b c u w

Other Precautions

Antiemetic effects may mask signs of overdosage of other drugs (e.g., antineoplastic agents) or obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).a b c u w

Specific Populations Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.e

Lactation

Not known but considered likely to distribute into human milk; possible effects on nursing infant unknown.e h n o r s Caution if used in nursing women; carefully assess potential benefits and risks.e n o

Pediatric Use

Safety not established in children <12 years of age.a b c u

Geriatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents.a b d h i u w

Use with caution.h (See Geriatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Drowsiness or sedation, extrapyramidal reactions (e.g., Parkinson-like symptoms, dystonia, akathisia, tardive dyskinesia), anticholinergic effects (e.g., dry mouth, blurred vision), hypotension.a b c u

Interactions for Navane Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased or decreased plasma thiothixene concentrations) with concomitant use of CYP enzyme inhibitors or inducers.a b h j l u (See Specific Drugs and Laboratory Tests under Interactions.)

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Alcohol

Potential additive CNS effects and hypotensiona b u w

Use with cautiona b h u w

Anticholinergic drugs (e.g., atropine)

Possible potentiation of anticholinergic effectsa b c u

Use with cautiona b u

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)

Anticonvulsants may decrease plasma thiothixene concentrationsa h j l

Thiothixene may lower seizure thresholda b c u

Barbiturates: Thiothixene does not appear to potentiate the anticonvulsant activity of barbituratesa b c u

Observe for signs and symptoms of reduced thiothixene effectivenessa

Dosage adjustments of anticonvulsants may be necessary i

Barbiturates: Do not reduce anticonvulsant dosage during concurrent usea b c u

Antidepressants, tricyclic (TCAs)

Possible increased plasma concentrations of thiothixenej l

?-Blockers (e.g., propranolol)

Possible decreased thiothixene clearancej l

Cimetidine

Possible decreased thiothixene clearanceh j l

CNS depressants (e.g., antihistamines, barbiturates, general anesthetics, opiate analgesics, sedative/hypnotics)

Possible additive CNS effects and hypotensiona b u

Use with caution to avoid excessive sedation or CNS depression; carefully adjust dosages of both agents as necessarya b h u

Epinephrine or dopamine

Possible further lowering of BPa b c u w

Do not use epinephrine or dopamine for thiothixene-induced hypotensiona b c u w (see Cardiovascular Effects under Cautions)

Hypotensive agents

Possible additive hypotensive effecta c

Observe closely for signs of excessive hypotensiona c

Isoniazid

Possible decreased thiothixene clearancel

Lithium

An acute encephalopathic syndrome reported occasionally, especially when high serum lithium concentrations present h w

Observe patients receiving combined therapy for evidence of adverse neurologic effects; promptly discontinue if such signs or symptoms appearw

Paroxetine

Pharmacokinetic interaction unlikelym

Smoking

Possible decreased plasma thiothixene concentrations h j l

Tests for pregnancy

False-positive results reported in some patients receiving phenothiazines; less likely to occur when serum test is useda b u

Navane Pharmacokinetics Absorption Bioavailability

Rapidly and well absorbed from GI tract following oral administration.c i k Peak plasma concentrations usually occur within 1–3 hours.i k t

Onset

Antipsychotic effects usually are apparent within 2–4 weeks after initiation of oral therapy and optimum therapeutic response usually occurs within 6 months or longer.c d w

Plasma Concentrations

Optimal therapeutic plasma concentrations not well defined, but clinical improvement associated with peak plasma concentrations of 2–15 mcg/L.t y

Distribution Extent

Widely distributed into body tissues.c i

Crosses placenta in animals; considered likely to cross placenta in humans.p x Not known if distributed into human milk but distribution into breast milk considered likely.e h o r

Plasma Protein Binding

>99%.i

Elimination Metabolism

Principally metabolized in the liver; undergoes extensive oxidative first-pass metabolism to form thiothixene sulfoxide and N-desmethylthiothixene.c h i j

Elimination Route

Excreted mainly in feces via biliary elimination as unchanged drug and as demethyl, sulfoxide, demethylated sulfoxide, and hydroxylated metabolites.c i

Unlikely to be removed by hemodialysis and peritoneal dialysis.a b u w

Half-life

34–35 hours.d i k m t

Special Populations

Clearance is reduced in females and in patients >50 years of age.h

Stability Storage Oral Capsules

Tight, light-resistant containers at 20–25°C; protect from light and moisture.b c u

ActionsActions

Produces pharmacologic effects similar to those of other conventional antipsychotic agents (e.g., phenothiazines, butyrophenones, chlorprothixene).a b c u w

Precise mechanism(s) of antipsychotic action not determined, but may be principally related to antidopaminergic effects.w Acts principally at subcortical levels on the reticular formation, hypothalamus, and limbic system.c w

Exhibits weak anticholinergic, antihistaminic, ?-adrenergic, and sedative effects and strong extrapyramidal effects; appears to possess antiemetic activity.a b c h u

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.a b c h u

Importance of clinicians informing patients in whom chronic use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.a b u

Importance of clinicians informing patients of risk of extrapyramidal reactions and providing reassurance that these reactions usually can be controlled by administration of antiparkinsonian drugs (e.g., benztropine) and by subsequent dosage reduction.a b c u w

Advise patients to avoid excessive sunlight.a b u w

Importance of avoiding exposure to temperature extremes.a b c w

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.a b u

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a b u

Importance of informing patients of other important precautionary information.a b u (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Thiothixene

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

1 mg*

Navane

Pfizer

Thiothixene Capsules

Mylan, Sandoz

2 mg*

Navane

Pfizer

Thiothixene Capsules

Mylan, Sandoz

5 mg*

Navane

Pfizer

Thiothixene Capsules

Mylan, Sandoz

10 mg*

Navane

Pfizer

Thiothixene Capsules

Mylan, Sandoz

20 mg

Navane

Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Navane 10MG Capsules (PFIZER U.S.): 90/$189.99 or 270/$565.95

Navane 2MG Capsules (PFIZER U.S.): 90/$92.99 or 270/$266.98

Navane 20MG Capsules (PFIZER U.S.): 90/$266 or 270/$779.99

Navane 5MG Capsules (PFIZER U.S.): 90/$139.99 or 270/$409.96

Thiothixene 1MG Capsules (SANDOZ): 90/$22.99 or 270/$49.97

Thiothixene 2MG Capsules (MYLAN): 90/$26.99 or 270/$71.97

Thiothixene 5MG Capsules (SANDOZ): 90/$25.99 or 270/$59.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions March 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. Roerig, Division of Pfizer Inc. Navane (thiothixene) capsules and solution, concentrate prescribing information. New York, NY. 2008 Mar.

b. Sandoz Inc. Thiothixene capsules prescribing information. Princeton, NJ. 2007 Feb.

c. AHFS drug information 2008. McEvoy GK, ed. Thiothixene. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2516-7.

d. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. From the APA website

e. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:1577-8.

f. American Academy of Pediatrics. Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn. Pediatrics. 2000; 105:880-87. [PubMed 10742343]

g. The United States Pharmacopeial Convention, Inc. USAN and the USP Dictionary drug names. Rockville, MD: United States Pharmacopeial Convention, Inc; 2007:853.

h. AMA Division of Drugs. AMA drug evaluations. Chicago: American Medical Association; 1994:2:1-2:29.

i. Balant-Gorgia AE, Balant L. Antipsychotic drugs: clinical pharmacokinetics of potential candidates for plasma concentration monitoring. Clin Pharmacokinet. 1987: 13:65-90.

j. Ereshefsky L, Saklad SR, Watanabe MD, et al. Thiothixene pharmacokinetic interactions: a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables. J Clin Psychopharmacol. 1991; 11:296-301. [PubMed 1765572]

k. Hobbs DC, Welch WM, Short MJ, et al. Pharmacokinetics of thiothixene in man. Clin Pharmacol Ther. 1974; 16:473-8. [PubMed 4415039]

l. Ereshefsky L, Jann MW, Saklad SR, et al. Bioavailability of psychotropic drugs: historical perspective and pharmacokinetic overview. J Clin Psychiatry. 1986; 47 (Suppl):6-15. [PubMed 3528134]

m. Guthrie SK, Hariharan M, Kumar AA, et al. The effect of paroxetine on thiothixene pharmacokinetics. J Clin Pharm Ther. 1997; 22:221-6. [PubMed 9447478]

n. Webb RT, Howard L, Abel KM. Antipsychotic drugs for non-affective psychosis during pregnancy and postpartum. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD004411. DOI: 10.1002/14651858.CD004411.pub2.

o. Cohen LS, Heller VL, Rosenbaum JF. Treatment guidelines for psychotropic drug use in pregnancy. Psychosomatics. 1989; 30:25-33. [PubMed 2643809]

p. Altshuler LL, Cohen L, Szuba MP, et al. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry. 1996; 153:592-606. [PubMed 8615404]

q. Mortola JF. The use of psychotropic agents in pregnancy and lactation. Psychiatr Clin North Am. 1989; 12:69-87. [PubMed 2652114]

r. Goldberg H, Nissim R. Psychotropic drugs in pregnancy and lactation. Int J Psychiatry Med. 1994; 24:129-49. [PubMed 7960421]

s. Calabrese JR, Gulledge AD. Psychotropics during pregnancy and lactation: a review. Psychosomatics. 1985; 26:413-26. [PubMed 2859631]

t. Milton GV, Jann MW. Emergency treatment of psychotic symptoms: pharmacokinetic considerations for antipsychotic drugs. Clin Pharmacokinet. 1995; 28:494-504. [PubMed 7656507]

u. Mylan Pharmaceuticals Inc. Thiothixene capsules prescribing information. Morgantown, WV; 2003 Oct.

v. Roerig, Division of Pfizer Inc. Navane (thiothixene hydrochloride) intramuscular for injection prescribing information. New York, NY. 2008 Jan.

w. AHFS drug information 2008. McEvoy GK, ed. Phenothiazines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2008: 2497-508.

x. Schmidt MH, Lee T. Investigation of striatal dopamine D2 receptor acquisition following prenatal neuroleptic exposure. Psychiatry Res. 1991; 36:319-28. [PubMed 1676523]

y. Mavroidis ML, Kanter DR, Hirschowitz J et al. Clinical relevance of thiothixene plasma levels.J Clin Psychopharmacol. 1984; 4:155-7. [PubMed 6736276]

More Navane resources Navane Side Effects (in more detail) Navane Use in Pregnancy & Breastfeeding Drug Images Navane Drug Interactions Navane Support Group 3 Reviews for Navane - Add your own review/rating Navane Prescribing Information (FDA) Navane MedFacts Consumer Leaflet (Wolters Kluwer) Navane Concise Consumer Information (Cerner Multum) Navane Advanced Consumer (Micromedex) - Includes Dosage Information Thiothixene Prescribing Information (FDA) Thiothixene Professional Patient Advice (Wolters Kluwer) thiothixene Advanced Consumer (Micromedex) - Includes Dosage Information Compare Navane with other medications Psychosis
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Triamterene


Class: Potassium-sparing Diuretics
VA Class: CV704
CAS Number: 396-01-0
Brands: Dyazide, Dyrenium, Maxzide

Hyperkalemia (i.e., serum potassium concentrations ?5.5 mEq/L) may occur with all potassium-sparing agents, including triamterene.b c d More likely to occur in patients with renal impairment and diabetes (even without evidence of renal impairment), and in geriatric or severely ill patients or those receiving prolonged therapy with large doses.a b c d

Uncorrected hyperkalemia may be fatal; monitor serum potassium concentrations at frequent intervals especially during initial therapy, after dosage adjustment, or in patients with concurrent illness that may affect renal function.b c d

Introduction

Potassium-sparing diuretic; pteridine derivative.b

Uses for Triamterene Edema

Management of edema associated with CHF, cirrhosis of the liver, or nephrotic syndrome.b

Management of steroid-induced edema, idiopathic edema, and edema caused by secondary hyperaldosteronism.b

May be used alone but most valuable when used in combination with other diuretics to promote diuresis and/or decrease potassium excretion caused by kaliuretic diuretics.b

May be particularly useful in patients excreting excessive amounts of potassium (especially those who cannot tolerate potassium supplements) and for those in whom potassium loss could be detrimental, such as patients receiving digitalis glycosides or those with myasthenia gravis.a b

Promotes increased diuresis in patients resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism.b

May be effective in some patients unresponsive to spironolactone; unlike spironolactone, diuretic effect of triamterene is independent of aldosterone concentrations.a

Used in fixed combination with hydrochlorothiazide for treatment of edema in patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked.c d

Used in fixed combination with hydrochlorothiazide for treatment of edema in patients who develop hypokalemia during hydrochlorothiazide monotherapy.c d

Do not use for routine therapy in pregnant women with mild edema who are otherwise healthy.b c d

CHF

In the management of edema associated with CHF, generally used in conjunction with other more effective, rapidly acting diuretics (e.g., thiazides, chlorthalidone, loop diuretics).a Some patients resistant to triamterene monotherapy may respond to such combined therapy.a

Most experts state that all patients with symptomatic CHF who have evidence or a prior history of fluid retention generally should receive diuretic therapy in conjunction with moderate sodium restriction (?3 g of sodium daily), an ACE inhibitor, and usually a ?-adrenergic blocking agent, with or without a cardiac glycoside.112 113

Most experts state that the diuretics of choice for most patients with CHF are loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide).a

Do not use diuretics as monotherapy in CHF even if symptoms (e.g., peripheral edema, pulmonary congestion) are well controlled; diuretics alone do not prevent progression of heart failure.

Once fluid retention in CHF has resolved, diuretic therapy should be maintained to prevent its recurrence. Ideally, diuretic therapy should be adjusted according to changes in body weight (as an indicator of fluid retention) rather than maintained at a fixed dosage.

Diuretics should be continued in CHF and comorbid conditions (e.g., hypertension) where ongoing therapy with the drugs is indicated.

Hypertension

Triamterene alone has little if any hypotensive effect; however, it may be used with another diuretic (e.g., hydrochlorothiazide) or a hypotensive agent in the management of mild to moderate hypertension.a However, JNC 7 recommends that thiazides be used as initial therapy for the treatment of uncomplicated hypertension in most patients, either alone or combined with other classes of antihypertensive drugs that have demonstrated benefit (e.g., ACE inhibitors, angiotensin II receptor antagonists, ?-blockers, calcium-channel blockers).119

Used principally in patients with diuretic-induced hypokalemia or to prevent hypokalemia in patients receiving diuretics who are at risk of this adverse effect.a

Used in fixed combination with hydrochlorothiazide for treatment of hypertension in patients who require a thiazide diuretic and in whom the development of hypokalemia cannot be risked.c d

Used in fixed combination with hydrochlorothiazide for treatment of hypertension in patients who develop hypokalemia during hydrochlorothiazide monotherapy.c d

Used in fixed combination with hydrochlorothiazide for treatment of hypertension as an adjunct to other antihypertensive drugs (e.g., ?-blockers).c d

Triamterene Dosage and Administration General

Monitor serum potassium concentrations following changes in dosage or with concurrent illness or drug therapy.b d (See Hyperkalemia under Cautions and also see Interactions.)

Avoid use of potassium-sparing diuretics, including triamterene, in patients with renal insufficiency, in those with hyperkalemia who have serum potassium concentrations >5 mEq/L while not receiving drug therapy, and in those who develop hyperkalemia during therapy.109 119 b c d

Do not use concurrent potassium supplementation or potassium-containing salt substitutes.b Discontinue potassium supplementation when triamterene is added to other diuretic therapy or when patients are switched to triamterene from other diuretics.b

Do not use fixed-combination triamterene/hydrochlorothiazide tablets or capsules for initial therapy of edema or hypertension, except in patients in whom the clinical consequences of hypokalemia represent an important risk (e.g., patients receiving cardiac glycosides or patients with cardiac arrhythmias).a c d

Do not use as initial monotherapy in severe CHF since bowel edema or intestinal hypoperfusion may delay absorption and subsequent therapeutic effect.a

Careful etiologic diagnosis should precede the use of any diuretic.a

Administration Oral Administration

Capsules: Administer orally twice daily after meals.b

Fixed-combination triamterene/hydrochlorothiazide tablets or capsules: Administer orally once daily.c d

Twice-daily administration of the fixed combination of triamterene and hydrochlorothiazide may increase risk of electrolyte imbalance and renal dysfunction.d

Dosage

Individualize dosage according to patient’s requirements and response.b

If added to an existing antihypertensive regimen, initially reduce dosage of each antihypertensive agent and then individualize dosage according to patient’s requirements and response.b

Abrupt discontinuance may result in rebound kaliuresis; taper dosage gradually.b

Different commercially available fixed-combination triamterene/hydrochlorothiazide preparations may not be therapeutic equivalents.a The oral bioavailabilities of the individual drugs and the amounts and ratios of these drugs in various commercially available fixed-combination preparations may differ.a

Pediatric Patients Usual Dosage† Oral

Initially, 2–4 mg/kg daily or 115 mg/m2 daily, given in a single dose or 2 divided doses after meals.a e

If necessary, increase dosage to 6 mg/kg daily.a Do not exceed 300 mg daily.b e

Hypertension† Oral

Initially, 1–2 mg/kg daily given in 2 divided doses after meals.120 Increase dosage as necessary up to 3–4 mg/kg daily given in 2 divided doses.120 Do not exceed 300 mg daily.120

Adults Edema Monotherapy Oral

Initially, 100 mg twice daily after meals.b After edema is controlled, usual maintenance dosage is 100 mg daily or every other day.a Do not exceed 300 mg daily.b

Combination Therapy Oral

When Dyazide, Maxzide or Maxzide-25 mg, or therapeutically equivalent formulations of these combinations are used, the usual dosage in terms of triamterene is 37.5–75 mg once daily.c d

Patients receiving 25 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide-25 mg (37.5 mg triamterene/25 mg hydrochlorothiazide).d

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide (75 mg triamterene/50 mg hydrochlorothiazide).d

Hypertension Monotherapy Oral

Usual dosage recommended by JNC 7 as monotherapy: 50–100 mg daily.119 Some patients may benefit from dividing the daily dosage into 2 doses.119

Combination Therapy Oral

Usually combined with a kaliuretic diuretic.a

In conjunction with a kaliuretic diuretic, an initial triamterene dosage of 25 mg once daily has been recommended.109 Titrate dosage upward as needed and tolerated to a suggested maximum triamterene dosage of 100 mg daily.109 119

Initially, administer each drug separately to adjust dosage.a

May use in fixed combination with hydrochlorothiazide if optimum maintenance dosage corresponds to drug ratio in combination preparation.a

Administer each drug separately whenever dosage adjustment is necessary.a

When Dyazide, Maxzide or Maxzide-25 mg, or therapeutically equivalent formulations of these combinations are used, the usual dosage in terms of triamterene is 37.5–75 mg once daily.d

Patients receiving 25 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide-25 mg (37.5 mg triamterene/25 mg hydrochlorothiazide).d

Patients receiving 50 mg of hydrochlorothiazide who become hypokalemic may be switched to Maxzide (75 mg triamterene/50 mg hydrochlorothiazide).d

If BP is not adequately controlled by use of 75 mg once daily (of triamterene in the fixed combination of triamterene/hydrochlorothiazide), another antihypertensive agent may be added.d

Prescribing Limits Pediatric Patients Oral

Maximum 300 mg daily.120

Adults Oral

Maximum 300 mg daily.b

The manufacturer states there is no clinical experience to date with dosages of fixed-combination Maxzide or Maxzide-25 mg exceeding 75 mg of triamterene and 50 mg of hydrochlorothiazide daily.d

Special Populations Hepatic Impairment

No specific dosage recommendations for hepatic impairment; caution if using fixed combination with hydrochlorothiazide because of risk of precipitating hepatic coma.c d (See Contraindications under Cautions.)

Renal Impairment

No specific dosage recommendations for renal impairment; do not use in patients with renal impairment and elevated serum potassium; discontinue in patients who develop hyperkalemia while on the drug.b (See Contraindications under Cautions and also see Hyperkalemia under Cautions.)

Cautions for Triamterene Contraindications

Anuria, severe or progressive renal disease or dysfunction (except possibly nephrosis), acute or chronic renal insufficiency, substantial renal impairment.b c d

Preexisting hyperkalemia (?5.5 mEq/L).b d

History of triamterene-induced hyperkalemia.b c d

Concurrent potassium supplementation, including potassium salts or potassium-containing salt substitutes.b (See Interactions.)

Concurrent therapy with potassium-sparing agents (e.g., spironolactone, amiloride hydrochloride, or fixed-combination formulations containing triamterene).b (See Interactions.)

Severe hepatic disease.b

Known hypersensitivity to triamterene or any ingredient in the formulation.b c d

Warnings/Precautions Warnings Hyperkalemia

Hyperkalemia (i.e., serum potassium concentrations ?5.5 mEq/L) may occur with all potassium-sparing agents, including triamterene.b c d (See Boxed Warning.) Serum potassium concentrations persistently >6 mEq/L require careful observation and treatment.b

If hyperkalemia occurs, discontinue triamterene; if using a triamterene/hydrochlorothiazide fixed combination, switch to a thiazide alone.b c d

Evaluate BUN and serum potassium concentrations regularly, especially in patients with suspected or confirmed renal insufficiency.b Monitor serum potassium concentrations closely in geriatric and diabetic patients.b

Warning signs of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, and shock.c d

Hyperkalemia has been associated with cardiac irregularities.b Obtain ECG if hyperkalemia present or suspected.b If ECG does not show widening of QRS or arrhythmia in the presence of hyperkalemia, usually sufficient to discontinue triamterene and any potassium supplementation and switch to a thiazide alone.b May administer sodium polystyrene sulfonate to enhance excretion of excess potassium.b

Presence of widened QRS complex or arrhythmia in association with hyperkalemia requires prompt additional therapy.b For tachyarrhythmia, infuse 44 mEq of sodium bicarbonate or 10 mL of 10% calcium gluconate or calcium chloride over several minutes.b For asystole, bradycardia, or AV block, transvenous pacing also is recommended.b The effect of calcium and sodium bicarbonate is transient and repeated administration may be required.b When indicated by the clinical situation, excess potassium may be removed by dialysis or oral or rectal administration of sodium polystyrene sulfonate.b Infusion of glucose and insulin has also been used to treat hyperkalemia.b

Potassium Supplementation

Do not use potassium supplementation (e.g., potassium salts, high potassium diet, salt substitutes) in patients receiving triamterene alone.b Discontinue potassium supplements when triamterene is added to existing diuretic therapy or when patients are switched to triamterene from other diuretics.b

Do not use potassium supplementation with fixed-combination triamterene/hydrochlorothiazide except in severe cases of hypokalemia or if dietary intake of potassium is markedly impaired.a c Such concomitant therapy may be associated with rapid increases in serum potassium concentrations.c Monitor serum potassium concentrations frequently if potassium supplementation is used, especially in patients receiving digitalis or with a history of cardiac arrhythmias.c (See Interactions.)

If serious hypokalemia (serum potassium <3.0 mEq/L demonstrated by repeat serum potassium determinations) occurs in a patient receiving fixed-combination triamterene/hydrochlorothiazide, discontinue fixed combination and initiate potassium supplementation.c

If hyperkalemia occurs in a patient receiving fixed-combination triamterene/hydrochlorothiazide and supplemental potassium therapy, discontinue supplementation and substitute a thiazide diuretic alone for fixed-combination triamterene/hydrochlorothiazide until potassium concentrations return to normal.c

Sensitivity Reactions Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis, rash, photosensitivity) reported; monitor for blood dyscrasias, liver damage or other idiosyncratic reactions.b

General Precautions Use of Fixed Combinations

When triamterene is used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.d

Use during Pregnancy

Routine use of diuretics, including triamterene, in otherwise healthy women exposes mother and fetus to unnecessary risk and is not generally indicated.b c d Diuretics do not prevent development of toxemia of pregnancy and do not appear to be beneficial in the treatment of toxemia.b c d

Edema may develop during pregnancy due to comorbid pathology or the physiologic and mechanical consequences of pregnancy.b c d Diuretic therapy may be appropiate in the management of edema due to a pathologic cause manifesting during pregnancy.b c d However, dependent edema in pregnancy resulting from restriction of venous return by the gravid uterus may be treated by elevating the lower extremities and using support hose; diuretic therapy to lower intravascular volume is not appropriate in such cases.b c d

Hypervolemia and associated edema, including generalized edema, occurs in the majority of pregnant women and is not harmful to fetus or mother.b c d Increased recumbency will generally provide relief; however, edema may cause extreme discomfort which is not relieved by rest.b c d Rarely, in such cases, a short course of diuretic therapy may be appropriate to provide relief.b c d

Electrolyte Imbalance

Electrolyte imbalance may worsen or develop during diuretic therapy, including triamterene.b Risk of electrolyte imbalance is increased in patients with CHF, renal disease, or cirrhosis.b Full-dose diuretic therapy in patients on restricted salt intake may cause a low-salt syndrome.b

Monitor serum electrolytes regularly.d

Renal Effects

Elevations in BUN and/or Scr may occur, possibly secondary to a reversible reduction of GFR or a depletion of the intravascular fluid volume.d May occur more frequently in patients receiving twice-daily dosing with fixed combination of triamterene and hydrochlorothiazide.d

Monitor BUN and Scr, especially in geriatric patients and those with suspected or confirmed hepatic or renal disease.d If azotemia increases, discontinue fixed-combination triamterene/hydrochlorothiazide preparation.d

Nitrogen Retention

May cause mild nitrogen retention, which is reversible upon drug discontinuance; seldom observed with intermittent (every-other-day) therapy.b

Metabolic Acidosis

May cause a decreasing alkali reserve with the possibility of metabolic acidosis.b

Avoid use of potassium-sparing diuretics in severely ill patients in whom respiratory or metabolic acidosis may occur; acidosis may result in rapid increases in serum potassium concentrations.c d Perform frequent assessments of acid-base balance and serum electrolytes.c d

Megaloblastosis

Triamterene is a weak folic acid antagonist and may contribute to the appearance of megaloblastosis, especially in patients with depleted folic acid stores (e.g., pregnant women, alcoholics).a b Patients with cirrhosis and splenomegaly may have marked hematologic abnormalities; these patients should have periodic blood studies and be observed for exacerbations of underlying liver disease.b

Hyperuricemia

May cause elevations in serum uric acid concentrations, especially in patients predisposed to gouty arthritis.b

Renal Calculi

Has been reported in renal calcluli associated with usual calculus components.b c d Manufacturers state that triamterene may be used with caution in patients with histories of renal calcluli;b c d however, some clinicians recommend that the drug not be used in these patients because of the risk of triamterene nephrolithiasis.a

If a patient passes a urinary calculus during triamterene therapy, the drug should be discontinued and the calculus analyzed for the presence of triamterene and/or its metabolites.a

Rebound Kaliuresis

Because triamterene conserves potassium, it has been suggested that patients who have received intensive therapy or have been given the drug for prolonged periods may develop a rebound kaliuresis if such therapy is discontinued abruptly.b Discontinue drug gradually in such patients.b

Specific Populations Pregnancy

Category C.b c d

Lactation

Distributed into milk in animals and is likely to distribute into human milk.b Discontinue nursing or the drug.b

Pediatric Use

Safety and efficacy in pediatric patients remain to be fully established for triamterene or triamterene in fixed combination with hydrochlorothiazide;b c however, some experts have suggested a triamterene dosage for hypertension based on limited clinical experience.120

Geriatric Use

Reduced clearance and increased risk of hyperkalemia; monitor serum potassium concentrations frequently.b c d (See Hyperkalemia under Cautions.)

Hepatic Impairment

Use with caution in patients with impaired hepatic function.a Do not use in patients with severe hepatic disease.a Diuretic therapy in such patients should be initiated while the patient is hospitalized, because rapid alterations in fluid and electrolyte balance may precipitate hepatic coma.a Monitor serum potassium concentrations closely in patients with hepatic cirrhosis and administer potassium supplementation if required.a (See Contraindications under Cautions.)

Potassium loss has been reported during triamterene therapy in some patients with hepatic cirrhosis and may result in signs and symptoms of hepatic coma or precoma.a

Patients with cirrhosis and splenomegaly may have marked hematologic abnormalities; these patients should have periodic blood studies and be observed for exacerbations of underlying liver disease.b (See Megablastosis under Cautions.)

Renal Impairment

Use with caution; increased risk of hyperkalemia.b Monitor serum potassium concentrations closely.b Do not use in patients with renal impairment and elevated serum potassium; discontinue in patients who develop hyperkalemia while on the drug.b (See Contraindications under Cautions and also see Hyperkalemia under Cautions.)

Common Adverse Effects

Hyperkalemia, azotemia, increased BUN and creatinine, renal calculi, jaundice and/or liver enzyme abnormalities, nausea and vomiting, diarrhea, thrombocytopenia, megaloblastic anemia, weakness, fatigue, dizziness, headache, dry mouth.b

Interactions for Triamterene Specific Drugs, Foods, and Laboratory Tests

Drug, Food, or Test

Interaction

Comments

ACE inhibitor

Increased risk of hyperkalemiab c d

Use caution with concomitant ACE inhibitor therapy; monitor serum potassium concentrations frequentlya b d

Use potassium-sparing diuretics with great caution, if at all, in patients receiving an ACE inhibitor (e.g., enalapril) for CHFa

Discontinue or reduce dosage of potassium-sparing diuretics as necessary in patients receiving an ACE inhibitora

Anesthetic agents

Possible potentiation of anesthetic effectsb

Antidiabetic agents (e.g., insulin, oral agents)

Possible increase in blood glucose concentrationb

Adjust dosage of antidiabetic agent during triamterene therapy and after discontinuanceb

Antihypertensive agents

Possible additive antihypertensive effectsb

Blood products

Increased risk of hyperkalemiab

May promote potassium accumulation; plasma from blood bank may contain up to 30 mEq/L of potassium and whole blood may contain up to 65 mEq/L if stored for >10 daysb

Chlorpropamide

Possible increased risk of severe hyponatremiab c

Diuretics

Possible potentiation of diuretic effectsb

Diuretics, potassium-sparing (e.g. amiloride, spironolactone, other fixed-dose combination formulations containing triamterene)

Increased risk of hyperkalemia; fatalities reportedb

Concomitant use contraindicatedb

Laxatives

Possible decreased potassium-retaining effects of triamterenec

Chronic use or overuse of laxatives may reduce serum potassium concentrations by promoting excessive potassium loss from Gl tractc

Lithium

Reduced renal clearance of lithium and increased risk of lithium toxicityb c

Concomitant use generally contraindicated; if concomitant therapy is necessary, monitor serum lithium concentrations closely and adjust dosageb c

Nondepolarizing neuromuscular blocking agents

Potential increase in neuromuscular blockadeb

NSAIAs (e.g., indomethacin)

Concomitant use with indomethacin may adversely affect renal function (e.g., decreased Clcr, acute anuric renal failure)105 106

Concomitant use with indomethacin not recommendeda

Use caution with other concomitant NSAIAsa c

Preanesthetic agents

Possible potentiation of effects of preanesthetic agentb

Potassium supplements, potassium-containing medications (e.g., parenteral penicillin G potassium) and/or foods containing potassium (e.g., salt substitutes, low-salt milk)

Increased risk of hyperkalemia, especially in patients with renal insufficiencyb

Concomitant use generally contraindicatedb

Tests, fluorometric (e.g., lactic dehydrogenase activity)

Possible interference due to pale blue fluorescence in urinea

Tests, fluorometric assay for quinidine

Interferes with the fluorometric assay of quinidine; the two drugs have similar fluorescence spectrab c

Triamterene Pharmacokinetics Absorption Bioavailability

Triamterene and fixed combinations with hydrochlorothiazide are rapidly absorbed following oral administration;c d peak plasma concentrations achieved within 1–4 hours.a b d Interindividual variation in degree of absorption reported.a

Oral bioavailabilities of triamterene and hydrochlorothiazide from Dyazide capsules are comparable to those of aqueous suspensions of the individual drugs, averaging 85 and 82%, respectively, for the fixed-dose formulation and 100 and 100%, respectively, for the suspensions.111 Dyazide capsules also are bioequivalent to single-entity 25-mg hydrochlorothiazide tablets and 37.5-mg triamterene capsules.110

Oral bioavailabilities of triamterene and hydrochlorothiazide from Maxzide tablets are comparable to those of aqueous suspensions of the individual drugs.d The hydrochlorothiazide component of Maxzide tablets is bioequivalent to single-entity hydrochlorothiazide tablet formulations.d

Onset

Onset of diuresis following oral administration of triamterene usually occurs within 2–4 hours; maximum therapeutic effect may not occur until after several days of therapy.b

Onset of diuresis after oral administration of Dyazide usually occurs within 1 hour and peaks at 2–3 hours.c

Duration

After oral administration of triamterene, diuresis diminishes in approximately 7–9 hours,a b although the total duration of action may be ?24 hours.a

After oral administration of Dyazide, diuresis diminishes in approximately 7–9 hours.c

Food

Administration of Dyazide with a high-fat meal in healthy adults increased the average bioavailabilities of triamterene, 6-p-hydroxytriamterene, and hydrochlorothiazide by about 67, 50, and 17%, respectively; increased the peak concentrations of triamterene and its p-hydroxy metabolite; and delayed absorption of the active drugs by up to 2 hours.110

Administration with food does not affect absorption of triamterene or hydrochlorothiazide from Maxzide tablets.d

Distribution Extent

Distributed into bile.a

Crosses the placenta and distributes into milk in animals.b

Plasma Protein Binding

Approximately 67%.b

Elimination Metabolism

Primarily metabolized to 6-p-hydroxytriamterene and its sulfate conjugate.b 107

Elimination Route

Excreted in urine, primarily as 6-p-hydroxytriamterene.b

Half-life

100–150 minutes.a

Special Populations

Renal clearances of triamterene, hydroxytriamterene sulfate, and hydrochlorothiazide may be reduced in geriatric patients receiving combined triamterene and hydrochlorothiazide therapy, principally as a result of age-related reductions in renal function.107 a

Stability Storage Oral Capsules

Tight, light resistant containers at 15–30°C.a b

Fixed-dose Combination Formulations

Dyazide capsules: Tight, light resistant containers at 20–25°C.c

Maxzide tablets: Tight, light resistant containers at 15–30°C.d

ActionsActions

A pteridine derivative, potassium-sparing diuretic that is structurally related to folic acid.a b

Does not competitively inhibit aldosterone; activity is independent of aldosterone concentrations.b

Does not inhibit carbonic anhydrase.a

Acts directly on the distal renal tubule of the nephron to depress aldosterone-stimulated reabsorption of sodium and excretion of potassium and hydrogen at that site.b

Increases excretion of sodium, calcium, magnesium, and bicarbonate.a

Potassium excretion usually reduced; serum concentrations of potassium and chloride are usually increased.a b

Serum bicarbonate concentrations consistently decreased; urinary pH increased slightly.a

Reductions in glomerular filtration observed during daily, but not intermittent, administration; suggests a reversible effect on renal blood flow.a

Although effective alone, often used in combination with other diuretics that act at different sites in the nephron.a

Little if any hypotensive effect when used alone.a

Advice to Patients

Importance of taking drug after meals to help avoid stomach upset.b

Importance of informing patients that if a single daily dose is prescribed, it may be preferable to take it in the morning to minimize the effect of increased frequency of urination on nighttime sleep.b

Importance of informing patients that if a dose is missed, the patient should take only the prescribed dose at the next dosing interval.b

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.b c d

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.b c d

Importance of informing patients of other important precautionary information. (See Cautions.)b c d

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Triamterene

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Dyrenium (with benzyl alcohol and povidone)

WellSpring

100 mg

Dyrenium (with benzyl alcohol and povidone)

WellSpring

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Triamterene and Hydrochlorothiazide (Co-triamterzide)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

37.5 mg Triamterene and Hydrochlorothiazide 25 mg*

Dyazide (with benzyl alcohol and povidone)

GlaxoSmithKline

Triamterene and Hydrochlorothiazide Capsules

Barr, Mylan, Sandoz, UDL

50 mg Triamterene and Hydrochlorothiazide 25 mg*

Triamterene and Hydrochlorothiazide Capsules

TEVA, Sandoz

Tablets

37.5 mg Triamterene and Hydrochlorothiazide 25 mg*

Maxzide-25 mg (scored)

Mylan

Triamterene and Hydrochlorothiazide Tablets

Barr, Mylan, Pliva, Sandoz, Watson

75 mg Triamterene and Hydrochlorothiazide 50 mg*

Maxzide (scored)

Mylan

Triamterene and Hydrochlorothiazide Tablets

Barr, Mylan, Pliva, Sandoz, Teva, UDL, Watson

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Dyazide 37.5-25MG Capsules (GLAXO SMITH KLINE): 30/$45.99 or 90/$109.92

Dyrenium 100MG Capsules (WELLSPRING PHARMACEUTICAL CORP): 30/$75.99 or 90/$205.53

Dyrenium 50MG Capsules (WELLSPRING PHARMACEUTICAL CORP): 30/$49.83 or 90/$124.54

Maxzide 75-50MG Tablets (MYLAN): 30/$79.99 or 90/$219.96

Maxzide-25 37.5-25MG Tablets (MYLAN BERTEK): 30/$37.5 or 90/$85.87

Triamterene-HCTZ 37.5-25MG Capsules (SANDOZ): 100/$19.99 or 200/$25.98

Triamterene-HCTZ 37.5-25MG Tablets (SANDOZ): 100/$29.99 or 200/$45.96

Triamterene-HCTZ 50-25MG Capsules (SANDOZ): 100/$155.99 or 300/$439.98

Triamterene-HCTZ 75-50MG Tablets (SANDOZ): 100/$17.99 or 300/$39.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Upton RA, Williams RL, Lin ET et al. Absence of a significant pharmacokinetic interaction between hydrochlorothiazide and triamterene when coadministered. J Pharmacokinet Biopharm. 1984; 12:575-86. [IDIS 197834] [PubMed 6533293]

101. Blume CD, Williams RL, Upton RA et al. Bioequivalence study of a new tablet formulation of triamterene and hydrochlorothiazide. Am J Med. 1984; 77(Suppl 5A):59-61. [IDIS 192689] [PubMed 6496560]

102. Blume CD, Williams RL. A new antihypertensive agent: Maxzide (75 mg triamterene/50 mg hydrochlorothiazide). Am J Med. 1984; 77(Suppl 5A):52-8. [IDIS 192688] [PubMed 6388327]

104. Houston MC. Thiazides and thiazide-like diuretics in hypertension. Ann Intern Med. 1985; 103:303. [IDIS 202760] [PubMed 4014913]

105. Favre L, Glasson P, Vallotton MB. Reversible acute renal failure from combined triamterene and indomethacin. Ann Intern Med. 1982; 96:317-20. [IDIS 146179] [PubMed 6949485]

106. Weinberg MS, Quigg RJ, Salant DJ et al. Anuric renal failure precipitated by indomethacin and triamterene. Nephron. 1985; 40:216-8. [PubMed 4000350]

107. Williams RL, Thornhill MD, Upton RA et al. Absorption and disposition of two combination formulations of hydr


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Clindamycin Phosphate and Benzoyl Peroxide



Clindamycin Phosphate and Benzoyl Peroxide Description

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% contains clindamycin phosphate, (7(S)-chloro-7-deoxylincomycin-2-phosphate). Clindamycin phosphate is a water soluble ester of the semi-synthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin.

Chemically, clindamycin phosphate is (C18H34ClN2O8PS). The structural formula for clindamycin is represented below:

Clindamycin phosphate has a molecular weight of 504.97 and its chemical name is Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans- 4-propyl-L-2-pyrrolidinecarboxamido) - 1-thio-L- threo-alpha-D- galacto-octopyranoside 2-(dihydrogen phosphate).

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% also contains benzoyl peroxide, for topical use.

Chemically, benzoyl peroxide is (C14H10O4). It has the following structural formula:

Benzoyl peroxide has a molecular weight of 242.23.

Each gram of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% contains, as dispensed, 10 mg (1%) clindamycin as phosphate and 50 mg (5%) benzoyl peroxide in a base of carbomer, propylene glycol, potassium hydroxide, and purified water.

Clindamycin Phosphate and Benzoyl Peroxide - Clinical Pharmacology

An in vitro percutaneous penetration study comparing ClindamycinPhosphate and Benzoyl Peroxide Gel, 1%/5% and topical 1% clindamycin gel alone, demonstrated there was no statistical difference in penetration between the two drugs. Mean systemic bioavailability of topical clindamycin in ClindamycinPhosphate and Benzoyl Peroxide Gel, 1%/5% is suggested to be less than 1%.

Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid. Less than 2% of the dose enters systemic circulation as benzoic acid. It is suggested that the lipophilic nature of benzoyl peroxide acts to concentrate the compound into the lipid-rich sebaceous follicle.

Microbiology

The clindamycin and benzoyl peroxide components individually have been shown to have in vitro activity against Propionibacterium acnes an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with this product.

Clinical Studies

In two adequate and well controlled clinical studies of 758 patients, 214 used Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5%, 210 used benzoyl peroxide, 168 used clindamycin, and 166 used vehicle. Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% applied twice daily for 10 weeks was significantly more effective than vehicle in the treatment of moderate to moderately severe facial acne vulgaris. Patients were evaluated and acne lesions counted at each clinical visit; weeks 2, 4, 6, 8 and 10. The primary efficacy measures were the lesion counts and the investigator’s global assessment evaluated at week 10. Patients were instructed to wash the face with a mild soap, using only the hands. Fifteen minutes after the face was thoroughly dry, application was made to the entire face. Non-medicated make-up could be applied at one hour after the Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% application. If a moisturizer was required, the patients were provided a moisturizer to be used as needed. Patients were instructed to avoid sun exposure. Percent reductions in lesion counts after treatment for 10 weeks in these two studies are shown below:

Study 1 Clindamycin Phosphate and Benzoyl Peroxide Gel,
1%/5%
n = 120 Benzoyl peroxide
n = 120 Clindamycin
n = 120 Vehicle
n = 120 Mean percent reduction in inflammatory lesion counts 46% 32% 16% +3% Mean percent reduction in non-inflammatory lesion counts 22% 22% 9% +1% Mean percent reduction in total lesion counts 36% 28% 15% 0.2% Study 2 Clindamycin Phosphate and Benzoyl Peroxide Gel,
1%/5%
n = 95 Benzoyl peroxide
n = 95 Clindamycin
n = 49 Vehicle
n = 48 Mean percent reduction in inflammatory lesion counts 63% 53% 45% 42% Mean percent reduction in non-inflammatory lesion counts 54% 50% 39% 36% Mean percent reduction in total lesion counts 58% 52% 42% 39%

The Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% group showed greater overall improvement than the benzoyl peroxide, clindamycin and vehicle groups as rated by the investigator.

Indications and Usage for Clindamycin Phosphate and Benzoyl Peroxide

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% is indicated for the topical treatment of acne vulgaris.

Contraindications

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% is contraindicated in those individuals who have shown hypersensitivity to any of its components or to lincomycin. It is also contraindicated in those having a history of regional enteritis, ulcerative colitis, or antibiotic-associated colitis.

Warnings

ORALLY AND PARENTERALLY ADMINISTERED CLINDAMYCIN HAS BEENASSOCIATED WITH SEVERE COLITIS WHICH MAY RESULT IN PATIENTDEATH. USE OF THE TOPICAL FORMULATION OF CLINDAMYCIN RESULTSIN ABSORPTION OF THE ANTIBIOTIC FROM THE SKIN SURFACE. DIARRHEA,BLOODY DIARRHEA, AND COLITIS (INCLUDING PSEUDOMEMBRANOUSCOLITIS) HAVE BEEN REPORTED WITH THE USE OF TOPICAL ANDSYSTEMIC CLINDAMYCIN. STUDIES INDICATE A TOXIN(S) PRODUCED BYCLOSTRIDIA IS ONE PRIMARY CAUSE OF ANTIBIOTIC- ASSOCIATED COLITIS.THE COLITIS IS USUALLY CHARACTERIZED BY SEVERE PERSISTENTDIARRHEA AND SEVERE ABDOMINAL CRAMPS AND MAY BE ASSOCIATEDWITH THE PASSAGE OF BLOOD AND MUCUS. ENDOSCOPIC EXAMINATION MAY REVEAL PSEUDOMEMBRANOUS COLITIS. STOOL CULTUREFOR Clostridium Difficile AND STOOL ASSAY FOR C. difficile TOXIN MAYBE HELPFUL DIAGNOSTICALLY. WHEN SIGNIFICANT DIARRHEA OCCURS,THE DRUG SHOULD BE DISCONTINUED. LARGE BOWEL ENDOSCOPYSHOULD BE CONSIDERED TO ESTABLISH A DEFINITIVE DIAGNOSIS INCASES OF SEVERE DIARRHEA. ANTIPERISTALTIC AGENTS SUCH AS OPIATESAND DIPHENOXYLATE WITH ATROPINE MAY PROLONG AND/ORWORSEN THE CONDITION. DIARRHEA, COLITIS, AND PSEUDOMEMBRANOUSCOLITIS HAVE BEEN OBSERVED TO BEGIN UP TO SEVERAL WEEKSFOLLOWING CESSATION OF ORAL AND PARENTERAL THERAPY WITHCLINDAMYCIN.

Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against C. difficile colitis.

Precautions General

For dermatological use only; not for ophthalmic use. Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents.

The use of antibiotic agents may be associated with the overgrowth of nonsusceptible organisms including fungi. If this occurs, discontinue use of this medication and take appropriate measures.

Avoid contact with eyes and mucous membranes.

Clindamycin and erythromycin containing products should not be used in combination. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known.

Information for Patients

Patients using Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% should receive the following information and instructions:

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% is to be used as directed by the physician. It is for external use only. Avoid contact with eyes, and inside the nose, mouth, and all mucous membranes, as this product may be irritating. This medication should not be used for any disorder other than that for which it was prescribed. Patients should not use any other topical acne preparation unless otherwise directed by physician. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using Clindamycin Phospate and Benzoyl Peroxide Gel, 1%/5%. To minimize exposure to sunlight, a wide-brimmed hat or other protective clothing should be worn, and a sunscreen with SPF 15 rating or higher should be used. Patients who develop allergic symptoms such as severe swelling or shortness of breath should discontinue Clindamycin Phosphate and Benzoly PeroxideGel, 1%/5% and contact their physician immediately. In addition, patients should report any signs of local adverse reactions to their physician. Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% may bleach hair or colored fabric. Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% can be stored at room temperature up to 25°C (77°F) for 3 months. Do not freeze. Discard any unused product after 3 months. Before applying Clindamycin Phosphate and Benzoyl Peroxide Gel,1%/5% to affected areas wash the skin gently, then rinse with warm water and pat dry. Carcinogenesis, Mutagenesis, Impairment of Fertility

Benzoyl peroxide has been shown to be a tumor promoter and progression agent in a number of animal studies. The clinical significance of this is unknown. Benzoyl peroxide in acetone at doses of 5 and 10 mg administered twice per week induced skin tumors in transgenic Tg.AC mice in a study using 20 weeks of topical treatment.

In a 52 week dermal photocarcinogenicity study in hairless mice, the median time to onset of skin tumor formation was decreased and the number of tumors per mouse increased following chronic concurrent topical administration of Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% with exposure to ultraviolet radiation (40 weeks of treatment followed by 12 weeks of observation).

Genotoxicity studies were not conducted with Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5%. Clindamycin phosphate was not genotoxic in Salmonella typhimurium or in a rat micronucleus test. Clindamycin phosphate sulfoxide, an oxidative degradation product of Clindamycin Phosphate and Benzoyl Peroxide, was not clastogenic in a mouse micronucleus test. Benzoyl peroxide has been found to cause DNA strand breaks in a variety of mammalian cell types, to be mutagenic in S. typhimurium tests by some but not all investigators, and to cause sister chromatid exchanges in Chinese hamster ovary cells. Studies have not been performed with Clindamycin Phosphateand Benzoyl Peroxide Gel, 1%/5% or benzoyl peroxide to evaluate the effect on fertility. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 120 times the amount of clindamycin in the highest recommended adult human dose of 2.5 grams Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5%, based on mg/m2) revealed no effects on fertility or mating ability.

Pregnancy Teratogenic Effects Pregnancy Category C

Animal reproductive/developmental toxicity studies have not been conducted with Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% or benzoyl peroxide. Developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (240 and 120 times amount of clindamycin in the highest recommended adult human dose based on mg/m2, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (100 and 50 times the amount of clindamycin in the highest recommended adult human dose based on mg/m2, respectively) revealed no evidence of teratogenicity.

There are no well-controlled trials in pregnant women treated with ClindamycinPhosphate and Benzoyl Peroxide Gel, 1%/5%. It also is not known whether Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% can cause fetal harm when administered to a pregnant woman.

Nursing Women

It is not known whether Clindamycin Phosphate and Benzoyl Peroxide Gel,1%/5% is ex creted in human milk after topical application. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of this product in pediatric patients below the age of 12 have not been established.

Adverse Reactions

During clinical trials, the most frequently reported adverse event in the Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% treatment group was dry skin (12%). The Table below lists local adverse events reported by at least 1% of patients in the Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% and vehicle groups.

Local Adverse Events - all causalities in >/= 1% of patients Clindamycin Phosphate and BenzoylPeroxide Gel, 1%/5%
n = 420 Vehicle
n = 168 Application Site Reaction 13 (3%) 1 (< 1%) Dry Skin 50 (12%) 10 (6%) Pruritis 8 (2%) 1 (< 1%) Peeling 9 (2%) - Erythema 6 (1%) 1 (< 1%) Sunburn 5 (1%) -

The actual incidence of dry skin might have been greater were it not for the use of a moisturizer in these studies.

Anaphylaxis, as well as allergic reactions leading to hospitalization, have been reported during post-marketing use of clindamycin/benzoyl peroxide products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Clindamycin Phosphate and Benzoyl Peroxide Dosage and Administration

Clindamycin Phosphate and Benzoyl Peroxide Gel, 1%/5% should be applied twice daily, morning and evening, or as directed by a physician, to affected areas after the skin is gently washed, rinsed with warm water and patted dry.

HOW SUPPLIED AND COMPOUNDING INSTRUCTIONS Size
(Net Weight) NDC # Benzoyl Peroxide Gel Clindamycin Phosphate Solution (in plastic bottle) 50 grams 0378-8688-54 40 grams 10 grams

Prior to dispensing, add the solution in the bottle to the gel and stir until homogenous in appearance (1 to 11?2 minutes). Clindamycin Phosphate andBenzoyl Peroxide Gel, 1%/5% can be stored at room temperature up to 25°C (77°F) for 3 months. Place a 3 month expiration date on the labeling immediately following mixing.

Store at room temperature up to 25°C (77°F) [See USP].

Do not freeze. Keep tightly closed. Keep out of the reach of children.

US Patents 5,733,886; 6,117,843

Distributed by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

Manufactured by:
Contract Pharmaceuticals Ltd.
Buffalo, NY 14213

090068

REVISED JUNE 2009
DW-M-CLBZPX:R3

PRINCIPAL DISPLAY PANEL - 1%/5% GEL

NDC 0378-8688-54

CLINDAMYCIN PHOSPHATE and
BENZOYL PEROXIDE GEL, 1%*/5%
FOR TOPICAL USE ONLY

Rx only

One 50 gram Jar
(after admixing)

CLINDAMYCIN PHOSPHATE and
BENZOYL PEROXIDE GEL, 1%*/5%

Each gram of Clindamycin Phosphate and Benzoyl
Peroxide Gel, 1%*/5% as dispensed, contains 10 mg
(1%) *clindamycin as phosphate and 50 mg (5%)
benzoyl peroxide in a base of carbomer, propylene
glycol, potassium hydroxide, and purified water.
Usual Dosage: Apply twice daily, morning and eve-
ning, or as directed by physician, to affected areas
after the skin is gently washed, rinsed with warm
water an patted dry. See package insert for full
prescribing information. Use within 3 months after
mixing. Store at room temperature up to 25°C (77°F)
[see USP]. Do not freeze. Keep tightly closed.

Precautions: For external use only. Avoid contact
with eyes. Keep out of reach of children. May bleach
fabric or hair.

US Patents 5,733,886; 6,117,843

TO THE PHARMACIST:

Important: Prior to dispensing, add the solution in
the bottle to the gel and stir until homogenous in
appearance (1 to 1? minutes). Clindamycin Phosphate
and Benzoyl Peroxide Gel, 1%/5% can be stored at room
temperature up to 25°C (77°F) for 3 months. Place a 3 month
expiration date on the labeling immediately following mixing.

Distributed by:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

Manufactured by:
Contract Pharmaceuticals Ltd.
Buffalo, NY 14213

DW-M-8688-2C:R3


Clindamycin Phosphate and Benzoyl Peroxide 
Clindamycin Phosphate and Benzoyl Peroxide  kit Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-8688 Packaging # NDC Package Description Multilevel Packaging 1 0378-8688-54 1 KIT In 1 CARTON None QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 BOTTLE, PLASTIC   10 g Part 2 1 JAR   40 g Part 1 of 2 CLINDAMYCIN PHOSPHATE 
clindamycin  solution Product Information       Route of Administration TOPICAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLINDAMYCIN PHOSPHATE (CLINDAMYCIN) CLINDAMYCIN 1 mg  in 1 g Inactive Ingredients Ingredient Name Strength CARBOMER HOMOPOLYMER TYPE C   PROPYLENE GLYCOL   POTASSIUM HYDROXIDE   WATER   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 10 g In 1 BOTTLE, PLASTIC None Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065443 12/11/2009
Part 2 of 2 BENZOYL PEROXIDE 
benzoyl peroxide  gel Product Information       Route of Administration TOPICAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BENZOYL PEROXIDE (BENZOYL PEROXIDE) BENZOYL PEROXIDE 50 mg  in 1 g Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 40 g In 1 JAR None Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065443 12/11/2009
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065443 12/11/2009
Labeler - Mylan Pharmaceuticals Inc. (059295980) Revised: 06/2009Mylan Pharmaceuticals Inc. More Clindamycin Phosphate and Benzoyl Peroxide resources Clindamycin Phosphate and Benzoyl Peroxide Use in Pregnancy & Breastfeeding Clindamycin Phosphate and Benzoyl Peroxide Drug Interactions Clindamycin Phosphate and Benzoyl Peroxide Support Group 53 Reviews for Clindamycin Phosphate and Benzoyl Peroxide - Add your own review/rating Compare Clindamycin Phosphate and Benzoyl Peroxide with other medications Acne
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Tretinoin topical


Class: Cell Stimulants and Proliferants
VA Class: DE752
CAS Number: 302-79-4
Brands: Avita, Renova Emollient, Retin-A, Retin-A Micro

Introduction

All trans-retinoic acid; a retinoid.128

Uses for Tretinoin Acne

Treatment of acne vulgaris,134 135 137 c principally grades I–III, in which comedones, papules, and pustules predominate.b

Generally not effective for treatment of severe pustular and deep nodulocystic acne; however, may be used as adjunctive therapy in the management of associated comedones.b

Photoaging

Palliative therapy to improve dermatologic changes (e.g., fine wrinkling, mottled hyperpigmentation, roughness) associated with photodamage.104 105 112 113 114 115 116 117 120 122 126 128 129 136

Use as an adjunct to a comprehensive skin care plan and sun avoidance program; reserve use for patients who do not achieve the desired effects with such programs alone (i.e., without tretinoin).128

Safety and efficacy not established in individuals with moderately or highly pigmented skin or patients with actinic keratoses or a history of skin cancer.128 136

Tretinoin Dosage and Administration General

Excessive use does not increase therapeutic effects and may produce marked inflammatory reactions (e.g., erythema, peeling, discomfort).128 135 136 b c (See Dermatologic Effects under Cautions.)

Use of moisturizers concomitantly at night may dilute the therapeutic effect of the drug; if required, moisturizers should be used during the day.104 124 125 126

Administration Topical Administration

Apply topically to the skin as a cream, gel, or solution.128 134 135 136 137 c

Gently wash skin with mild soap, pat dry, and wait 20–30 minutes before applying tretinoin to affected areas; avoid the eyes, ears, nostrils, mucous membranes, and mouth.115 117 121 123 124 126 128 129 136 c

A transient feeling of warmth or minor stinging may occur immediately after application.128 134 135 136 137 c

If therapy is not well tolerated, temporarily discontinue or decrease frequency of applications;105 113 122 123 124 125 126 c reinitiate therapy when patient is able to tolerate the drug.115 122 123 124 125 136 c Closely monitor patient response and tolerance to changes in dosage form, drug concentration, or application frequency.125 135

Acne

Apply a sufficient amount of cream, gel, or solution to cover affected area lightly.134 135 137 c

Apply cream or gel using clean fingertips.134 c

Apply solution using clean fingertips, gauze pad, or cotton swab;137 avoid oversaturation of gauze or cotton so solution will not run onto unaffected areas.137

Excessive application of gel results in “pilling” or “caking,” which minimizes overapplication.135 137

Photoaging

Apply 0.02 or 0.05% cream topically to face using a clean fingertip;115 117 121 123 124 126 128 129 136 apply a sufficient amount to cover entire face lightly.128 136

Gently wash treated skin with fingertips to peel away loose outer layers of the skin that may form during therapy.b Erosion may occur if patients are not careful with scale removal.129

Dosage Pediatric Patients Acne Topical

Adolescents ?12 years of age: Apply once daily at bedtime.135 137 c d e

Because of potential to cause severe irritation and peeling, therapy can be initiated using a lower concentration cream or gel applied every 2 or 3 days at bedtime; if tolerated, solution or higher concentration cream or gel can be used.b

Initial response (redness, scaling, and possibly more pronounced comedones) occurs within 7–10 days.135 137 b c Therapeutic effects usually are apparent after 2–3 weeks; optimal effects may require >6 weeks of therapy.137 c

Relapses generally occur within 3–6 weeks after therapy is discontinued.b

Adults Acne Topical

Apply once daily at bedtime.135 137 c

Because of potential to cause severe irritation and peeling, therapy can be initiated using a lower concentration cream or gel applied every 2 or 3 days at bedtime; if tolerated, solution or higher concentration cream or gel can be used.b

Initial response (redness, scaling, and possibly more pronounced comedones) occurs within 7–10 days.135 137 b c Therapeutic effects usually are apparent after 2–3 weeks; optimal effects may require >6 weeks of therapy.137 c

Relapses generally occur within 3–6 weeks after therapy is discontinued.b

Photoaging Topical

Apply a pea-sized amount of the 0.02 or 0.05% cream104 113 114 122 126 128 136 once daily at bedtime.128 136

Individualize dosage according to patient response and tolerance, depending on skin type, degree of photoaging present, race, and/or age of the patient.115 121 124 125 Mild scaling can be used as a guide in determining tolerance level.115 124

If therapy is not well tolerated, may reduce frequency to every other night or every third night.105 113 122 123 124 125 126

Maintenance regimen of 2–4 applications weekly suggested for some patients once maximum response has been achieved.115 123 124 125 126

Therapeutic response occurs gradually over 6 months; clinically important decreases in fine wrinkles may not be apparent for 8 weeks.105 121 123 129 136

Therapeutic effects may be lost when therapy and accompanying comprehensive skin care and sun avoidance are discontinued.136

Prescribing Limits Adults Photoaging Topical

Safety and efficacy of therapy with 0.02% cream for >52 weeks128 or with 0.05% cream for >48 weeks not established.136

Cautions for Tretinoin Contraindications

Known hypersensitivity to tretinoin or any ingredient in the formulation.128 135 c

Warnings/Precautions Warnings Gel Formulations

Gels are flammable;137 c avoid heat, flames, or smoking during use of gel formulations (Retin-A, Avita).a

Dermatologic Effects

Possible severe erythema, edema, blistering, or crusting of the skin.128 135 137 c If severe reaction occurs, use less frequently, discontinue until skin integrity is restored, or permanently discontinue, depending on the severity of the reaction.128 135 137 c

Avoid contact of drug with the eyes, mouth, angles of the nose, mucous membranes, or open wounds.128 135 137 c

Atypical changes in melanocytes and keratinocytes and increased dermal elastosis reported with use of 0.05% cream for >48 weeks; clinical importance is unknown.136

Exposure to Utraviolet (UV) Light

Exposure to UV light increases the intensity of the inflammatory reaction to tretinoin therapy.b (See Photosensitivity under Cautions.)

Tretinoin, especially at high concentrations, may increase the tumorigenic potential of UV radiation.128 b

Eczema

Possible severe irritation of eczematous skin.128 135 137 c Use with extreme caution in patients with eczema.128 135 137 c

Sensitivity Reactions Photosensitivity

Increased risk for sunburn.104 105 115 123 124 125 126 128 129 c

Cautious use recommended in patients subjected to considerable occupational sun exposure and those with inherent sensitivity to the sun; use of sunscreen products (SPF 15 or greater)128 135 136 137 c and protective clothing over treated areas recommended when exposure cannot be avoided.128 134 135 136 137 c

Avoid concomitant use of photosensitizing agents (see Specific Drugs under Interactions).128 136

Use not recommended for patients with sunburn until full recovery occurs.128 135 137 c

Minimize exposure to sunlight and avoid use of sunlamps.128 134 135 137 c

Other Sensitivity Reactions

Contact allergy occurs rarely.137 c

Discontinue therapy if sensitivity reaction, chemical irritation, or systemic adverse reaction occurs.128 134 135 136 137 c

General Precautions Environmental Stimuli

Possible increased skin irritation in patients exposed to environmental extremes (e.g., wind, cold) and other stimuli (e.g., excessive heat, diaphoresis, increased skin contact with jewelry, concomitant use of irritating cosmetics or facial saunas).104 105 115 123 124 125 126 128 129 137 c

Dry Skin

Possible excessive dry skin in patients receiving gel formulation for acne; an appropriate emollient may be used during the day.135

Moisturizers (used at least every morning) are recommended as part of a comprehensive skin care plan for individuals with photoaging.128 136

Facial Cleansing

Use of mild, bland soap not more than 2 or 3 times daily is recommended; use of medicated or drying soaps and abrasive soaps and cleansers generally should be avoided.128 135 136 c

Cosmetic Agents or Processes

Avoid use of irritating cosmetics and other preparations or processes (e.g., electrolysis) that might dry or irritate the skin.128 135 136 137 c (See Other Topical Preparations under Interactions.) Medicated cosmetics are not recommended.b

Specific Populations Pregnancy

Category C.128 135 c

Lactation

Not known whether topical tretinoin is distributed into milk.134 135 136 137 Caution advised if topical tretinoin is used.134 135 136 137

Pediatric Use

Safety and efficacy not established for treatment of acne in children <12 years of age (Retin-A Micro) or for treatment of photoaging in children <18 years of age (Renova).128 135 136

Geriatric Use

Safety and efficacy of emollient cream formulation (Renova 0.05%) or cream formulation (Renova 0.02%) for treatment of photoaging not etablished in adults ?51 or ?72 years of age, respectively.128 136

Insufficient experience in patients ?65 years of age to determine whether safety and efficacy of gel formulation (Retin-A, Retin-A Micro) for treatment of acne in geriatric patients differ from safety and efficacy in younger adults.135 a

Common Adverse Effects

Transitory feeling of warmth or slight stinging, redness and scaling of the skin, peeling, dry skin, burning, pruritus.128 135 136 b

Interactions for Tretinoin Specific Drugs

Drug

Interaction

Comments

Keratolytic agents (e.g., sulfur, resorcinol, benzoyl peroxide, salicylic acid)

Possible additive effects135 137 c

Allow sufficient time for the effects of the keratolytic agent to subside before initiating tretinoin therapy135 137 c

Photosensitizing agents (e.g., fluoroquinolone anti-infectives, thiazide diuretics, sulfonamides, tetracyclines, phenothiazines)

Possible increased phototoxicity128 136

Avoid concomitant use128 136

Other Topical Preparations

Potential pharmacodynamic interaction (increased skin irritation).115 124 125 126 127 128 135 136 To the extent possible, avoid concurrent use of topical preparations with high concentrations of alcohol, menthol, spices, or lime (e.g., lotions, astringents, perfume); irritating cosmetics (e.g., toners, peeling [desquamating] agents); permanent wave solutions; electrolysis; or hair depilatories or waxes.115 124 125 126 127 128 135 136

Tretinoin Pharmacokinetics Absorption Bioavailability

Minimally absorbed following topical application.128 134 135 b c

Stability Storage Topical Cream, Gel, or Solution

Tight, light-resistant containers at 15–30°C;b do not freeze.134 136 c

Do not expose gel formulations (Retin-A, Avita) to heat or flame.a c

ActionsActions

Precise mechanism of action for treatment of acne not determined.b May inhibit keratinization,b irritate the follicular epithelium (preventing horny cells from sticking together),135 b c or incite inflammatory reactions (resulting in acanthosis and parakeratosis).b

Increases horny cell production in existing comedones and causes formation of an intrafollicular abscess, resulting in suppurative discharge of comedones.135 b c Inhibits formation of additional comedones by expelling horny cells from the follicular orifice.135 b c

Modulates proliferation and differentiation of epidermal cells via activation of nuclear retinoic acid receptors, which causes change in gene expression; relationship to regulation of skin function not understood.135

Partially reverses photodamaged skin histologically and clinically.104 105 112 113 115 116 121 122 123 124 125 126 129 Use associated with restoration of epidermis to a normal morphologic appearance and increased epidermal thickness;104 105 113 114 117 123 124 125 126 129 reduction or eradication of microscopic actinic keratoses;104 105 124 dispersion of melanin granules and decreased melanin content;104 113 114 123 124 125 126 129 stratum corneum compaction;104 105 113 117 126 new collagen formation in the papillary dermis;104 116 123 124 125 129 increased epidermal-dermal anchoring fibrils;112 114 116 126 129 angiogenesis;104 123 124 125 exfoliation of retained follicular horn;104 126 reduction of fine wrinkling and, to a lesser degree, coarse wrinkling and tactile roughness of the skin; and increased skin pinkness.104 105 112 113 115 116 121 122 123 124 125 126 129

May reduce collagen degradation by inducing tissue inhibitors of collagenase.112 116 118 119

Advice to Patients

Importance of advising patients that topical tretinoin is not a cosmetic preparation.128

Importance of clinicians instructing patients about proper use of the drug, including associated precautions.128 Provide copy of the manufacturer’s patient instructions.128

Importance of avoiding use of shaving lotions, astringents, perfumes, toners, peeling [desquamating] agents, permanent wave solutions, electrolysis, hair depilatories or waxes, medicated cosmetics, or other products that may irritate the skin.115 124 125 126 127 128 136 135

Importance of avoiding excessive use of topical tretinoin.128 135 136 b c Importance of temporarily discontinuing therapy or decreasing frequency of application if therapy is not well tolerated.105 113 122 123 124 125 126

Risk of photosensitivity reaction; importance of using sunscreen products and wearing protective clothing over treated areas.104 105 115 123 124 125 126 128 129

Importance of using moisturizers, if required (e.g., in patients with photoaging, to relieve dryness associated with tretinoin preparation), only during the day.104 124 125 126

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.128 135 c

Importance of patients informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.128 135 c

Importance of avoiding heat, flames, or smoking during use of gel formulations (Retin-A, Avita).135 a

Importance of informing patients of other important precautionary information.128 135 c (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Tretinoin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Topical

Cream

0.02%

Renova Emollient (with methylparaben)

OrthoNeutrogena

0.025%*

Avita

Mylan Bertek

Retin-A

OrthoNeutrogena

0.05%

Renova Emollient (with methylparaben)

OrthoNeutrogena

Retin-A

OrthoNeutrogena

0.1%*

Retin-A

OrthoNeutrogena

Gel

0.01%

Retin-A (with denatured alcohol 90% and butylated hydroxytoluene)

OrthoNeutrogena

0.025%

Avita

Mylan Bertek

Retin-A (with denatured alcohol 90% and butylated hydroxytoluene)

OrthoNeutrogena

Gel (containing microspheres)

0.04%

Retin-A Micro (with benzyl alcohol and propylene glycol)

OrthoNeutrogena

0.1%

Retin-A Micro (with benzyl alcohol and propylene glycol)

OrthoNeutrogena

Solution

0.05%*

Retin-A (with denatured alcohol 55%, butylated hydroxytoluene, and polyethylene glycol 400)

OrthoNeutrogena

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 05/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Atralin 0.05% Gel (VALEANT): 45/$213.63 or 135/$595.11

Avita 0.025% Cream (MYLAN): 20/$75.99 or 60/$205.96

Avita 0.025% Cream (MYLAN): 45/$145.98 or 135/$399.95

Avita 0.025% Gel (MYLAN): 45/$145.98 or 135/$399.95

Refissa 0.05% Cream (VALEANT): 40/$145.98 or 120/$409.95

Renova 0.02% Cream (ORTHO DERM): 40/$188.19 or 80/$349.8

Renova 0.02% Cream (ORTHO DERM): 60/$225.98 or 180/$629.97

Renova Pump 0.02% Cream (ORTHO DERM): 44/$189.99 or 132/$534.99

Retin-A 0.01% Gel (ORTHO DERM): 15/$70.99 or 45/$205.96

Retin-A 0.01% Gel (ORTHO DERM): 45/$155.98 or 135/$440.97

Retin-A 0.025% Cream (ORTHO DERM): 20/$89.99 or 60/$249.96

Retin-A 0.025% Cream (ORTHO DERM): 45/$155.99 or 135/$439.96

Retin-A 0.025% Gel (ORTHO DERM): 15/$75.99 or 45/$205.96

Retin-A 0.025% Gel (ORTHO DERM): 45/$150.98 or 135/$435.97

Retin-A 0.05% Cream (ORTHO DERM): 20/$99.99 or 60/$279.97

Retin-A 0.05% Cream (ORTHO DERM): 45/$166.99 or 135/$469.97

Retin-A 0.1% Cream (ORTHO DERM): 20/$115.99 or 60/$325.97

Retin-A 0.1% Cream (ORTHO DERM): 45/$191 or 135/$545.97

Retin-A Micro 0.04% Gel (ORTHO DERM): 20/$123.99 or 60/$340.99

Retin-A Micro 0.04% Gel (ORTHO DERM): 45/$206 or 135/$576

Retin-A Micro 0.1% Gel (ORTHO DERM): 20/$120 or 60/$329.96

Retin-A Micro 0.1% Gel (ORTHO DERM): 45/$209.99 or 135/$576

Retin-A Micro Pump 0.04% Gel (ORTHO DERM): 50/$239.99 or 150/$679.93

Retin-A Micro Pump 0.1% Gel (ORTHO DERM): 50/$239.99 or 150/$675.94

Tretinoin 0.01% Gel (PERRIGO PHARMACEUTICALS): 15/$35.99 or 45/$96.97

Tretinoin 0.01% Gel (PERRIGO PHARMACEUTICALS): 45/$82.99 or 135/$229.98

Tretinoin 0.025% Cream (PERRIGO PHARMACEUTICALS): 20/$39.99 or 60/$99.98

Tretinoin 0.025% Cream (PERRIGO PHARMACEUTICALS): 45/$59.19 or 135/$177.57

Tretinoin 0.025% Gel (PERRIGO PHARMACEUTICALS): 15/$34.99 or 45/$89.97

Tretinoin 0.025% Gel (PERRIGO PHARMACEUTICALS): 45/$75.99 or 135/$215.96

Tretinoin 0.05% Cream (PERRIGO PHARMACEUTICALS): 20/$45.99 or 60/$125.97

Tretinoin 0.05% Cream (PERRIGO PHARMACEUTICALS): 45/$73.49 or 135/$204.75

Tretinoin 0.1% Cream (PERRIGO PHARMACEUTICALS): 20/$46.19 or 60/$125.97

Tretinoin 0.1% Cream (PERRIGO PHARMACEUTICALS): 45/$105.99 or 135/$290.98

Tretinoin (Emollient) 0.05% Cream (OCEANSIDE PHARMACEUTICALS): 40/$129.99 or 120/$379.97

Tretinoin (Emollient) 0.05% Cream (OCEANSIDE PHARMACEUTICALS): 60/$190.09 or 180/$546.84

Tretin-X 0.01% GEL Kit (TRIAX PHARMACEUTICALS): 1/$189.99 or 3/$529.96

Tretin-X 0.025% CREAM Kit (TRIAX PHARMACEUTICALS): 1/$196 or 3/$565.99

Tretin-X 0.05% CREAM Kit (TRIAX PHARMACEUTICALS): 1/$236 or 3/$685.98

Tretin-X 0.1% CREAM Kit (TRIAX PHARMACEUTICALS): 1/$240 or 3/$665.96

Ziana 1.2-0.025% Gel (MEDICIS): 30/$223 or 90/$655.99

Ziana 1.2-0.025% Gel (MEDICIS): 60/$416.01 or 180/$1186.01

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 01, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Kligman LH, Duo CH, Kligman AM. Topical retinoic acid enhances repair of ultraviolet damaged dermal connective tissue. Connect Tissue Res. 1984; 12:139-50. [PubMed 6723309]

101. Kligman LH. Photoaging: manifestations, prevention, and treatment. Dermatol Clin. 1986; 4:517-28. [PubMed 3521997]

102. Kligman LH. Effects of all-trans-retinoic acid on the dermis of hairless mice. J Am Acad Dermatol. 1986; 15(4 Part 2):779-85,884-7. [PubMed 3771852]

103. Anon. Ortho testing antiaging use of acne remedy. Med Advert News. 1986; 5(Oct 1):1.

104. Kligman AM, Grove GL, Hirose R et al. Topical tretinoin for photoaged skin. J Am Acad Dermatol. 1986; 15(4 Part 2):836-59. [PubMed 3771853]

105. Weiss JS, Ellis CN, Headington JT et al. Topical tretinoin improves photoaged skin: a double-blind vehicle-controlled study. JAMA. 1988; 259:527-32. [IDIS 237360] [PubMed 3336176]

106. Gilchrest BA. At last! A medical treatment for skin aging. JAMA. 1988; 259:569-70. Editorial. [IDIS 237363] [PubMed 3336180]

107. Anon. Tretinoin for aging skin. Med Lett Drugs Ther. 1988; 30:69-70.

108. Anon. Does topical tretinoin prevent cutaneous ageing? Lancet. 1988; 1:977-8. Editorial.

109. Okun MR. Topical tretinoin for photoaged skin. JAMA. 1988; 259:3271-2. Letter.

110. Kanigsberg ND. Topical tretinoin for photoaged skin. JAMA. 1988; 259:3272. Letter.

111. Anon. Retin-A risky, unproven for wrinkles. FDA Consum. 1988; 22:4.

112. Woodley DT, Zelickson AS, Briggaman RA et al. Treatment of photoaged skin with topical tretinoin increases epidermal-dermal anchoring fibrils. JAMA. 1990; 263:3057-9. [IDIS 267119] [PubMed 2342217]

113. Olsen EA, Katz HI, Levine N et al. Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol. 1992; 26:215-24. [PubMed 1552056]

114. Anon. Tretinoin for photodamaged skin. Med Lett Drugs Ther. 1992; 34:28-9.

115. Kligman AM. Current status of topical tretinoin in the treatment of photoaged skin. Drugs Aging. 1992; 2:7-13. [PubMed 1554975]

116. Griffiths CEM, Russman AN, Majmudar G et al. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med. 1993; 329:530-5. [IDIS 319084] [PubMed 8336752]

117. Rafal ES, Griffiths CEM, Ditre CM et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med. 1992; 326:368-74. [IDIS 290598] [PubMed 1729619]

118. Bauer EA, Seltzer JL, Eisen AZ. Inhibition of collagen degradative enzymes by retinoic acid in vitro. J Am Acad Dermatol. 1982; 6:603-7. [PubMed 6279711]

119. Clark SD, Kobayashi DK, Welgus HG. Regulation of the expression of tissue inhibitor of metalloproteinases and collagenase by retinoids and glucocorticoids in human fibroblasts. J Clin Invest. 1987; 80:1280-8. [PubMed 2824558]

120. Anon. Ortho’s Renova effective for cosmetic treatment of photodamaged skin, advisory panel finds; reduction seen in appearance of fine wrinkles, hyperpigmentation. F-D-C Rep. 1992; 54:3-4.

121. Lever L, Kumar P, Marks R. Topical retinoic acid for treatment of solar damage. Br J Dermatol. 1990; 122:91-8. [IDIS 262489] [PubMed 2404514]

122. Weinstein GD, Nigra TP, Pochi PE et al. Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol. 1991; 127:659-65. [IDIS 281814] [PubMed 2024983]

123. Goldfarb MT, Ellis CN, Weiss JS et al. Topical tretinoin and photoaged skin. Cutis. 1989; 43:476-82. [PubMed 2721243]

124. Kligman AM. Guidelines for the use of topical tretinoin (Retin-A) for photoaged skin. J Am Acad Dermatol. 1989; 21:650-4. [PubMed 2778128]

125. Kligman AM. The treatment of photoaged human skin by topical tretinoin. Drugs. 1989; 38:1-8. [PubMed 2766960]

126. Noble S, Wagstaff AJ. Tretinoin: a review of its pharmacological properties and clinical efficacy in the topical treatment of photodamaged skin. Drugs Aging. 1995; 6:479- 96. [PubMed 7663068]

127. Ortho Pharmaceutical Corporation, Raritan, NJ: Personal communication.

128. Ortho Pharmaceutical Corporation. Renova (tretinoin) 0.02% emollient cream prescribing information. Raritan, NJ; 2000 Aug.

129. Goldfarb MT, Ellis CN, Weiss JS et al. Topical tretinoin therapy: its use in photoaged skin. J Am Acad Dermatol. 1989; 21:645-50. [PubMed 2674226]

130. Anon. Update on birth defects with isotretinoin. FDA Drug Bull. 1984; 14:15-6.

131. Roche Laboratories. Accutane (isotretinoin) capsule prescribing information. Nutley, NJ; 1990 May.

132. Benke PJ. The isotretinoin teratogen syndrome. JAMA. 1984; 251:3267-9 (IDIS 186330) [IDIS 186330] [PubMed 6587131]

133. de la Cruz E, Sun S, Vangvanichyakorn K et al. Multiple congenital malformations associated with maternal isotretinoin therapy. Pediatrics. 1984; 74:428-30 [IDIS 189774] [PubMed 6591112]

134. Bertek Pharmaceuticals. Avita (tretinoin cream) 0.025% prescribing information (dated 2002 Jan). In: Physicians’ desk reference. 57th ed. Montvale, NJ: Medical Economics Company Inc; 2003:986-8.

135. Ortho Pharmaceutical Corporation. Retin-A Micro (tretinoin gel) microsphere, 0.1% prescribing information. Skillman, NJ; 2002 May.

136. Ortho Pharmaceutical Corporation. Renova (tretinoin emollient cream) 0.05% prescribing information. Raritan, NJ; 1998 Feb.

137. Ortho Pharmaceutical Corporation. Retin-A (tretinoin) liquid/cream/gel prescribing information. Raritan, NJ; 1996 Dec.

a. Food and Drug Administration. Retin-A (tretinoin) liquid, cream & gel [June 10, 2002: Johnson & Johnson]. MedWatch drug labeling changes. Rockville, MD; August 1997. From FDA website ().

b. AHFS drug information 2003. McEvoy GK, ed. Tretinoin. Bethesda, MD: American Society of Health-System Pharmacists; 2003:page 3421-3423.

c. Bertek Pharmaceutical Inc. Avita (tretinoin gel) 0.025% prescribing information (dated 2001 Nov). In: Physicians’ desk reference. 57th ed. Montvale, NJ: Medical Economics Company Inc; 2003:988-9.

d. Darmstadt GL, Sudbury R. Acne. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:2242-6.

e. Gunn VL, Nechyba C, eds. The Harriet Lane handbook. 16th ed. Philadelphia: Mosby; 2002:870.

More Tretinoin topical resources Tretinoin topical Use in Pregnancy & Breastfeeding Tretinoin topical Drug Interactions Tretinoin topical Support Group 42 Reviews for Tretinoin - Add your own review/rating Atralin Topical Advanced Consumer (Micromedex) - Includes Dosage Information Atralin Consumer Overview Avita Prescribing Information (FDA) Avita Cream MedFacts Consumer Leaflet (Wolters Kluwer) Refissa Prescribing Information (FDA) Renova Emollient Cream MedFacts Consumer Leaflet (Wolters Kluwer) Renova Consumer Overview Retin-A Prescribing Information (FDA) Tretin-X Cream MedFacts Consumer Leaflet (Wolters Kluwer) Compare Tretinoin topical with other medications Acne Lichen Sclerosus Necrobiosis Lipoidica Diabeticorum Photoaging of the Skin
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Glyburide


Class: Sulfonylureas
VA Class: HS502
Chemical Name: 1-[[p-[2-(5-Chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclohexylurea
Molecular Formula: C23H28ClN3O5S
CAS Number: 10238-21-8
Brands: DiaBeta, Glucovance, Glycron, Glynase, Micronase

Introduction

Antidiabetic agent; sulfonylurea.1 2 3 4

Uses for Glyburide Diabetes Mellitus

Used alone or in fixed combination with metformin as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet alone.1 2 3 4 49 50 51 52 53 54 55 56 57 58 59 60 158

Used in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy.1 124 126 158 162 165 166 168 169 170 195 196 197 198 199 200 201 202 203

Alternative therapy in some type 2 diabetic patients being treated with insulin.1 2 3 Useful in combination with insulin therapy to improve glycemic control and/or decrease insulin dosage in some type 2 diabetic patients.116 117 118 119 120 162 165 166 168 169 170

Not effective as sole therapy for patients with type 1 diabetes mellitus; 1 3 60 insulin is necessary.1 2 60

Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; insulin is necessary.1 2 3

Glyburide Dosage and Administration General

Adjust dosage according to patient’s tolerance and urine and/or fasting blood glucose determinations.1 2 Monitor glycosylated hemoglobin (hemoglobin A1c, HbA1c) to determine minimum effective dosage and to detect primary or secondary failure.1 2

During transfer from insulin therapy, patients should test their blood for glucose 2 60 106 and their urine for glucose and/or ketones at least 3 times daily.1 2 124 126 Persistent ketonuria with glycosuria, 1 2 ketosis, 86 and/or inadequate lowering or persistent elevation of blood glucose concentration 86 during transfer from insulin indicate the need for insulin therapy.1 2 86

Micronized formulations are not bioequivalent with conventional formulations; retitrate dosage when transferring patients from micronized to conventional formulations, or vice versa.124

Administration Oral Administration

Administer conventional or micronized formulations once daily with breakfast or first main meal.1 2 3 124 May administer in 2 divided doses in some patients (i.e., those receiving >10 mg daily [as conventional formulations]1 2 or >6 mg [as micronized glyburide]).b

Administer fixed combination with metformin hydrochloride once or twice daily with a meal.158

Dosage Adults Diabetes Mellitus Initial Dosage in Previously Untreated Patients Oral

Conventional formulations: Initially, 2.5–5 mg daily.1 2

Micronized formulations: Initially, 1.5 –3 mg daily.124

Fixed combination with metformin hydrochloride: Initially, 1.25 mg of glyburide and 250 mg of metformin hydrochloride once daily.158 For severe hyperglycemia (baseline HbA1c >9% or fasting blood glucose >200 mg/dL), 1.25 mg of glyburide and 250 mg of metformin hydrochloride twice daily, given with the morning and evening meals.158

Initial Dosage in Patients Transferred from Other Oral Antidiabetic Agents Oral

Conventional formulations: Initially, 2.5–5 mg daily.1 2

Micronized formulations: Initially, 1.5–3 mg daily.124

May discontinue most other oral hypoglycemic agents (except chlorpropamide) immediately.1 2 3 96 b During transfer from chlorpropamide (a drug with a long elimination half-life), monitor closely for hypoglycemia during initial 2 weeks of transition period.1 2 b

Fixed combination with metformin hydrochloride: Initially, 2.5 or 5 mg of glyburide and 500 mg of metformin hydrochloride twice daily with morning and evening meals in patients not adequately controlled by monotherapy with glyburide (or another sulfonylurea) or metformin.158 For patients previously receiving combination therapy with glyburide (or another sulfonylurea) and metformin, initial dosage should not exceed previous individual dosages of glyburide (or equivalent dosage of another sulfonylurea) and metformin.158 Titrate in increments ?5 mg of glyburide and 500 mg of metformin hydrochloride to achieve adequate blood glucose control.158

Initial Dosage in Patients Transferred from Insulin Oral

Conventional formulations: Initially, 2.5–5 mg once daily (if insulin dosage is <20 units daily) or 5 mg once daily (if insulin dosage is 20–40 units daily); may discontinue insulin immediately.1 2 96 If insulin dosage is >40 units daily, reduce insulin dosage by 50% and initiate glyburide at 5 mg daily; withdraw insulin gradually and increase glyburide dosage in increments of 1.25–2.5 mg daily every 2–10 days.1 2

Micronized formulations: Initially, 1.5–3 mg once daily (if insulin dosage is <20 units daily) or 3 mg once daily (if insulin dosage is 20–40 units daily); may discontinue insulin immediately.124 b If insulin dosage is >40 units daily, reduce insulin dosage by 50% and initiate glyburide at 3 mg daily; withdraw insulin gradually and increase glyburide dosage in increments of 0.75–1.5 mg daily every 2–10 days.b

Titration and Maintenance Dosage Oral

Conventional formulations: Increase dosage in increments of ?2.5 mg daily at weekly intervals.1 2 Usual maintenance dosage is 1.25–20 mg daily.1 2 96

Micronized formulations: Increase dosage in increments of ?1.5 mg daily at weekly intervals.b Usual maintenance dosage is 0.75–12 mg daily.124

Fixed combination with metformin hydrochloride: Titrate in increments of 1.25 mg of glyburide and 250 mg of metformin hydrochloride daily at 2-week intervals to achieve adequate blood glucose control.158

Prescribing Limits Adults

Conventional formulations: Maximum 20 mg daily.1 2 96

Micronized formulations: Maximum 12 mg daily.b

Fixed combination with metformin hydrochloride: Maximum 20 mg of glyburide and 2 g of metformin hydrochloride daily.158

Special Populations Hepatic Impairment

Conventional formulations: Initially, 1.25 mg daily.1 2

Micronized formulations: Initially, 0.75 mg daily.124

Renal Impairment

Conventional formulations: Initially, 1.25 mg daily.1 2

Micronized formulations: Initially, 0.75 mg daily.124

Geriatric Patients

Conventional formulations: Initially, 1.25 mg daily1 2

Micronized formulations: Initially, 0.75 mg daily.124

Fixed combination with metformin hydrochloride: Do not titrate to maximum recommended dosage.158

Other Populations

Cautious dosing recommended in debilitated or malnourished patients or in patients with adrenal or pituitary insufficiency.1 2 124 158

Conventional formulations: Initially, 1.25 mg daily1 2

Micronized formulations: Initially, 0.75 mg daily.124

Fixed combination with metformin hydrochloride: Do not titrate to maximum recommended dosage.158

Cautions for Glyburide Contraindications

Known hypersensitivity to glyburide or any ingredient in the formulation.1 2 158

Diabetic ketoacidosis, with or without coma.1 2 3

Monotherapy for type 1 diabetes mellitus.1 a

Warnings/Precautions Warnings Cardiovascular Effects

Increased cardiovascular mortality reported with other sulfonylurea antidiabetic agents (i.e., tolbutamide, phenformin).1 2 63 However, the American Diabetes Association considers the benefits of intensive glycemic control with insulin or sulfonylureas to outweigh the risks overall.128 130 131 138 144

Sensitivity Reactions Dermatologic and Sensitivity Reactions

Possible allergic skin reaction (e.g., pruritus, erythema, urticaria, morbilliform or maculopapular eruptions).1 2 Discontinue the drug if allergic reaction persists.1 2

Angioedema, arthralgia, myalgia, and vasculitis reported.123

General Precautions Hypoglycemia

Severe,1 2 67 68 69 74 105 occasionally fatal,67 68 74 105 hypoglycemia reported. Debilitated, malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or pituitary insufficiency may be particularly susceptible.1 105 158 Strenuous exercise, alcohol ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may increase risk.1 2 96 105 Hypoglycemia may be difficult to recognize in geriatric patients or in those receiving ?-adrenergic blocking agents.1 105 158 (See Interactions.)

Concurrent Illness

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).1 2

Temporary discontinuance of glyburide and administration of insulin may be required.1 2

Use of Fixed Combinations

When used in fixed combination with metformin hydrochloride, consider the cautions, precautions, and contraindications associated with metformin.

Specific Populations Pregnancy

Category B.1

Many experts recommend that insulin be used during pregnancy.1 2 106

Lactation

Not known whether glyburide is distributed into milk; discontinue nursing or the drug.1 2

Pediatric Use

Safety and efficacy not established.1 2

Geriatric Use

Increased risk of hypoglycemia; hypoglycemia may be difficult to recognize.1 105 158 Cautious dosing recommended.1 2 124 158 See Geriatric Patients under Dosage and Administration.

Hepatic Impairment

Increased risk of hypoglycemia.1 2 96 105 106 Cautious dosing recommended.1 2 124 158 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Increased risk of hypoglycemia.1 2 96 105 106 Cautious dosing recommended.1 2 124 158 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

With conventional and micronized formulations, nausea, epigastric fullness, heartburn.1 2 3 62

With fixed-combination glyburide/metformin hydrochloride preparation, upper respiratory tract infection, diarrhea, headache, nausea/vomiting, abdominal pain, dizziness.158

Interactions for Glyburide

When using fixed-combination preparation containing metformin hydrochloride, consider the drug interactions associated with metformin.158

Protein-bound Drugs

Potential pharmacokinetic interaction and possible potentiation of hypoglycemic effects when used concomitantly with other highly protein-bound drugs.1 2 37 38 39 40 62 85

Observe for adverse effects when glyburide therapy is initiated or discontinued and vice versa.1 2

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible disulfiram-like reactions1 2 87

Anticoagulants, oral

Possible displacement from plasma proteins and potentiation of hypoglycemic effects1 2 37 38 39 40 62 85

Observe for adverse effects when glyburide or oral anticoagulants are initiated or discontinued1 2

Antifungals, oral (i.e., fluconazole, miconazole)

Increased glyburide concentrations; possible hypoglycemia1 124 158 210 211

?-Adrenergic blocking agents

Impaired glucose tolerance60 62 85 or potentiation of hypoglycemic effects60 62 85

If concomitantly therapy is necessary, a ?1-selective adrenergic blocking agent may be preferred62

Calcium-channel blocking agents

May exacerbate diabetes mellitus1 2 90

Observe carefully for loss of glycemic control or for hypoglycemia when calcium-channel blocking agents are discontinued1 124 158

Chloramphenicol

Potentiation of hypoglycemic effects1 2 60 62 85

Observe carefully for hypoglycemic effects or loss of glycemic control when chloramphenicol is discontinued1 124 158

Contraceptives, oral

May exacerbate diabetes mellitus1 2 62 85

Observe carefully for loss of glycemic or for hypoglycemia when oral contraceptives are discontinued1 124 158

Corticosteroids

May exacerbate diabetes mellitus1 2 62 85

Observe carefully for loss of glycemic control or for hypoglycemia when corticosteroids are discontinued1 124 158

Diuretics

May exacerbate diabetes mellitus1 2 62 85

Observe carefully for loss of glycemic control or for hypoglycemia when diuretics are discontinued1 124 158

Estrogens

May exacerbate diabetes mellitus1 2 62

Observe carefully for loss of glycemic control or for hypoglycemia when estrogens are discontinued1 124 158

Fluoroquinolone anti-infectives

Potentiation of hypoglycemic effects1 2 126

Observe carefully for hypoglycemic effects or loss of glycemic control when fluoroquinolone anti-infectives are discontinued1 124 158

Hydantoins

Possible displacement from plasma protein and potentiation of hypoglycemic effects1 2 37 38 39 40 62 85

Observe for adverse effects when glyburide or hydantoins are initiated or discontinued1 2

Isoniazid

May exacerbate diabetes mellitus1 2

Observe carefully for loss of glycemic control or for hypoglycemia when isoniazid is discontinued1 124 158

MAO inhibitors

Potentiation of hypoglycemic effects1 2 62 85

Observe closely for hypoglycemic effects of loss of glycemic control when MAO inhibitors are discontinued1 124 158

Niacin

May exacerbate diabetes mellitus1 2 62

Observe carefully for loss of glycemic control or for hypoglycemia when nicotonic acid is discontinued1 124 158

NSAIAs

Possible displacement from plasma proteins and potentiation of hypoglycemic effects1 2 37 38 39 40 62 85

Observe for adverse effects when glyburide or NSAIAs are initiated or discontinued1 2

Phenothiazines

May exacerbate diabetes mellitus1 2 62 85

Observe carefully for loss of glycemic control or for hypoglycemia when phenothiazines are discontinued1 124 158

Phenylbutazone

Potentiation of hypoglycemic effects84

Monitor blood glucose control; adjust glyburide dosage when phenylbutazone is initiated or discontinued85

Phenytoin

May exacerbate diabetes mellitus1 2 62

Observe carefully for loss of glycemic control or for hypoglycemia when phenytoin is discontinued1 124 158

Probenecid

Potentiation of hypoglycemic effects1 2 62

Observe closely for hypoglycemic effects or loss of glycemic control when probencid is discontinued1 124 158

Rifampin

May exacerbate diabetes mellitus62 85

Observe carefully for loss of glycemic control or for hypoglycemia when rifampin is discontinued1 124 158

Sulfonamides

Possible displacement from plasma proteins and potentiation of hypoglycemic effects1 2 37 38 39 40 62 85

Observe for adverse effects when glyburide or sulfonamides are initiated or discontinued1 2

Sympathomimetic agents

May exacerbate diabetes mellitus1 2 62

Observe carefully for loss of glycemic control or for hypoglycemia when sympathomimetic agents are discontinued1 124 158

Thyroid agents

May exacerbate diabetes mellitus1 2 62 85

Observe carefully for loss of glycemic control or for hypoglycemia when thyroid agents are discontinued1 124 158

Glyburide Pharmacokinetics Absorption Bioavailability

Almost completely absorbed following oral administration.4 23 24 94

Onset

Hypoglycemic action generally begins within 45–60 minutes and is maximal within 1.5–3 hours.4 27 32 49

Duration

In nonfasting diabetic patients, the hypoglycemic action may persist for up to 24 hours.1 2 33

Food

Food does not affect rate or extent of absorption.27 28 94

Special Populations

In patients with renal1 2 27 or hepatic1 2 impairment, serum concentrations may be increased.

Distribution Extent

Distributed in substantial amounts into bile.1 2 3 25 26 36

Appears to cross the placenta.81 101 Not known if distributed into breast milk.1 2

Plasma Protein Binding

>99% (for glyburide).7 25 37

>97% (for major metabolite 4-trans-hydroxyglyburide).25

Elimination Metabolism

Appears to be completely metabolized, 25 26 31 36 probably in the liver.31

Elimination Route

Excreted as metabolites in urine and feces in approximately equal proportions.1 2 23 25 26 30 31 47

Minimally removed by hemodialysis.42

Half-life

1.4–1.8 hours (for glyburide)24 27 29 41 97 or approximately 10 hours (for glyburide and metabolites).25 30 31 32

Special Populations

In patients with severe renal impairment, clearance may be decreased and half-life prolonged.42 43

Stability Storage Oral Conventional or Micronized Tablets

Well-closed containers at 15–30°C.1 2 124 126

Fixed-combination Tablets

Light-resistant containers up to 25°C.158

ActionsActions

Stimulates secretion of endogenous insulin from beta cells of the pancreas.1 2 3 4 8 9 10 11 12 Lowers blood glucose concentration in diabetic and nondiabetic individuals.3 4 8 9 10 11

During prolonged administration, extrapancreatic effects (e.g., enhanced peripheral sensitivity to insulin, reduction of basal hepatic glucose production) contribute to the hypoglycemic action.4 8 9 10 11 12 15 16 17 110 111 112 121

Advice to Patients

Importance of regular clinical and laboratory evaluations, including urine and/or fasting blood glucose determinations.1 2

Importance of adhering to diet and exercise regimen.1 2

Risks of hypoglycemia, the symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of hypoglycemic reactions.1

Understanding of primary and secondary failure to oral sulfonylurea antidiabetic agents.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Glyburide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

1.25 mg*

DiaBeta (scored)

Sanofi-Aventis

Glyburide Tablets

Greenstone, Sandoz, Teva

Micronase (scored)

Pfizer

2.5 mg*

DiaBeta (scored)

Sanofi-Aventis

Glyburide Tablets

Greenstone, Sandoz, Teva

Micronase (scored)

Pfizer

5 mg*

DiaBeta (scored)

Sanofi-Aventis

Glyburide Tablets

Greenstone, Sandoz, Teva

Micronase (scored)

Pfizer

Tablets (micronized)

1.5 mg*

Glyburide Micronized Tablets

Amide, Greenstone, Mylan, Stada, Teva, West-Ward

Glycron (scored)

Zoetica

Glynase PresTab (scored)

Pfizer

3 mg*

Glyburide Micronized Tablets

Amide, Greenstone, Mylan, Stada, Teva, West-Ward

Glycron (scored)

Zoetica

Glynase PresTab (scored)

Pfizer

4.5 mg*

Glycron (scored)

Zoetica

6 mg*

Glyburide Micronized Tablets

Amide, Greenstone, Mylan, Stada, Teva, West-Ward

Glycron (scored)

Zoetica

Glynase PresTab (scored)

Pfizer

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Glyburide Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

1.25 mg with Metformin Hydrochloride 250 mg*

Glucovance (with povidone)

Bristol-Myers Squibb

Glyburide with Metformin Hydrochloride Tablets

Actavis, Par, Sandoz, Teva

2.5 mg with Metformin Hydrochloride 500 mg*

Glucovance (with povidone)

Bristol-Myers Squibb

Glyburide with Metformin Hydrochloride Tablets

Actavis, Par, Sandoz, Teva

5 mg with Metformin Hydrochloride 500 mg*

Glucovance (with povidone)

Bristol-Myers Squibb

Glyburide with Metformin Hydrochloride Tablets

Actavis, Par, Sandoz, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Diabeta 1.25MG Tablets (SANOFI-AVENTIS U.S.): 50/$23.99 or 100/$45.97

Diabeta 2.5MG Tablets (SANOFI-AVENTIS U.S.): 30/$25.99 or 60/$49.97

Diabeta 5MG Tablets (SANOFI-AVENTIS U.S.): 30/$42.36 or 90/$117.67

Glucovance 2.5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$85.99 or 180/$249.98

Glucovance 5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$92 or 180/$246.06

GlyBURIDE 1.25MG Tablets (TEVA PHARMACEUTICALS USA): 30/$15.99 or 60/$23.98

GlyBURIDE 5MG Tablets (TEVA PHARMACEUTICALS USA): 30/$18.99 or 60/$29.98

GlyBURIDE Micronized 1.5MG Tablets (DAVA PHARMACEUTICALS): 90/$26.99 or 180/$52.97

GlyBURIDE Micronized 3MG Tablets (DAVA PHARMACEUTICALS): 90/$15.01 or 180/$17.99

GlyBURIDE Micronized 6MG Tablets (DAVA PHARMACEUTICALS): 90/$17 or 180/$21

GlyBURIDE-MetFORMIN 2.5-500MG Tablets (IVAX PHARMACEUTICALS INC.): 60/$45.99 or 180/$125.96

GlyBURIDE-MetFORMIN 5-500MG Tablets (TEVA PHARMACEUTICALS USA): 100/$83.99 or 300/$246.97

Glynase 1.5MG Tablets (PFIZER U.S.): 60/$53.99 or 180/$147.97

Glynase 3MG Tablets (PFIZER U.S.): 60/$75.99 or 180/$227.98

Glynase 6MG Tablets (PFIZER U.S.): 60/$129.99 or 180/$369.98

Micronase 1.25MG Tablets (PFIZER U.S.): 30/$22.99 or 90/$68.97

Micronase 2.5MG Tablets (PFIZER U.S.): 30/$28.99 or 90/$86.97

Micronase 5MG Tablets (PFIZER U.S.): 30/$41.99 or 90/$114.96

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pharmacia & Upjohn Company. Micronase (glyburide) prescribing information. Kalamazoo, MI; 2002 Mar.

2. Hoechst-Roussel Pharmaceuticals Inc. Dia?eta (glyburide) prescribing information. Somerville, NJ; 1987 Dec.

3. Anon. Glibenclamide: a review. Drugs. 1971; 1:116-40. [PubMed 5004340]

4. Jackson JE, Bressler R. Clinical pharmacology of sulphonylurea hypoglycaemic agents: part 1. Drugs. 1981; 22:211-45. [IDIS 140932] [PubMed 7021124]

5. Vomel VW, Sauer W. Zur Frage einer antimikrobiellen Wirkung des neuen oralen Antidiabeticums HB 419. (German; with English abstract) Arzneim-Forsch. 1969; 19:1491-4.

6. The British pharmacopoeia. London: Her Majesty’s Stationery Office; 1980:210.

7. Hadju VP, Kohler KF, Schmidt FH et al. Physikalisch-chemische und analytische Unter suchungen an HB 419. (German; with English abstract) Arzneim-Forsch. 1969; 19:1381-6.

8. Skillman TG, Feldman JM. The pharmacology of sulfonylureas. Am J Med. 1981; 70:361-72. [IDIS 164995] [PubMed 6781341]

9. Kolterman OG, Gray RS, Shapiro G et al. The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes. 1984; 33:346-54. [IDIS 184146] [PubMed 6423429]

10. Duckworth WC, Solomon SS, Kitabchi AE. Effect of chronic sulfonylurea therapy on plasma insulin and proinsulin levels. J Clin Endocrinol Metab. 1972; 35:585-91. [IDIS 28916] [PubMed 5052977]

11. Feldman JM, Lebovitz HE. Endocrine and metabolic effects of glybenclamide: evidence for an extrapancreatic mechanism of action. Diabetes. 1971; 20:745-55.

12. DeFronzo RA, Ferrannini E, Koivisto V. New concepts in the pathogenesis and treatment of noninsulin-dependent diabetes mellitus. Am J Med. 1983; 74(Suppl 1A):52-81. [IDIS 164138] [PubMed 6337486]

13. Lockwood DH, Maloff BL, Nowak SM et al. Extrapancreatic effects of sulfonylureas: potentiation of insulin action through post-binding mechanisms. Am J Med. 1983; 74(Suppl 1A):102-8. [PubMed 6401922]

14. Brogden RN, Heel RC, Pakes GE et al. Glipizide: a review of its pharmacological properties and therapeutic use. Drugs. 1979; 18:329-53. [IDIS 107972] [PubMed 389600]

15. Kolterman OG, Prince MJ, Olefsky JM. Insulin resistance in noninsulin-dependent diabetes mellitus: impact of sulfonylurea agents in vivo and in vitro. Am J Med. 1983; 74(Suppl 1A):82-101. [IDIS 164139] [PubMed 6401923]

16. Beck-Nielsen H, Pedersen O, Lindskov HO. Increased insulin sensitivity and cellular insulin binding in obese diabetics following treatment with glibenclamide. Acta Endocrinol. 1979; 90:451-62. [PubMed 106617]

17. Hjollund E, Richelsen B, Beck-Nielsen H et al. The effect of glibenclamide on insulin receptors in normal man: comparative studies of insulin binding to monocytes and erythrocytes. J Clin Endocrinol Metab. 1983; 57:1257-62. [IDIS 178711] [PubMed 6415086]

18. Moses AM, Howanitz J, Miller M. Diuretic action of three sulfonylurea drugs. Ann Intern Med. 1973; 78:541


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Metoprolol Tartrate


Class: beta-Adrenergic Blocking Agents
Note: This monograph also contains information on Metoprolol Succinate
VA Class: CV100
Molecular Formula: C22H23ClN6O•K ?C4H4 O4
CAS Number: 98418-47-4
Brands: Toprol XL, Lopressor, Lopressor HCT

Introduction

?1-Selective adrenergic blocking agent.109 147 281

Uses for Metoprolol Tartrate Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).100 111 157 160 161

One of several preferred initial therapies in hypertensive patients with ischemic heart disease, heart failure, or diabetes mellitus.232

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.232

Angina

Management of chronic stable angina pectoris.109 147

A component of the standard therapeutic measures in the management of unstable angina or non-ST-segment elevation/non-Q-wave MI.158 218 219 281

AMI

Secondary prevention following AMI to reduce the risk of reinfarction and mortality.109 123 124 126 127 144 158 281

Supraventricular Tachyarrhythmias

?-Adrenergic blocking agents, including metoprolol, are one of several preferred antiarrhythmic agents for the treatment of stable, narrow-complex supraventricular tachycardias (e.g., paroxysmal supraventricular tachycardia† [reentry supraventricular tachycardia], ectopic† or multifocal atrial tachycardia†, junctional tachycardia†) if the rhythm is not controlled by vagal maneuvers or adenosine in patients with preserved left ventricular function and for rate control in atrial fibrillation or flutter† in patients with preserved left ventricular function.281

Ventricular Tachyarrhythmias

Reduction of the incidence of ventricular fibrillation† associated with myocardial ischemia or infarction.158 197 281

Treatment of sustained polymorphic ventricular tachycardia† following AMI.158 197

CHF

Management of mild to moderately severe (NYHA class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin (in conjunction with ACE inhibitors, diuretics, and cardiac glycosides).147 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 215 216

Vascular Headache

Prophylaxis of migraine headache†; not recommended for the treatment of a migraine attack that has already started.231

Metoprolol Tartrate Dosage and Administration General

?1-Adrenergic blocking selectivity diminishes as dosage is increased.109 147

If long-term therapy is discontinued, reduce dosage gradually over a period of 1–2 weeks.109 147 (See Abrupt Withdrawal of Therapy under Cautions.)

Hypertension

Metoprolol/hydrochlorothiazide fixed combination is not recommended for initial combination therapy;159 adjust initial and subsequent dosages by administering each drug separately.a

Administration

Administer orally109 147 or by IV injection.109

For ACLS during CPR, may be administered by intraosseous infusion†.281

Oral Administration Conventional Tablets

Administer metoprolol tartrate conventional tablets daily as a single dose or in divided doses, with or immediately following meals.109

Extended-release Tablets

Administer metoprolol succinate extended-release tablets daily as a single dose.147

Extended-release tablets are scored and can be divided.147 However, swallow tablet or half tablet whole; do not chew or crush.147

When switching from conventional tablets to extended-release tablets, administer the same daily dosage.147

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Monitor heart rate, BP, and ECG during IV therapy.158

Discontinue IV therapy when therapeutic efficacy is achieved (e.g., slowing of ventricular rate in atrial fibrillation) or if systolic BP or heart rate declines to <100 mm Hg or 50 bpm, respectively.158 Discontinue therapy in patients with severe intolerance to IV therapy.109

Rate of Administration

Administer as a rapid IV injection.109 Administer over 1–2 minutes for the management of unstable angina or non-ST-segment elevation/non-Q-wave MI†.218

Dosage

Available as metoprolol tartrate and metoprolol succinate; dosage expressed in terms of the tartrate.109 147

Pediatric Patients Hypertension† Oral

Some experts recommend an initial dosage of 1–2 mg/kg daily given in 2 divided doses.260 Increase dosage as necessary up to a maximum dosage of 6 mg/kg (up to 200 mg) daily given in 2 divided doses.260

Adults Hypertension Oral

Initially, 50–100 mg given once daily (extended-release tablets) or in single or divided doses daily (conventional tablets).109 147 232 Increase dosage at weekly (or longer) intervals until optimum effect is achieved.109 147

If satisfactory BP response is not maintained throughout the day, larger doses, more frequent administration, or use of extended-release tablets may be required.a

Angina Long-term Management Oral

Initially, 100 mg given once daily (extended-release tablets) or in 2 divided doses daily (conventional tablets).109 147 Increase dosage at weekly intervals until optimum response is obtained or pronounced slowing of heart rate occurs.109 147

Usual maintenance dosage is 100–400 mg daily.109

Unstable Angina or Non-ST-Segment Elevation MI† IV, then Oral

Patients at high risk for ischemic events should receive IV loading dose followed by conversion to an oral regimen; oral therapy is recommended for lower risk patients.218 219

5 mg IV every 5 minutes up to a total of 15 mg.218 If IV dose is tolerated, 25–50 mg orally, initiated 15 minutes after the last IV dose and repeated every 6 hours for 48 hours, followed by 100 mg twice daily.218 Target resting heart rate is 50–60 bpm in the absence of dose-limiting adverse effects.218

AMI

As soon as clinical condition allows, administer oral therapy (conventional tablets) to patients who have contraindications to or do not tolerate IV therapy during the early phase of definite or suspected AMI or to patients in whom therapy is delayed.a

Early Treatment. IV, then Oral

2.5–5 mg IV every 2–5 minutes up to a total of 15 mg over 10–15 minutes.a If total IV dose is tolerated, 50 mg orally, initiated 15 minutes after the last IV dose and repeated every 6 hours for 48 hours, followed by 100 mg twice daily.109 If total IV dose is not tolerated, 25 or 50 mg (depending on the degree of intolerance) orally every 6 hours beginning 15 minutes after the last IV dose or as soon as clinical condition allows.109

Late Treatment Oral

100 mg twice daily for at least 3 months.109

Supraventricular Tachyarrhythmias Paroxysmal Supraventricular Tachycardia†, Junctional Tachycardia†, Ectopic Tachycardia†, Multifocal Atrial Tachycardia† IV or Intraosseous

5 mg every 5 minutes, up to a total dose of 15 mg.281

Atrial Fibrillation†. IV, then Oral

2.5–5 mg IV every 2–5 minutes as necessary to control rate, up to a total of 15 mg over 10–15 minutes.158 197 203 281 Then, 25–100 mg orally twice daily for long-term control.203

Intraosseous

5 mg every 5 minutes, up to a total dose of 15 mg.281

CHF Oral

Initially, 25 mg (extended-release tablets) once daily in adults with NYHA class II heart failure.147 In patients with more severe heart failure, use an initial dosage of 12.5 mg (extended-release tablets) once daily.147 Double the dosage every 2 weeks to a dosage of 200 mg or until highest tolerated dosage is reached.147

Some experts recommend initiation of therapy with 12.5 mg (extended-release tablets) daily or 6.25 mg (conventional tablets) twice daily for 2–4 weeks.163 173 205 If tolerated, increase to 25 mg daily for 2–4 weeks; subsequent dosages can be doubled every 2–4 weeks.163 147

If deterioration occurs during titration, increase dosage of concurrent diuretic147 205 and decrease dosage of metoprolol or temporarily discontinue metoprolol.147 205 Do not continue dosage titration until symptoms of worsening heart failure have stabilized.147 205 Initial difficulty in dosage titration should not preclude subsequent attempts to successfully titrate the dosage.147 205

Reduce dosage in patients with CHF who experience symptomatic bradycardia (e.g., dizziness) or 2nd or 3rd degree heart block.147 205

Vascular Headache Migraine† Oral

Dosages of 50–300 mg daily have been used in clinical studies; usual effective dosage was 200 mg daily.231

Prescribing Limits Pediatric Patients Hypertension† Oral

Maximum 6 mg/kg (up to 200 mg) daily.260

Adults Hypertension Oral

Dosages >400 mg (extended-release tablets) and 450 mg (conventional tablets) daily have not been studied.109 147

Angina Oral

Dosages >400 mg daily have not been studied.109 147

IV

Maximum 15 mg over 15 minutes in patients with unstable angina or non-ST-segment elevation MI†.218

AMI IV

Maximum 15 mg over 10–15 minutes.a

Supraventricular Tachyarrhythmias Atrial Fibrillation†. Oral

Maximum 100 mg twice daily.203

IV

Maximum 15 mg over 10–15 minutes.158 203 281

CHF Oral

Up to 200 mg daily.147

Special Populations Hepatic Impairment

Elimination occurs mainly in the liver; dosage reductions may be necessary.109 a

Renal Impairment

Dosage adjustments are not required.109 147

Geriatric Patients

Cautious dosage selection recommended; initiate therapy at the lower end of the dosage range.147

Cautions for Metoprolol Tartrate Contraindications

Patients with sinus bradycardia, heart block greater than 1st degree, cardiogenic shock, overt or decompensated cardiac failure, or sick sinus syndrome (unless a permanent pacemaker is in place).109 147 159 281

Patients with AMI who have a heart rate <45–60 bpm, heart block greater than 1st degree, systolic BP <100 mm Hg, or moderate to severe cardiac failure.109 281

Warnings/Precautions Warnings Abrupt Withdrawal of Therapy

Abrupt discontinuance may exacerbate angina symptoms or precipitate MI in patients with CAD.109 147 a Avoid abrupt discontinuance.109 147 Gradually decrease dosage over 1–2 weeks and monitor patients carefully.109 147 If exacerbation of angina occurs or acute coronary insufficiency develops, reinstitute therapy promptly, at least temporarily, and initiate appropriate measures for the management of unstable angina.109 147

Cardiac Failure

Possible precipitation of CHF;109 possible decreased exercise tolerance in patients with left ventricular dysfunction.a

Initiate therapy and subsequent dosage adjustments in patients with CHF under close medical supervision.147 163 205 Prior to initiation of metoprolol, stabilize patient on other therapy (e.g., ACE inhibitor, diuretic, and/or cardiac glycoside).147 163 205 Symptomatic improvement may not be evident for 2–3 months after initiating therapy.163 205

Avoid use in patients with decompensated CHF;147 a use cautiously in patients with inadequate myocardial function and, if necessary, in patients with well-compensated heart failure (e.g., those controlled with ACE inhibitors, cardiac glycosides, and/or diuretics);147 a use with extreme caution in patients with substantial cardiomegaly.a

Adequate treatment (e.g., with a cardiac glycoside and/or diuretic) and close observation recommended if signs or symptoms of impending cardiac failure occur; if cardiac failure continues, discontinue therapy, gradually if possible.109 147

Bronchospastic Disease

Possible bronchoconstriction, especially at dosages >100 mg daily.109 a

Use with caution in patients with bronchospastic disease; administer lowest effective dosage (initially in 3 divided doses) and with maximal therapy with a ?2-adrenergic agonist.109 a

Bradycardia

Possible bradycardia and depressed SA node automaticity.109 147 a

Carefully monitor hemodynamic status of patients with MI; use with caution in patients with sinus node dysfunction.109 147 a

If heart rate < 40 bpm with evidence of decreased cardiac output, administer IV atropine; if bradycardia is refractory to atropine, discontinue metoprolol and consider cautious administration of isoproterenol or use of a cardiac pacemaker.109 281

AV Block

Possible intensification of AV block, AV dissociation, AV conduction delays,281 complete heart block, or cardiac arrest, especially in patients with preexisting heart block caused by digoxin or other factors.109 a

Use with caution, if at all, in patients with AV conduction defects.a

If heart block occurs in patients with MI, discontinue metoprolol and administer IV atropine; if the heart block is refractory to atropine, consider cautious administration of isoproterenol or use of a cardiac pacemaker.109

Hypotension

If hypotension (systolic BP <90 mm Hg) occurs in patients with MI, discontinue metoprolol and assess hemodynamic status and extent of myocardial damage.109 Invasive monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be necessary; appropriate therapy with IV fluids and other treatment modalities recommended.109

If hypotension is associated with severe bradycardia or heart block, provide treatment directed at reversing these.109 (See Bradycardia and also see AV Block under Cautions.)

Major Surgery

Possible increased risks associated with general anesthesia (e.g., severe hypotension, maintenance of heart beat) due to decreased ability of the heart to respond to reflex ?-adrenergic stimuli.109 147

Use with caution in patients undergoing major surgery involving general anesthesia; avoid use of anesthetics that cause myocardial depression (see Specific Drugs under Interactions).a

Diabetes and Hypoglycemia

Possible decreased signs and symptoms of hypoglycemia (e.g., tachycardia, palpitation, BP changes, tremor, feelings of anxiety) and increased insulin-induced hypoglycemia.109 147 a

Use with caution in patients with diabetes mellitus.109 147

Thyrotoxicosis

Signs of hyperthyroidism (e.g., tachycardia) may be masked.109 147 Possible thyroid storm if therapy is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.109 147

General Precautions Ocular Effects

Possible dry eyes and decreased tear production, minimal injection of conjunctivae and/or eyelids, punctate keratitis, keratoconjunctivitis or corneal ulceration.a Close observation recommended.a

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription; similarity in spelling between Toprol-XL (metoprolol succinate) and Topamax (trade name for topiramate, an anticonvulsant and antimigraine agent) may result in errors.261 262 263 264

Potential also exists for dispensing errors involving confusion between Toprol-XL and Tegretol or Tegretol-XR (trade names for carbamazepine, an anticonvulsant also used for relief of pain associated with trigeminal neuralgia, as well as for various psychiatric disorders).261 263

These medication errors have been associated with serious adverse events sometimes requiring hospitalization as a result of either lack of the intended medication (e.g., seizure recurrence, return of hallucinations, suicide attempt, hypertension recurrence) or exposure to the wrong drug (e.g., bradycardia in a patient erroneously receiving metoprolol).261 262 263 264 261 262 263 264

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.a

Specific Populations Pregnancy

Category C.109 147

Lactation

Distributed into milk.147 Use with caution.109

Pediatric Use

Safety and efficacy remain to be fully established in children;109 147 however, some experts have recommended dosages for hypertension based on current limited clinical experience.258

Geriatric Use

Among patients with heart failure, safety and efficacy profiles in geriatric individuals are similar to those in younger adults.147

BP determinations recommended in both the seated position and after patient stands quietly for 2–5 minutes (to recognize postural hypotension).160

Hepatic Impairment

Hepatic elimination; use with caution.109 147 a

Common Adverse Effects

Dizziness, tiredness, insomnia, gastric upset.a

Interactions for Metoprolol Tartrate

Metabolized by CYP2D6.147 200 201 202 208 210 211

Drugs Affecting Hepatic Microsomal Enzymes

CYP2D6 inhibitors: Potential pharmacodynamic (increased ?-adrenergic blockade, decreased cardioselectivity of metoprolol) and pharmacokinetic interaction (prolonged half-life and increased plasma concentrations of metoprolol).147 200 201 202 208 210 211

Specific Drugs

Drug

Interaction

Comments

Calcium-channel blocking agents, nondihydropyridine

Possible additive negative effects on SA or AV nodal conductiona

Digoxin

Possible additive negative effects on SA or AV nodal conductiona

Diuretics

Increased hypotensive effecta

Adjust dosage carefullya

Fluoxetine

Possible increased plasma metoprolol concentrations; potential for increased ?-adrenergic blockade and decreased cardioselectivity of metoprolol147 200 201 202 208 210 211

Anesthetics, general (myocardial depressant agents [e.g., diethyl ether])

Increased risk of hypotension and heart failure109

Avoid use of general anesthetics with myocardial depressant effectsa

Hydralazine

Increased risk of pulmonary hypertension in patients with uremia a

Hypotensive agents

Possible increased hypotensive effecta

Adjust dosage carefullya

Paroxetine

Possible increased plasma metoprolol concentrations; potential for increased ?-adrenergic blockade and decreased cardioselectivity of metoprolol147 200 201 202 208 210 211

Use with caution209 211 212

Propafenone

Possible increased plasma metoprolol concentrations; potential for increased ?-adrenergic blockade and decreased cardioselectivity of metoprolol147 200 201 202 208 210 211

Quinidine

Possible increased plasma metoprolol concentrations; potential for increased ?-adrenergic blockade and decreased cardioselectivity of metoprolol147 200 201 202 208 210 211

Reserpine

Additive effects109

Monitor for hypotension and bradycardia109

Sertraline

Possible increased plasma metoprolol concentrations; potential for increased ?-adrenergic blockade and decreased cardioselectivity of metoprolol147 200 201 202 208 210 211

When concomitant sertraline therapy is discontinued, may need to increase metoprolol dosage208

Sympathomimetic agents

Antagonism of ?1-adrenergic stimulating effectsa

Verapamil

Increased oral bioavailability105 106

Avoid concomitant use, if possible;105 106 if used concomitantly, adjust metoprolol dosage and monitor patient closely106

Metoprolol Tartrate Pharmacokinetics Absorption Bioavailability

Metoprolol tartrate is rapidly and almost completely absorbed from the GI tract.109 After an oral dose (as conventional tablets), about 50% of the drug undergoes first-pass metabolism in the liver.109

Peak plasma concentrations are reached in about 90 minutes following a single oral dose as conventional tabletsa or 7 hours following administration as extended-release tablets.148

Steady-state oral bioavailability of extended-release tablets given once daily is about 77% of that of conventional tablets at corresponding dosages.147 148 Following oral administration as extended-release tablets, peak plasma metoprolol concentrations are about 25–50% of those attained after administration of conventional tablets.147

Plasma concentrations attained after IV administration are approximately twice those attained following oral administration.a

Onset

Reduction in systolic BP during exercise reported within 15 minutes after a single oral dose of metoprolol tartrate 50–80 mg; with chronic therapy, effect on systolic BP usually is maximal within 1 week.a

The extended-release tablets, given once daily, produce similar hypotensive effects as conventional tablets at similar dosages.147 148

Maximum ?-adrenergic blocking activity occurs at 20 minutes after a 10-minute IV infusion.109

Duration

Reduction in systolic BP during exercise persisted for 6 hours following a single oral dose of metoprolol tartrate 50–80 mg.a Hypotensive effect of extended-release tablets may persist for 24 hours.147 Duration of ?-adrenergic blocking effect is dose related.109

Following IV infusion of metoprolol tartrate 5 or 15 mg, ?-adrenergic blocking activity persisted for approximately 5 or 8 hours, respectively.109

Food

Food does not affect bioavailability of extended-release tablets.147

When conventional tablets are administered with food, peak plasma concentrations are higher and the extent of absorption is increased.a

Distribution Extent

Widely distributed into body tissues.a Concentrations in heart, liver, lungs, and saliva exceed plasma concentration.a Crosses the blood-brain barrier;147 concentration in CSF is about 78% of the simultaneous plasma concentration.a

Crosses the placenta.a

Concentration in milk is about 3–4 times the maternal plasma concentrations, but the actual amount distributed into milk appears to be very small.101 102

Plasma Protein Binding

11–12% (albumin).109

Elimination Metabolism

Undergoes first-pass metabolism in the liver by CYP2D6 to inactive metabolites.109 147

Elimination Route

Excreted in urine, principally as metabolites.109

Half-life

3–4 hours.109

Special Populations

Half-life does not increase appreciably with impaired renal function.109

Half-life is about 7.6 hours in poor metabolizers of the drug.a Concomitant use of CYP2D6 inhibitors (see Drugs Affecting Hepatic Microsomal Enzymes under Interactions) in poor metabolizers will lead to increases in plasma metoprolol concentrations and a decrease in ?1-selectivity.147

Stability Storage Oral Tablets

Tight, light-resistant containers at 15–30°C.109 Protect from light.109

Extended-Release Tablets

25°C (may be exposed to 15–30°C).147

Parenteral Injection

30°C or less (preferably 15–30°C).109 Protect from light109 and freezing.a

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral Solution CompatibilityHID

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility Y-Site CompatibilityHID

Compatible

Abciximab

Alteplase

Argatroban

Meperidine HCl

Morphine sulfate

Incompatible

Amphotericin B cholesteryl sulfate complex

ActionsActions

Inhibits response to adrenergic stimuli by competitively blocking ?1-adrenergic receptors within the myocardium.109 147 Blocks ?2-adrenergic receptors within bronchial and vascular smooth muscle only in high doses.109 147

Decreases resting heart rate, reflex orthostatic tachycardia, myocardial contractility, and cardiac output at rest and during exercise (without increasing peripheral resistance); inhibits exercise-induced increases in heart rate; increases systolic ejection time and cardiac volume, without changing stroke volume; decreases conduction velocity through the SA and AV nodes; and decreases myocardial automaticity.109 147 a

No intrinsic sympathomimetic activity and little or no membrane-stabilizing effect on the heart.109 147

Reduces BP by decreasing cardiac output, decreasing sympathetic outflow from the CNS, suppressing renin release, and/or reducing peripheral resistance.109 147 a

In patients with MI, reduces heart rate, systolic BP, cardiac output, and ventricular fibrillation.109 a

In patients with angina, blocks catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and BP, resulting in decreased myocardial oxygen consumption.109 147

Increases airway resistance and decreases ventilatory capacity in asthmatic patients.109 147 a

Causes little inhibition of glycogenolysis in skeletal and cardiac muscles; inhibits increase in plasma glycerol during exercise; inhibits insulin release less than propranolol.a

Advice to Patients

Importance of taking metoprolol exactly as prescribed.214

Importance of not interrupting or discontinuing therapy without consulting clinician; patients should temporarily limit their physical activity when discontinuing therapy.109 147

If a dose is missed, importance of patient taking only the next scheduled dose (i.e., the next dose should not be doubled).109 147

Importance of immediately informing clinician at the first sign or symptom of impending cardiac failure (e.g., weight gain, increased shortness of breath) or if any difficulty in breathing occurs.109

In patients with heart failure, importance of informing clinician of signs or symptoms of exacerbation (e.g., weight gain, difficulty in breathing).147

Importance of patients informing anesthesiologist or dentist that they are receiving metoprolol therapy prior to undergoing major surgery.109 147

Importance of avoiding some activities (e.g., operating machinery, driving a motor vehicle) until effects on individual are known.109 147

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.109 147 159

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.109

Importance of informing patients of other important precautionary information.109 147 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Metoprolol Succinate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

23.75 mg (equivalent to 25 mg of metoprolol tartrate)

Toprol XL (scored)

AstraZeneca

47.5 mg (equivalent to 50 mg of metoprolol tartrate)

Toprol XL (scored)

AstraZeneca

95 mg (equivalent to 100 mg of metoprolol tartrate)

Toprol XL (scored)

AstraZeneca

190 mg (equivalent to 200 mg of metoprolol tartrate)

Toprol XL (scored)

AstraZeneca

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Metoprolol Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg*

Lopressor (scored)

Novartis

Metoprolol Tartrate Tablets

100 mg*

Lopressor (scored)

Novartis

Metoprolol Tartrate Tablets

Parenteral

Injection

1 mg/mL

Lopressor

Novartis

Metoprolol Tartrate Injection

Metoprolol Tartrate and Hydrochlorothiazide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg Metoprolol Tartrate and Hydrochlorothiazide 25 mg

Lopressor HCT (scored)

Novartis

100 mg Metoprolol Tartrate and Hydrochlorothiazide 25 mg

Lopressor HCT (scored)

Novartis

100 mg Metoprolol Tartrate and Hydrochlorothiazide 50 mg

Lopressor HCT (scored)

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Lopressor 100MG Tablets (NOVARTIS): 60/$162.98 or 180/$488.95

Lopressor 50MG Tablets (NOVARTIS): 60/$118.99 or 180/$327.99

Lopressor HCT 100-50MG Tablets (NOVARTIS): 30/$81.99 or 90/$224.97

Metoprolol Tartrate 25MG Tablets (MYLAN): 30/$12.99 or 60/$14.98

Metoprolol-Hydrochlorothiazide 100-25MG Tablets (MYLAN): 30/$49.99 or 90/$129.97

Metoprolol-Hydrochlorothiazide 100-50MG Tablets (MYLAN): 30/$55.99 or 90/$149.97

Metoprolol-Hydrochlorothiazide 50-25MG Tablets (MYLAN): 60/$60.97 or 180/$160.97

Toprol XL 100MG 24-hr Tablets (ASTRAZENECA LP): 30/$59.99 or 90/$155.97

Toprol XL 200MG 24-hr Tablets (ASTRAZENECA LP): 90/$266.98 or 180/$507.97

Toprol XL 25MG 24-hr Tablets (ASTRAZENECA LP): 30/$45.99 or 90/$109.97

Toprol XL 50MG 24-hr Tablets (ASTRAZENECA LP): 30/$44.99 or 90/$109.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1984 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1984; 144:1045-57. [IDIS 184763] [PubMed 6143542]

101. Sandstr?m B, Regardh CG. Metoprolol excretion into milk. Br J Clin Pharmacol. 1980; 9:518-9. [IDIS 114928] [PubMed 7397065]

102. Liedholm H, Melander A, Bitz?n PO et al. Accumulation of atenolol and metoprolol in human breast milk. Eur J Clin Pharmacol. 1981; 20:229-31. [IDIS 148916] [PubMed 7286041]

103. Searle & Co. Calan SR prescribing information. Chicago; 1986 Nov.

104. Searle & Co. Calan prescribing information. Chicago, IL; 1986 Nov.

105. McLea


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Sectral


Generic Name: Acebutolol Hydrochloride
Class: beta-Adrenergic Blocking Agents
VA Class: CV100
Chemical Name: (±)-N-[3-Acetyl-4-[2-hydroxy-3-[(1-meth ylethyl)amino]propoxy]phenyl]butanamide monohydrochloride
Molecular Formula: C18H28N2O4• HCl
CAS Number: 34381-68-5

Introduction

A short-acting ?1-selective adrenergic blocking agent.1 2 17 18 113

Uses for Sectral Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 172 280 306 321

One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, ischemic heart disease, and/or diabetes mellitus.354

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.354

Cardiac Arrhythmias

Treatment of frequent ventricular premature complexes (VPCs), including uniform and multiform VPCs and/or coupled VPCs, and R-on-T complexes1 2 137 185 186 187 188 189 190 193 194 195 196 197 198 199 201 204 in patients with primary arrhythmias or arrhythmias secondary to various cardiac disorders (e.g., CAD,137 185 186 187 188 189 194 MI,137 186 187 193 194 195 196 valvular disease).185 186 187 189 190

Management of various supraventricular tachyarrhythmias†.191 192 196 200 202 203 256 266

Angina

Management of chronic stable angina pectoris†.205 206 207 208 209 210 211 212 213 214 220 221 222 223 224 225

Acute Myocardial Infarction

Secondary prevention following AMI† to reduce the risk of reinfarction and mortality.289 290

Sectral Dosage and Administration General

Individualize dosage according to patient response.1 2 4

?-Adrenergic blocking selectivity diminishes as dosage is increased.1

If long-term therapy is discontinued, reduce dosage gradually over a period of about 2 weeks.1 2 (See Abrupt Withdrawal of Therapy under Cautions.)

When substituting another ?-adrenergic blocking agent for acebutolol, initiate at a comparable dosage without interruption of ?-blocker therapy.1 2

Hypertension

Monitor BP carefully during initial titration or subsequent dosage increases.354 354 Large or abrupt BP reductions generally should be avoided.354

Angina

Adjust dosage of ?-adrenergic blocking agents according to clinical response4 205 and to maintain a resting heart rate of 55–60 bpm.211 216

Administration

Acebutolol hydrochloride is administered orally.1 2 Also been administered IV†,25 27 28 29 41 191 192 196 200 202 203 266 but a parenteral dosage form is currently not commercially available in the US.

Oral Administration Hypertension

Usually administer as a single daily dose;1 245 321 however, for 24-hour BP control, some patients may require administration of the daily dose in 2 divided doses.1 142 143 144 145 149 155 354

Ventricular Arrhythmias

Twice-daily dosing of the drug appears to be more effective than once-daily dosing for the suppression and prevention of frequent VPCs.4 185 186 188 189 195 198 199 203 204 248

Angina

Once-daily administration may be as effective as divided doses;4 208 249 however, further studies are needed.4

Dosage

Available as acebutolol hydrochloride; dosage expressed in terms of acebutolol.1

Adults Hypertension Oral

Initially, 200–400 mg daily.1 245 321 Usual maintenance dosage is 200–800 mg daily, 1 140 142 143 144 145 149 150 151 152 153 154 245 246 247 321 354 but some patients may achieve adequate BP control with dosages as low as 200 mg daily.1 4 321 354 Increase dosage up to 1.2 g daily in two divided doses in patients with more severe hypertension or if adequate reduction of BP does not occur;1 2 4 140 142 143 144 145 149 150 151 152 154 155 alternatively, add another hypotensive agent (e.g., thiazide diuretic).1 2 4 142 144 157 158 160 161 165 166 168 172

Ventricular Arrhythmias Oral

Initially, 200 mg twice daily.1 187 196 Increase gradually until optimum effect is achieved.1 185 186 195 198 204 Usual maintenance dosage is 600–1200 mg daily.1 2 4 185 186 189 190 195 199 204

Angina Oral

Initially, 200 mg twice daily.4 205 208 Increase dosage gradually until optimum effect is achieved.4 205 Usual maintenance dosage is 800 mg or less daily,4 206 207 208 209 210 211 212 213 214 but patients with severe angina may require higher dosages.4 205 209 211

Prescribing Limits Adults Hypertension Oral

Maximum 1.2 g daily.1 2 4 140 142 143 144 145 149 150 151 152 154 155

Special Populations Renal Impairment

Active metabolite (diacetolol) eliminated principally by the kidneys;1 123 125 dosage and/or frequency of administration must be modified in response to the degree of renal impairment.1 2 86 123 124 125 126 127

Dosage Reductions in Patients with Renal Impairment

Reduction in Usual Daily Dosage

Clcr(mL/min)

50%

25–49 mL/minute

75%

<25 mL/minute

Acebutolol and diacetolol removed by hemodialysis;1 125 127 individualize dosage carefully in patients with severe renal impairment who undergo chronic intermittent hemodialysis.124 125

Geriatric Patients

Consider reduction in maintenance dosage.1 2 Avoid dosages >800 mg daily.1 2

Cautions for Sectral Contraindications

Patients with heart block >first degree, severe bradycardia, cardiogenic shock, or overt cardiac failure.1

Warnings/Precautions Warnings Cardiac Failure

Possible precipitation of CHF.1

Avoid use in patients with decompensated CHF; use cautiously in patients with inadequate myocardial function and, if necessary, in patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics).1

Adequate treatment (e.g., with a cardiac glycoside and/or diuretic) and close observation recommended if signs or symptoms of impending cardiac failure occur; if cardiac failure continues, discontinue therapy, gradually if possible.1

Abrupt Withdrawal of Therapy

Possible exacerbated angina symptoms or precipitation of MI in patients with CAD.1 Abrupt discontinuance of therapy is not recommended.1 276 Gradually decrease dosage over a period of about 2 weeks; monitor patients carefully and advise to temporarily limit their physical activity.1 276 If exacerbation of angina occurs, reinstitute therapy promptly and initiate appropriate measures for the management of unstable angina pectoris.1

Peripheral Vascular Disease

Possible reduction in cardiac output and precipitation or aggravation of symptoms of arterial insufficiency.1 Use with caution; observe for evidence of disease progression.1

Bronchospastic Disease

Possible bronchoconstriction.1

Use with caution in patients with bronchospastic disease; administer the lowest effective dosage (initially in divided doses). A bronchodilator (e.g., a ?2-adrenergic agonist, theophylline) should be available for immediate use, if necessary.1

Major Surgery

Possible risks associated with general anesthesia (e.g., severe hypotension, maintenance of heart beat) due to decreased ability of the heart to respond to reflex ?-adrenergic stimuli.1 Use with caution in patients undergoing major surgery involving general anesthesia; anesthetics used should not cause myocardial depression.1

Diabetes and Hypoglycemia

Possible decreased signs and symptoms of hypoglycemia (e.g., tachycardia, palpitation, BP changes, tremor, feelings of anxiety, but not sweating or dizziness) and increased insulin-induced hypoglycemia.1

Use with caution in patients with diabetes mellitus.1

Thyrotoxicosis

Signs of hyperthyroidism (e.g., tachycardia) may be masked.1 Possible thyroid storm if therapy is abruptly withdrawn; carefully monitor patients having or suspected of developing thyrotoxicosis.1

Sensitivity Reactions Anaphylactic Reactions

Patients with a history of anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking ?-blocking agents.1 Such patients may be unresponsive to usual doses of epinephrine.1

Specific Populations Pregnancy

Category B.1

Lactation

Distributed into milk in higher concentrations than in maternal plasma.1 2 105 Use not recommended by manufacturer.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.1 268

Geriatric Use

Insufficient experience in patients >65 years of age to determine whether geriatric patients respond differently than younger adults.1 However, reduction of maintenance dosage may be necessary,1 2 since bioavailability of acebutolol and diacetolol (active metabolite) may be increased compared with that in younger adults.1 2 122 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution.1 2 Cirrhosis does not appear to substantially affect the pharmacokinetics of acebutolol or diacetolol; however, the effects of hepatic impairment on elimination of the drug have not been fully evaluated.128

Renal Impairment

Use with caution; dosage should be reduced based on the degree of renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Fatigue, dizziness, headache, dyspnea, constipation, diarrhea, dyspepsia, nausea, flatulence, insomnia, increased micturition, chest pain, edema, depression, abnormal dreams, rash, arthralgia, myalgia, cough, rhinitis, abnormal vision.1

Interactions for Sectral Specific Drugs

Drug

Interaction

Comments

?-Adrenergic agonists1

Possible exaggerated hypertensive reactions1

Warn patients of potential hazard1

Calcium-channel blockers

Potential additive depressant effects on SA or AV nodal conduction318 319

Cardiac glycosides (digoxin)

Potential additive depressant effects on SA or AV nodal conduction318 319

Pharmacokinetic interaction unlikely1

Diuretics

Possible increased hypotensive effect1 2 142 144 157 158 160 172

Careful dosage adjustment recommended1 2 144 157 158 160 172

Glyburide

Possible decreased hypoglycemic action in type II diabetic patients, presumably by decreasing insulin secretion244

Hydralazine

Pharmacokinetic interaction unlikely1

Hydrochlorothiazide

Pharmacokinetic interaction unlikely1

Hypotensive agents

Possible increased hypotensive effect1 2 142 144 157 158 160 172

Careful dosage adjustment recommended1 2 144 157 158 160 172

NSAIAs

Potential blunting of hypotensive effects1

Oral contraceptives

Pharmacokinetic interaction unlikely1

Reserpine

Possible additive pharmacologic effects1

Observe closely for evidence of marked bradycardia or hypotension (e.g., vertigo, presyncope or syncope, or orthostatic changes in BP without compensatory tachycardia)1

Sulfinpyrazone

Pharmacokinetic interaction unlikely1

Sympathomimetic agents

Antagonism of ?1-adrenergic stimulating effects (e.g., bronchodilation)1 2 57 58 59 62

Increased dosage of ?-adrenergic agonist bronchodilators may be required 268 277

Tolbutamide

Interaction unlikely1

Warfarin

Interaction unlikely1

Sectral Pharmacokinetics Absorption Bioavailability

Well absorbed from the GI tract following oral administration;1 2 4 11 91 109 undergoes extensive first-pass metabolism in the liver.1 2 97 99 109 122 124

Peak plasma acebutolol and diacetolol concentrations occur within 2–2.5 hours (range: 1–4 hours) and 4 hours (range: 2.4–5 hours), respectively, in healthy individuals1 2 94 95 97 98 99 126 135 or patients with hypertension91 or arrhythmias.2 90 137

Absolute bioavailability is approximately 35–50%.1 4 94 97 102

Food

Food may slightly decrease the rate of absorption and peak plasma concentrations of acebutolol and its major metabolite (diacetolol), but the extent of absorption is not substantially affected.1 2 101

Onset

Effect on resting, reflex, or exercise-induced heart rate and systolic BP begins within 1–1.5 hours,1 3 21 91 100 in healthy1 21 98 100 or hypertensive91 individuals.

Duration

Effect may persist for up to 24 hours or longer.1 3 91 98 100

Special Populations

In geriatric patients, peak plasma concentrations and AUCs of acebutolol and diacetolol are increased twofold compared with those observed in younger patients.1 2 122

Distribution Extent

Acebutolol and diacetolol readily cross the placenta1 2 105 106 107 and can accumulate in the fetus.105 106 107

Acebutolol and diacetolol are distributed into milk at concentrations higher than those in maternal plasma. (See Lactation under Cautions.)1 2 105 106

Plasma Protein Binding

Approximately 11–25% (acebutolol) and 6–9% (diacetolol).2 93 103 Approximately 50% bound to erythrocytes.4 125

Elimination Metabolism

Rapidly and extensively metabolized in the liver2 110 113 to metabolites (acetolol and diacetolol).2 4 6 99 108 109 110 113

Elimination Route

Acebutolol and its metabolites are excreted in feces and urine.1 87 92 109 111 123

Half-life

About 3 hours in the initial distribution phase (t??) 95 and about 11 hours (range: 6–12 hours) in the terminal phase (t??).95 125 About 7.5 (range: 7–11 hours) and 3 hours, respectively, for diacetolol and acetolol following a single oral dose.101 108 125

Special Populations

Renal impairment may reduce clearances of acebutolol and diacetolol.125 Acebutolol and diacetolol are removed by hemodialysis.1 125 127

Stability Storage Oral Capsules

Tight containers1 253 at room temperature (approximately 25°C).1 2 3

Protect from light.1 305

ActionsActions

Pharmacologic effects result from both the unchanged drug and diacetolol, 1 2 114 115 116 117 which is equipotent to acebutolol.1 2 114 115 116 117

Inhibits response to adrenergic stimuli by competitively blocking ?1-adrenergic receptors within the myocardium.1 2 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 34 35 36 37 38 Blocks ?2-adrenergic receptors within bronchial and vascular smooth muscle only at high doses.4 24 35 178

Decreases exercise-induced heart rate,1 2 4 11 12 13 23 24 25 27 inhibits reflex orthostatic tachycardia,1 2 4 11 12 13 23 24 and may decrease1 2 25 28 29 140 193 or leave unchanged 26 140 cardiac output at rest2 25 140 193 or during exercise.1 28 29 Decreases systolic and diastolic BP at rest1 2 13 19 23 56 57 139 and during exercise.1 2 155 160 171

Precise mechanism of hypotensive action has not been determined.7 22 26 34 35 139 178 May reduce BP by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release.7 26 34 35 140

Exhibits antiarrhythmic activity;1 2 137 185 186 187 188 189 190 193 194 195 196 199 204 considered a class II antiarrhythmic agent.254

Can produce nervous system effects,1 2 4 6 150 152 154 158 170 198 although the frequency and/or severity of such effects may be less than those observed with some other ?-adrenergic blocking agents.152 154 156 262

Unlike some ?-adrenergic blocking agents147 148 does not consistently suppress plasma renin activity (PRA).26 71 139 140 141 142 143

May increase airway resistance and decrease ventilatory capacity,51 52 53 54 57 58 59 60 61 62 63 64 155 158 especially in patients with asthma and/or COPD or when high dosages are used.52 53 57 58 59 60 61 62 63 64 158 268

Does not appear to substantially affect glucose metabolism;73 75 however, the drug may potentiate insulin-induced hypoglycemia in diabetic patients receiving oral hypoglycemic agents.74 (See Interactions.)

Advice to Patients

Importance of taking acebutolol exactly as prescribed.1

Importance of not interrupting or discontinuing therapy without consulting clinician; patients should temporarily limit physical activity when discontinuing therapy.1 276

Importance of immediately informing clinician at the first sign or symptom of impending cardiac failure (e.g., weight gain, increased shortness of breath) or if any difficulty in breathing occurs.1

In patients with heart failure, importance of informing clinician of signs or symptoms of exacerbation (e.g., weight gain, difficulty in breathing).1

Importance of patients informing anesthesiologist or dentist that they are receiving acebutolol therapy prior to undergoing major surgery.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Acebutolol Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

200 mg (of acebutolol)*

Acebutolol Hydrochloride Capsules

Mylan, Par, Watson

Sectral (with povidone)

ESP Pharma

400 mg (of acebutolol)*

Acebutolol Hydrochloride Capsules

Mylan, Par, Watson

Sectral (with povidone)

ESP Pharma

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Acebutolol HCl 200MG Capsules (AMNEAL PHARMACEUTICALS): 100/$54.98 or 200/$91.1

Acebutolol HCl 400MG Capsules (AMNEAL PHARMACEUTICALS): 30/$21.99 or 90/$57.98

Sectral 200MG Capsules (PROMIUS PHARMA): 60/$179.98 or 180/$520.02

Sectral 400MG Capsules (PROMIUS PHARMA): 30/$125 or 90/$364.95

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2004. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Wyeth-Ayerst Laboratories. Sectral (acebutolol hydrochloride) prescribing information. In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:3381-3.

2. Ives Laboratories Inc. Sectral product monograph. New York, NY; 1985 Mar.

3. Ives Laboratories Inc. Sectral product information form for American Hospital Formulary Service. Philadelphia, PA; 1985 Jan.

4. Singh BN, Thoden WR, Ward A. Acebutolol: a review of its pharmacological properties and therapeutic efficacy in hypertension, angina pectoris and arrhythmia. Drugs. 1985; 29:531-69. [IDIS 200919] [PubMed 3891306]

5. Cowling CGD, Leary WP. Acebutolol: a review. Curr Ther Res. 1981; 30:765-74.

6. De Bono G, Kaye CM, Roland E et al. Acebutolol: ten years of experience. Am Heart J. 1985; 109(5 Part 2):1211-24. [IDIS 200170] [PubMed 2859785]

7. Anon. Acebutolol. Med Lett Drugs Ther. 1985; 27:58-60. [PubMed 3892259]

8. Abernethy DR, Arendt RM, Greenblatt DJ. Pharmacologic properties of acebutolol: relationship of hydrophilicity to central nervous system penetration. Am Heart J. 1985; 109(5 Part 2):1120-5. [IDIS 200156] [PubMed 2859774]

9. Ryan JR. Clinical pharmacology of acebutolol. Am Heart J. 1985; 109(5 Part 2):1131-6. [IDIS 200158] [PubMed 2859776]

10. Mimnaugh MN, Gearien JE. Adrenergic drugs. In: Foye WO, ed. Principles of medicinal chemistry. 2nd ed. Philadelphia: Lea & Febiger; 1981:377-93.

11. Maxwell DR, Collins RF. Acebutolol (Sectral): I—review of the pharmacology and pharmacokinetics. Clin Trials J. 1974; 11(Suppl 3):9-18.

12. Basil B, Jordan R, Loveless AH et al. ?-Adrenoceptor blocking properties and cardioselectivity of M & B 17,803A. Br J Pharmacol. 1973; 48:198-211. [PubMed 4147427]

13. Daly MJ, Flook JJ, Levy GP. The selectivity of ?-adrenoceptor antagonists on cardiovascular and bronchodilator responses to isoprenaline in the anaesthetized dog. Br J Pharmacol. 1975; 53:173-81. [PubMed 238697]

14. Harms HH. Isoproterenol antagonism of cardioselective beta adrenergic receptor blocking agents: a comparative study of human and guinea-pig cardiac and bronchial beta adrenergic receptors. J Pharmacol Exp Ther. 1976; 199:329-35. [PubMed 10427]

15. Baird JRC, Linnell J. The assessment of ?-adrenoceptor blocking potency and cardioselectivity in vitro and in vivo. J Pharm Pharmacol. 1972; 24:880-5.

16. Harms HH, Spoelstra AJG. Cardiac and bronchial ?-adrenoceptor antagonistic potencies of atenolol, metoprolol, acebutolol, practolol, propranolol and pindolol in the anaesthetized dog. Clin Exp Pharmacol Physiol. 1978; 5:53-9. [PubMed 25152]

17. Briant RH, Dollery CT, George CF. Cardiac and peripheral vascular beta-receptors in the dog and in man: the selectivity of acebutolol (Sectral). Clin Trials J. 1974; 11(Suppl 3):25-8.

18. Bilski A, Robertson HH, Wale JL. A study of the relationship between cardiac ?-adrenoceptor blockade and intrinsic sympathomimetic activity in rats depleted of catecholamines. Clin Exp Pharmacol Physiol. 1979; 6:1-9. [PubMed 32980]

19. Levy B. The selective beta receptor blocking properties of DL-1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3- isopropylaminopropane-HCl (M&B 17803-A) in the anesthetized dog. J Pharmacol Exp Ther. 1973; 186:134-44. [PubMed 4146701]

20. Dreyer AC, Offermeier J. In vitro assessment of the selectivities of various beta-adrenergic blocking agents. Life Sci. 1980; 27:2087-92. [PubMed


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Tolmetin Sodium


Class: Other Nonsteroidal Anti-inflammatory Agents
VA Class: MS120
Chemical Name: Sodium 1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate dihydrate
CAS Number: 64490-92-2
Brands: Tolectin

Cardiovascular Risk

Possible increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).240 Risk may increase with duration of use.240 Individuals with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.240 (See Cardiovascular Effects under Cautions.)

Contraindicated for the treatment of pain in the setting of CABG surgery.240

GI Risk

Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).240 Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.240 Geriatric individuals are at greater risk for serious GI events.240 (See GI Effects under Cautions.)

Introduction

Prototypical NSAIA; pyrrole acetic acid derivative. a

Uses for Tolmetin Sodium

Consider potential benefits and risks of tolmetin therapy as well as alternative therapies before initiating therapy with the drug.240 Use lowest possible effective dosage and shortest duration of therapy consistent with patient's treatment goals.240

Inflammatory Diseases

Symptomatic treatment of osteoarthritis and rheumatoid arthritis.240

Management of juvenile rheumatoid arthritis in children ?2 years of age.240

Has been reported to be effective in the management of ankylosing spondylitis† (late stages did not respond as well as early stages); has also been used with some success in the treatment of adhesive capsulitis shoulder† (frozen shoulder), radiohumeral bursitis† (tennis elbow), and local trauma† (e.g., recent sprains).a

Tolmetin Sodium Dosage and Administration General

Consider potential benefits and risks of tolmetin therapy as well as alternative therapies before initiating therapy with the drug.240

Administration Oral Administration

Administer orally 3 or 4 times daily.240

Administration with antacids (i.e., antacid containing aluminum and magnesium hydroxides) may minimize adverse GI effects.240

Dosage

Available as tolmetin sodium; dosage expressed in terms of tolmetin.240

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.240 Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.240

Pediatric Patients Inflammatory Diseases Juvenile Rheumatoid Arthritis Oral

Children ?2 years of age: Initially, 20 mg/kg daily in 3 or 4 divided doses.240 Adjust dosage based on response and tolerance.240

Usual effective dosage: 15–30 mg/kg daily.240

Adults Inflammatory Diseases Osteoarthritis or Rheumatoid Arthritis Oral

Initially, 400 mg 3 times daily, preferably including a dose on arising and at bedtime.240 Adjust dosage based on response (after 1 or 2 weeks) and tolerance.a

Usual effective dosage: 600 mg to 1.8 g daily in 3 divided doses.240

Ankylosing Spondylitis† Oral

600 mg to 1.6 g daily in divided dose has been used.a

Adhesive Capsulitis Shoulder† (frozen shoulder), Radiohumeral Bursitis† (tennis elbow), Local Trauma† (e.g., recent sprains) Oral

>600 mg or 1.2 g daily in divided doses has been used.a

Prescribing Limits Pediatric Patients Inflammatory Diseases Juvenile Rheumatoid Arthritis Oral

Dosages >30 mg/kg daily have not been studied and are not recommended.240

Adults Inflammatory Diseases Osteoarthritis or Rheumatoid Arthritis Oral

Dosages >1.8 g daily have not been studied and are not recommended.240

Special Populations Renal Impairment

Reduce dosage if necessary.240

Geriatric Patients

Select dosage with caution (potential for age-related renal function decline).247

Cautions for Tolmetin Sodium Contraindications

Known hypersensitivity to tolmetin or any ingredient in the formulation.240

History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.240

Treatment of perioperative pain in the setting of CABG surgery.240

Warnings/Precautions Warnings Cardiovascular Effects

Selective COX-2 inhibitors have been associated with increased risk of cardiovascular events (e.g., MI, stroke) in certain situations.241 Several prototypical NSAIAs also have been associated with increased risk of cardiovascular events.244 245 246 Current data insufficient to assess risk associated with tolmetin.244 245 246

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events), and at the lowest effective dose for the shortest duration necessary.240

Short-term use to relieve acute pain, especially at low dosages, does not appear to be associated with increased risk of serious cardiovascular events (except immediately following CABG surgery).241

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.240 (See Specific Drugs and Laboratory Tests under Interactions.)

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.240 Use with caution in patients with hypertension; monitor BP.240 Impaired response to certain diuretics may occur.240 (See Specific Drugs and Laboratory Tests under Interactions.)

Fluid retention and edema reported.240 Caution in patients with fluid retention or heart failure.240

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.200 201 212 240 227 230 237

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;203 227 228 229 alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)203 227 228 or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).228

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.240

Potential for overt renal decompensation.204 240 Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.204 240 243 247 (See Renal Impairment under Cautions.)

Sensitivity Reactions Hypersensitivity Reactions

Anaphylactoid reactions reported. 240

Immediate medical intervention and discontinuance for anaphylaxis.240

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.240

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.240 Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).240

General Precautions Ocular and Otic Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.240

Tinnitus reported; deterioration in hearing reported rarely.a

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs. 240

Elevations of serum ALT or AST reported.240 Elevations of serum alkaline phosphatase also reported.a

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.240 Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.240

Hematologic Effects

Anemia reported rarely.240 Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.240

Small and transient decreases in hemoglobin concentration or hematocrit (not associated with GI bleeding), leukopenia (including granulocytopenia), thrombocytopenia, and hemolytic anemia reported.a One case of fatal agranulocytosis reported. a

May inhibit platelet aggregation and prolong bleeding time.240

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.240

May mask certain signs of infection.240

Obtain CBC and chemistry profile periodically during long-term use.240

Specific Populations Pregnancy

Category C.240 Avoid use in third trimester because of possible premature closure of the ductus arteriosus.240

Lactation

Distributed into milk in humans.240 Discontinue nursing or the drug.240

Pediatric Use

Safety and efficacy not established in children <2 years of age.240

Geriatric Use

Caution advised.240 Geriatric adults appear to tolerate NSAIA-induced adverse effects less well than younger individuals.247 Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.240

Hepatic Impairment

Monitor closely.240

Renal Impairment

Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.240

Common Adverse Effects

Nausea, dyspepsia, GI distress, diarrhea, abdominal pain, flatulence, vomiting, dizziness, headache, asthenia, elevated BP, edema, weight change.240

Interactions for Tolmetin Sodium Protein-bound Drugs

Potential for tolmetin to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.a Observe for adverse effects.a

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to the ACE inhibitor240

Monitor BP240

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist247

Monitor BP247

Anticoagulants (warfarin)

Possible bleeding complications240

Increased PT and bleeding reported rarelya

Caution advised 240

Antidiabetic agents

Administration with insulin or sulfonylureas does not appear to alter the clinical effects of the NSAIA or the antidiabetic agenta 240

Diuretics (furosemide, thiazides)

Reduced natriuretic effects 240

Monitor for diuretic efficacy and renal failure240

Lithium

Increase plasma lithium concentrations240

Monitor for lithium toxicity240

Methotrexate

Possible increased and prolonged blood concentrations of methotrexate205 206 207 208 209 210 211

Use with caution240

NSAIAs

NSAIAs including aspirin: Increased risk of GI ulceration or other complications 240

Aspirin: No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs240

Concomitant use not recommended240

Tests for urinary protein

False-positive results with tests that use sulfosalicylic acid reagent240

Use dye-impregnated reagent strips (e.g., Albustix, Uristix)240

Tolmetin Sodium Pharmacokinetics Absorption Bioavailability

Well absorbed following oral administration.a

Food

Bioavailability reduced 16% when administered immediately after food or with milk. a 240 Peak plasma concentrations reduced 50% when administered immediately after food.a 240

Distribution Extent

Distributed into human milk.240

Crosses the blood-brain barrier and placenta in animals.a

Plasma Protein Binding

99%.a

Elimination Metabolism

Oxidized in liver to an inactive dicarboxylic acid metabolite.a

Elimination Route

Excreted in the urine within 24 hours as the dicarboxylic acid metabolite (60%), unchanged tolmetin (20%), and tolmetin conjugates (20%).a

Half-life

Approximately 1 hour in healthy males.a

Special Populations

Patients with rheumatoid arthritis: Pharmacokinetic values generally similar to values in healthy individuals; however, increase in renal clearance of tolmetin and its metabolites reported in one study.a

Stability Storage Oral Capsules and Tablets

Tight, light-resistant containers at 15–30°C.240

ActionsActions

Inhibits cyclooxygenase-1 (COX-1) and COX-2.221 222 223 224 225 226

Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.a

Advice to Patients

Importance of reading the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.240

Risk of serious cardiovascular events with long-term use.240

Risk of GI bleeding and ulceration.240

Risk of serious skin reactions.240 Risk of anaphylactoid and other sensitivity reactions.240

Risk of hepatotoxicity.240

Importance of notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.240

Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.240

Importance of discontinuing tolmetin and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.240 Importance of seeking immediate medical attention if an anaphylactic reaction occurs.240

Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.240

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.240 Importance of avoiding tolmetin in late pregnancy (third trimester).240

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant diseases.240

Importance of informing patients of other important precautionary information.240 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Tolmetin Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

400 mg (of tolmetin)*

Tolectin DS

Ortho-McNeil

Tolmetin Sodium Capsules

Actavis, Mutual, Mylan, Sandoz, Teva

Tablets

200 mg (of tolmetin)*

Tolectin (scored)

Ortho-McNeil

Tolmetin Sodium Tablets

Mutual, Sandoz

Tablets, film-coated

600 mg (of tolmetin)*

Tolectin

Ortho-McNeil

Tolmetin Sodium Tablets

Actavis, Mylan, Sandoz, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Tolmetin Sodium 200MG Tablets (MUTUAL PHARMACEUTICAL): 100/$75.99 or 300/$209.97

Tolmetin Sodium 400MG Capsules (TEVA PHARMACEUTICALS USA): 90/$89.99 or 100/$99.97

Tolmetin Sodium 600MG Tablets (MYLAN): 100/$200.99 or 300/$579.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions November 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

200. Palmer JF. Letter sent to Siegfried J. of McNeil Pharmaceuticals regarding labeling revisions about gastrointestinal adverse reactions to Tolectin (tolmetin). Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products; 1988 Sep.

201. Food and Drug Administration. Labeling revisions for NSAIDs. FDA Drug Bull. 1989; 19:3-4.

202. Searle. Cytotec (misoprostol) prescribing information. 1989 Jan.

203. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64. [PubMed 10887424]

204. McNeil. Tolectin (tolmetin tablets and capsules) prescribing information. Spring House, PA; 1997 Jun

205. Thyss A, Milano G, Kubar J et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet. 1986; 1:256-8. [IDIS 210465] [PubMed 2868265]

206. Ellison NM, Servi RJ. Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration. Cancer Treat Rep. 1985; 69:342-3. [IDIS 198404] [PubMed 3978662]

207. Singh RR, Malaviya AN, Pandey JN et al. Fatal interaction between methotrexate and naproxen. Lancet. 1986; 1:1390. [IDIS 217293] [PubMed 2872507]

208. Day RO, Graham GG, Champion GD et al. Anti-rheumatic drug interactions. Clin Rheum Dis. 1984; 10:251-75. [PubMed 6150784]

209. Daly HM, Scott GL, Boyle J et al. Methotrexate toxicity precipitated by azapropazone. Br J Dermatol. 1986; 114:733-5. [IDIS 217458] [PubMed 3718865]

210. Hansten PD, Horn JR. Methotrexate interactions: ketoprofen (Orudis). Drug Interact Newsl. 1986; 6(Updates):U5-6.

211. Maiche AG. Acute renal failure due to concomitant action of methotrexate and indomethacin. Lancet. 1986; 1:1390. [IDIS 217292] [PubMed 2872506]

212. Soll AH, Weinstein WM, Kurata J et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med. 1991; 114:307-19. [IDIS 277370] [PubMed 1987878]

213. Ciba Geigy, Ardsley, NY: Personal communication on diclofenac 28:08.04.

214. Reviewers’ comments (personal observations) on diclofenac 28:08.04.

215. Corticosteroid interactions: nonsteroidal anti-inflammatory drugs (NSAIDs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:562.

216. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994; 343:769-72. [IDIS 328176] [PubMed 7907735]

217. Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies. Am J Med. 1994; 96:274-81. [IDIS 328041] [PubMed 8154516]

218. Schubert TT, Bologna SD, Yawer N et al. Ulcer risk factors: interaction between Helicobacter pylori infection, nonsteroidal use, and age. Am J Med. 1993; 94:413-7. [IDIS 314155] [PubMed 8475935]

219. Piper JM, Ray WA, Daugherty JR et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1991; 114:735-40. [IDIS 280191] [PubMed 2012355]

220. Bateman DN, Kennedy JG. Non-steroidal anti-inflammatory drugs and elderly patients: the medicine may be worse than the disease. BMJ. 1995; 310:817-8. [IDIS 345154] [PubMed 7711609]

221. Hawkey CJ. COX-2 inhibitors. Lancet. 1999; 353:307-14. [IDIS 418284] [PubMed 9929039]

222. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384:644-8. [PubMed 8967954]

223. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol. 1997; 75:1088-95. [PubMed 9365818]

224. DeWitt DL, Bhattacharyya D, Lecomte M et al. The differential susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs: aspirin derivatives as selective inhibitors. Med Chem Res. 1995; 5:325-43.

225. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase—a review. Prostaglandins Other Lipid Mediators. 1998; 56:341-61. [PubMed 9990677]

226. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med. 1999; 106(Suppl 5B):37-42S.

227. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999; 340:1888-99. [IDIS 426864] [PubMed 10369853]

228. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002;46:328-46.

229. Lanza FL, and the members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol. 1998; 93:2037-46. [IDIS 417402] [PubMed 9820370]

230. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999; 26(suppl 56):18-24.

231. in’t Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med. 2001; 345:1515-21. [PubMed 11794217]

232. Breitner JCS, Zandi PP. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer’s disease? N Engl J Med. 2001; 345:1567-8. Editorial.

233. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology. 1996; 47:425-32. [IDIS 371394] [PubMed 8757015]

234. Beard CM, Waring SC, O’sBrien PC et al. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease: a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc. 1998; 73:951-5. [IDIS 416502] [PubMed 9787743]

235. in’t Veld BA, Launer LJ, Hoes AW et al. NSAIDs and incident Alzheimer’s disease: the Rotterdam Study. Neurobiol Aging. 1998; 19:607-11. [PubMed 10192221]

236. Stewart WF, Kawas C, Corrada M et al. Risk of Alzheimer’s disease and duration of NSAID use. Neurology. 1997; 48:626-32. [IDIS 383303] [PubMed 9065537]

237. Pharmacia. Daypro (oxaprozin) caplets prescribing information. Chicago, IL; 2002 May.

238. Chan FKL, Hung LCT, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002; 347:2104-10. [IDIS 490812] [PubMed 12501222]

239. Graham DY. NSAIDs, Helicobacter pylori, and Pandora’s box. N Engl J Med. 2002; 347:2162-4. [IDIS 490815] [PubMed 12501230]

240. Ortho-McNeil Pharmaceuticals. Tolectin DS (tolmetin sodium) capsules and Tolectin 600 (tolmetin sodium) tablets prescribing information. Raritan, NJ; 2006 Feb.

241. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.

242. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology website (). Accessed 2005 Oct 12.

243. Novartis Pharmaceuticals. Diovan (valsartan) capsules prescribing information (dated 1997 Apr). In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:2013-5.

244. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296: 1633-44. [PubMed 16968831]

245. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006; 332: 1302-5. [PubMed 16740558]

246. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA. 2006; 296:1653-6. [PubMed 16968830]

247. Merck & Co. Clinoril (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.

248. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available at: .

a. AHFS Drug Information 2007. McEvoy GK, ed. Tolmetin. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2118-2122.

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Trifluoperazine Hydrochloride


Class: Phenothiazines
VA Class: CN701
Chemical Name: 10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine
Molecular Formula: C21H24F3N3S
CAS Number: 117-89-5

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.a e l m o

Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.a l m

Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).a m

Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.a e l

Antipsychotic agents, including trifluoperazine, are not approved for the treatment of dementia-related psychosis.a l m

Introduction

Propylpiperazine-derivative phenothiazine; conventional (prototypical, first-generation) antipsychotic agent.a b c

Uses for Trifluoperazine Hydrochloride Schizophrenia

Treatment of schizophrenia.a b c e

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).e APA considers conventional antipsychotic agents first-line in patients with acute psychotic episodes who have been treated successfully in the past with, or who prefer, conventional agents.e

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.e i p q

Nonpsychotic Anxiety

Short-term management of nonpsychotic anxiety in patients with generalized anxiety disorder.a b c

Not established whether trifluoperazine is useful for the management of other nonpsychotic conditions in which anxiety or manifestations that mimic anxiety are evident (e.g., physical illness, organic mental conditions, agitated depression, character pathologies).a b

Because of the risks of toxicity, use only as an alternative to other less toxic anxiolytic agents (e.g., benzodiazepines) in most patients.a b

Mental Retardation

Efficacy not established for the management of behavioral complications in patients with mental retardation.a b

Trifluoperazine Hydrochloride Dosage and Administration General

Adjust dosage carefully according to individual requirements and response; use the lowest possible effective dosage.a b c

For symptomatic relief of psychotic disorders, optimum therapeutic response usually occurs within 2–3 weeks.a b

Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued.a b c

Administration Oral Administration

Administered orally.a b c Has been given parenterally† as trifluoperazine hydrochloride, but a parenteral dosage form of the drug is no longer commercially available in the US.b

Because of the long duration of action, may be administered once or twice daily.a b

Dosage

Available as trifluoperazine hydrochloride; dosage expressed in terms of trifluoperazine.a b

Pediatric Patients Psychotic Disorders Oral

Adjust dosage based on weight and severity of symptoms.a b

Children 6–12 years of age: Initially, 1 mg once or twice daily for hospitalized or well-supervised children.a b Gradually increase dosage until symptoms are controlled or adverse effects become troublesome.a b Most children respond to a dosage of ?15 mg daily.a b

Dosage for children <6 years of age not established.a b

Adults Psychotic Disorders Oral

Initially, 2–5 mg given twice daily.a b Gradually increase dosage until symptoms are controlled or adverse effects become troublesome.a b Although most patients exhibit optimum response with 15–20 mg daily, dosages up to 40 mg or more daily may be required in some patients.a b e

Nonpsychotic Anxiety Oral

Usually, 1 or 2 mg twice daily for ?12 weeks.a b

Prescribing Limits Pediatric Patients Psychotic Disorders Oral

Maximum 15 mg daily for children 6–12 years of age.a b Dosages >15 mg daily should be used only in older children with severe symptoms.a b

Adults Nonpsychotic Anxiety Oral

Maximum 6 mg daily; do not administer for >12 weeks.a b

Special Populations Geriatric Patients

Generally, select dose at the lower end of recommended range; increase dosage more gradually and monitor closely.a b e (See Geriatric Use under Cautions.)

Debilitated or Emaciated Patients

Increase dosage more gradually.a b

Cautions for Trifluoperazine Hydrochloride Contraindications

Comatose states or in the presence of large amounts of CNS depressants (e.g., alcohol, barbiturates, opiates).a c (See Specific Drugs and Laboratory Tests under Interactions.)

Bone marrow depression or blood dyscrasias.a c

Liver damage.a c

Known hypersensitivity to phenothiazines.a c

Warnings/Precautions Warnings

Shares the toxic potentials of other phenothiazines; observe the usual precautions of phenothiazine therapy.a b

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.a e l m o

Antipsychotic agents, including trifluoperazine, are not approved for the treatment of dementia-related psychosis.a l m (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported with use of antipsychotic agents, including trifluoperazine.a c

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.a In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.a

APA recommends assessing patients receiving conventional antipsychotic agents for abnormal involuntary movements every 6 months; for patients at increased risk for tardive dyskinesia, assess every 3 months.e Consider discontinuance of trifluoperazine if signs and symptoms of tardive dyskinesia appear.a However, some patients may require treatment despite the presence of the syndrome.a

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents.a

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs.a Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.a

Concomitant Therapy with Lithium

Although most patients receiving lithium and an antipsychotic agent concurrently do not develop unusual adverse effects, an acute encephalopathic syndrome occasionally has occurred, especially when high serum lithium concentrations were present.a c (See Specific Drugs and Laboratory Tests under Interactions.)

Cognitive and Motor Impairment

May impair mental and/or physical abilities, especially during the first few days of therapy.a c (See Specific Drugs and Laboratory Tests under Interactions and see also Advice to Patients.)

Sensitivity Reactions

Possible sensitivity reactions (e.g., cholestatic jaundice, blood dyscrasias, skin reactions, photosensitivity).a c Use generally not recommended in patients who have previously demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) to a phenothiazine, unless potential benefits outweigh the possible risks.a c

Contact dermatitis occurs rarely following skin contact with trifluoperazine hydrochloride preparations; use care to avoid skin contact with preparations of the drug.a b c

General Precautions Hematologic Effects

Leukopenia, neutropenia, and agranulocytosis temporally related to antipsychotic agents, including trifluoperazine.a r s Thrombocytopenia, anemia, and pancytopenia also reported in patients receiving trifluoperazine.a r

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.r s Monitor CBC frequently during the first few months of therapy in patients with such risk factors.r Discontinue trifluoperazine at the first sign of a decline in WBC count in the absence of other causative factors.r

Carefully monitor patients with clinically important neutropenia for fever or other signs and symptoms of infection and treat promptly if they occur.r (See Advice to Patients.) In patients with severe neutropenia (ANC <1000/mm3), discontinue trifluoperazine and monitor WBC until recovery occurs.r

Hepatic Effects

Cholestatic jaundice or liver damage reported.a c

Perform hepatic function tests immediately in patients who develop fever accompanied by flu-like symptoms (e.g., nausea, vomiting, anorexia) during therapy; if hepatic function test results are abnormal, discontinue drug.a c

Cardiovascular Effects

Possible hypotension and exacerbation of angina; avoid large dosages in patients with cardiovascular disorders.a c If severe hypotension occurs, may use norepinephrine or phenylephrine to alleviate; epinephrine should not be used.a c (See Specific Drugs and Laboratory Tests under Interactions.)

Ocular Effects

Consider possibility of pigmentary retinopathy and lenticular and corneal deposits in patients receiving prolonged therapy.a c Periodic ophthalmic examinations recommended in patients receiving prolonged phenothiazine therapy with moderate to high dosages.a c Discontinue drug if ophthalmic examination or visual field studies demonstrate retinal changes.a c

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence).a c

If contemplating trifluoperazine therapy in patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.a

Mutagenicity

Chromosomal aberrations in spermatocytes and abnormal sperm have been demonstrated in rodents.a c

Body Temperature Regulation

Phenothiazines depress the hypothalamic mechanism for body temperature regulation; possible hyperthermia or hypothermia when exposed to temperature extremes.a c

Use with caution in patients exposed to extreme heat or cold.a c

Anticholinergic Effects

Possible anticholinergic effects (e.g., dry mouth, blurred vision, mydriasis, constipation, obstipation, nausea, adynamic ileus, atonic colon, urinary retention, decreased perspiration, impotence).a c

Use with caution in patients with glaucoma.a c

Other Precautions

Antiemetic effects may mask signs of overdosage of other drugs (e.g., antineoplastic agents) or obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).a c

Specific Populations Pregnancy

Category C.d

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.a h j k Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.a h j k

Lactation

Phenothiazines are distributed into milk.a c d Discontinue nursing or the drug.a c

Pediatric Use

Safety and efficacy not established in children <6 years of age.a b

Geriatric Use

Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents.a b c e

Common Adverse Effects

Extrapyramidal reactions (e.g., Parkinson-like symptoms, dystonia, akathisia), drowsiness, fatigue, muscular weakness, insomnia, blurred vision, skin reactions or rash, anorexia, dry mouth, hypotension, amenorrhea, galactorrhea.a b c e

Interactions for Trifluoperazine Hydrochloride Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Anticoagulants, oral

Potential decreased effect of oral anticoagulantsa

Anticonvulsants (e.g., phenytoin)

Trifluoperazine may lower seizure thresholda c

Trifluoperazine may interfere with phenytoin metabolism and precipitate phenytoin toxicitya

Dosage adjustments of anticonvulsants may be necessarya c

CNS depressants (e.g., alcohol, anesthetics, opiate analgesics, sedative/hypnotics)

Possible additive effects or potentiated action of other CNS depressantsa c

Use with caution to avoid excessive sedation or CNS depressiona c

Epinephrine

Possible further lowering of BPa c

Do not use epinephrine for phenothiazine-induced hypotensiona c (see Cardiovascular Effects under Cautions)

Guanethidine and related compounds

Potential for decreased effectiveness of guanethidine and related compoundsa

Lithium

An acute encephalopathic syndrome reported occasionally, especially when high serum lithium concentrations presenta c

Observe patients receiving combined therapy for evidence of adverse neurologic effects; promptly discontinue if such signs or symptoms appeara c

Propranolol

Increased plasma concentrations of trifluoperazine and propranolola

Test for phenylketonuria (PKU)

Potential false-positive test resultsa c

Thiazide diuretics

Potential for increased orthostatic hypotensiona

Trifluoperazine Hydrochloride Pharmacokinetics Absorption Bioavailability

Phenothiazines are generally well absorbed from the GI tract.c f Considerable interindividual variation in peak concentrations reported.c f g

Distribution Extent

Not fully characterized.c

Crosses the placenta.c d Distributed into breast milk.a c d

Plasma Protein Binding

Phenothiazines are highly bound to plasma proteins.c

Elimination Metabolism

Metabolic fate not fully elucidated.c f Appears to be extensively metabolized, principally in the liver.c f

Elimination Route

Phenothiazines and their metabolites are excreted in urine and feces.c

Half-life

12–24 hours.e f g

Stability Storage Oral Tablets

Tight, light-resistant containers at 20–25°C; protect from moisture.a

ActionsActions

Precise mechanism(s) of antipsychotic action not determined, but may be principally related to antidopaminergic effects.b c

Exhibits weak anticholinergic and sedative effects and strong extrapyramidal effects and antiemetic activity.b c

Advice to Patients

Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.a e l m Inform patients and caregivers that trifluoperazine is not approved for treating geriatric patients with dementia-related psychosis.a m

Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.a c

Importance of clinicians informing patients in whom chronic trifluoperazine use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.a c n Importance of informing patients to report any muscle movements that cannot be stopped.n

Importance of avoiding exposure to temperature extremes.a c

Importance of informing clinician if sore throat or other signs of infection occur.a c

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).a c

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a h Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).a h Importance of advising patients not to stop taking trifluoperazine if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.h

Importance of informing patients of other important precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Trifluoperazine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

1 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

2 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

5 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

10 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 07/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Trifluoperazine HCl 10MG Tablets (SANDOZ): 60/$55.99 or 180/$135.98

Trifluoperazine HCl 2MG Tablets (MYLAN): 60/$35.99 or 180/$85.97

Trifluoperazine HCl 5MG Tablets (SANDOZ): 60/$35.99 or 180/$98.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions June 13, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

HID. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:622-3.

a. Sandoz Inc. Trifluoperazine hydrochloride tablets prescribing information. Princeton, NJ; 2010 Sep.

b. AHFS drug information 2007. McEvoy GK, ed. Trifluoperazine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2457.

c. AHFS drug information 2007. McEvoy GK, ed. Phenothiazines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2439-50.

d. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia, PA: Williams & Wilkins; 2005:1626-7.

e. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161(Suppl):1-56.

f. Midha KK, Korchinski ED, Verbeeck RK et al. Kinetics of oral trifluoperazine disposition in man. Br J Clin Pharmacol. 1983; 15:380-2. [PubMed 6849769]

g. Midha KK, Hawes EM, Hubbard JW et al. A pharmacokinetic study of trifluoperazine in two ethnic populations. Psychopharmacol. 1988; 95:333-8.

h. US Food and Drug Administration. FDA drug safety communication: Antipsychotic drug labels updated in use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns.. Rockville, MD; 2010 Feb 22. From the FDA website: .

i. Lahti AC, Tamminga CA. Recent developments in the neuropharmacology of schizophrenia. Am J Health-Syst Pharm. 1995; 52(Suppl 1):S5-8. [PubMed 7749964]

j. Sexson WR, Barak Y. Withdrawal emergent syndrome in an infant associated with maternal haloperidol therapy. J Perinatol. 1989; 9:170-2. [PubMed 2738729]

k. Coppola D, Russo LJ, Kwarta RF Jr. et al. Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes. Drug Saf. 2007; 30:247-64. [PubMed 17343431]

l. Food and Drug Administration. Information for Healthcare Professionals: Conventional antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website: .

m. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website: ().

n. Food and Drug Administration. Patient information sheet: aripiprazole (marketed as Abilify). 2006 Sep 6.

o. Banerjee S. The use of antipsychotic medication for people with dementia: time for action. A report for the Minister of State for Care Services. United Kingdom Department of Health. From the website: .

p. Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother. 2009; 10:1917-28. [PubMed 19558339]

q. Lieberman JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry. 1996; 57(Suppl 11):68-71. [PubMed 8941173]

r. Mylan Pharmaceuticals Inc. Trifluoperazine hydrochloride tablets prescribing information. Morgantown, WV; 2010 Sep.

s. Qureshi SU, Rubin E. Risperidone- and aripiprazole-induced leukopenia: a case report. Prim Care Companion J Clin Psychiatry. 2008; 10:482-3. [PubMed 19287562]

More Trifluoperazine Hydrochloride resources Trifluoperazine Hydrochloride Side Effects (in more detail) Trifluoperazine Hydrochloride Dosage Trifluoperazine Hydrochloride Use in Pregnancy & Breastfeeding Drug Images Trifluoperazine Hydrochloride Drug Interactions Trifluoperazine Hydrochloride Support Group 3 Reviews for Trifluoperazine Hydrochloride - Add your own review/rating Trifluoperazine MedFacts Consumer Leaflet (Wolters Kluwer) Stelazine Concise Consumer Information (Cerner Multum) Compare Trifluoperazine Hydrochloride with other medications Anxiety Schizophrenia
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Levodopa/Carbidopa


Class: Dopamine Precursors
VA Class: CN500
CAS Number: 59-92-7
Brands: Lodosyn, Parcopa, Sinemet, Sinemet CR, Stalevo

Introduction

Antiparkinsonian; levodopa is the levorotatory isomer of dihydroxyphenylalanine and the metabolic precursor of dopamine, and carbidopa is a decarboxylase inhibitor that inhibits the peripheral decarboxylation of levodopa to dopamine.104 105 106 107 108

Uses for Levodopa/Carbidopa Parkinsonian Syndrome

Symptomatic treatment of idiopathic Parkinson’s disease (paralysis agitans), parkinsonian syndrome (postencephalitic parkinsonism), and symptomatic parkinsonism resulting from carbon monoxide intoxication and/or manganese intoxication.104 105 106 107 108

Levodopa is the most effective drug for relieving the symptoms of parkinsonian syndrome.d

Levodopa provides symptomatic relief (e.g., akinesia, rigidity, tremor); does not alter the disease course.d

Drug of choice in the management of idiopathic parkinsonian syndrome, especially in patients >70 years of age, those with cognitive impairment, and those with severe disease.101 103 d

Levodopa is used in conjunction with a decarboxylase inhibitor, carbidopa.104 105 106 107 108 Levodopa-carbidopa can be used alone or in conjunction with other antiparkinsonian drugs (e.g. ergot- and nonergot-derivative dopamine receptor agonists, catechol-O-methyltransferase [COMT] inhibitor, and/or selegiline).d 106

Drug-induced Extrapyramidal Effects

Not effective in the management of extrapyramidal effects† induced by antipsychotic agents (e.g., phenothiazines).d

Levodopa/Carbidopa Dosage and Administration Administration Oral Administration

Administer extended-release tablets as whole or half tablets; do not chew or crush.105

Just prior to administration of the orally disintegrating tablet, gently remove the tablet from the bottle with dry hands.104 Place tablet on tongue to dissolve (usually within seconds) and swallow with saliva.104

Administration of orally disintegrating tablet with water is not necessary.104

Do not divide the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo); administer only one tablet per dosing interval.106

Dosage

Dosage expressed in terms of levodopa and carbidopa.104 105 106 107 108

Available in combination products containing a 1:4 or 1:10 ratio of carbidopa to levodopa.104 105 106 107 Additional carbidopa can be administered separately if a higher carbidopa dosage than is available in the combination preparations is needed.108 The treatment regimen can include levodopa-carbidopa extended-release tablets, conventional tablets, and orally disintegrating tablets and carbidopa tablets based on individual requirements.104 105 107 108 Levodopa no longer is commercially available in the US as a single-entity preparation.d

Also available as a fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo); available in a 1:4 ratio of carbidopa to levodopa.106 Used if optimum maintenance dosage of the 3 drugs corresponds to the dosage in the combination preparation.106 No experience transferring patients receiving levodopa-carbidopa extended-release tablets or levodopa-carbidopa preparations containing the 1:10 ratio.106

For some patients (maintenance levodopa dosage ?600 mg daily, no dyskinesias), the fixed combination containing levodopa, carbidopa, and entacapone (Stalevo) can be used when initiating entacapone therapy if optimum maintenance dosage of levodopa-carbidopa corresponds to dosage in the combination preparation.106

Adjust levodopa-carbidopa dosage carefully according to individual requirements, response, and tolerance.104 105 106 107 108

Dosage adjustment may be needed when other antiparkinsonian drugs are added to or discontinued from the regimen.104 105 106 107 108

Daily dosage of carbidopa should be at least 70–100 mg daily; patients receiving <70–100 mg daily are likely to experience nausea and vomiting.104 105 107 108 d

Observe patient closely if dosage is reduced abruptly or the drug is discontinued; risk of precipitating a symptom complex resembling neuroleptic malignant syndrome (NMS).104 105 106 107 (See Neuroleptic Malignant Syndrome under Cautions.)

If general anesthesia required, continue therapy as long as patient permitted to take oral medications; resume as soon as patient is able to take oral medication.104 105 106 107 If therapy interrupted, observe for NMS.104 105 106 107 (See Neuroleptic Malignant Syndrome under Cautions.)

Adults Parkinsonian Syndrome Levodopa-Carbidopa Conventional Tablets or Orally Disintegrating Tablets Oral

Initially, levodopa 100 mg/carbidopa 25 mg (as 1 tablet) 3 times daily.104 107 109

Increase dosage by levodopa 100 mg/carbidopa 25 mg (1 tablet) daily or every other day until a daily dosage of levodopa 800 mg/carbidopa 200 mg is reached or adverse effects prevent further increases or necessitate discontinuance.104 107 109 d

Alternatively, initiate with levodopa 100 mg/carbidopa 10 mg (as 1 tablet) 3 or 4 times daily; this dosage will not provide an adequate dose of carbidopa for most patients.104 107 109 Increase dosage by levodopa 100 mg/carbidopa 10 mg (1 tablet) daily or every other day until a daily dosage of levodopa 800 mg/carbidopa 80 mg is reached.104 107 109

Levodopa-Carbidopa Extended-release Tablets Oral

Initially, levodopa 200 mg/carbidopa 50 mg (as 1 extended-release tablet) twice daily; initial dosage should not be given at intervals <6 hours.105 Adjust dosage based on response and tolerance at intervals ?3 days.105 Most patients are treated adequately with levodopa 400 mg to 1.6 g daily and carbidopa 100–400 mg daily, administered in divided doses at intervals ranging from 4–8 hours while awake.105 Higher dosages (levodopa 2.4 g/carbidopa 600 mg) and shorter intervals (<4 hours) have been used but usually are not recommended.105 If the dosing interval is <4 hours and/or the divided doses are not equal, the smaller doses can be given at the end of the day.105

Dosage may be initiated, titrated, and stabilized initially with conventional (immediate-release) tablets.105 107

Transfer to extended-release tablets: initial dosage should provide 10% more levodopa daily than dosage previously received as conventional tablets; levodopa dosage may need to be increased up to 30% more daily, depending on response.105 (See Bioavailability under Pharmacokinetics.)

Carbidopa

Carbidopa: 25 mg with first dose of levodopa/carbidopa each day for patients who need additional carbidopa; additional 12.5- or 25-mg doses may given during the day with each dose of levodopa/carbidopa.108

Prescribing Limits Adults Parkinsonian Syndrome Oral

Experience with carbidopa dosages >200 mg daily limited.104 105 107 108

If fixed-combination preparations containing levodopa 50–150 mg, carbidopa 12.5–37.5 mg, and entacapone 200 mg (Stalevo 50, 75, 100, 125, and 150) are used, maximum of 8 tablets daily.106

If fixed-combination preparation containing levodopa 200 mg, carbidopa 50 mg, and entacapone 200 mg (Stalevo 200) is used, maximum of 6 tablets daily.106

Cautions for Levodopa/Carbidopa Contraindications

Concomitant use with a nonselective MAO inhibitor.104 105 106 107 (See Specific Drugs and Foods under Interactions.)

Angle-closure glaucoma.104 105 106 107 d

Known hypersensitivity to levodopa, carbidopa, or any ingredient in the formulation.104 105 106 107

Malignant melanoma, history of melanoma, or suspicious undiagnosed skin lesions.104 105 106 107

Warnings/Precautions Warnings Nervous System and Muscular Effects

Therapy associated with dyskinesias; dosage reduction may be needed.104 105 106 107

Mental disturbances reported.104 105 106 107 d Observe patients for depression with concomitant suicidal tendencies.104 105 106 107 d Use with caution in patients with current or past psychoses.104 105 106 107 d

Bradykinetic Episodes

“On-off” phenomenon: Sudden loss of effectiveness with abrupt onset of akinesia (“off” effect; persists 1–60 minutes) followed by sudden return of effectiveness (“on” effect); may recur many times daily and respond to increased dosing frequency.d

Akinesia Paradoxica (“start hesitation”): Sudden hypotonic freezing (patient falls frequently while attempting to walk); may respond to decreased dosage.d

Cardiovascular Effects

Risk of orthostatic hypotension; usually asymptomatic and tolerance usually develops within a few months.d

Use with care in patients with a history of MI who have residual atrial, nodal, or ventricular arrhythmias; monitor cardiac function in a facility with intensive cardiac care immediately available during the initial dosage adjustment.104 105 106 107 d

Use with caution in patients with severe cardiovascular disease.104 105 106 107 d

Respiratory Effects

Caution in patients with pulmonary disease (e.g., emphysema) or asthma who may require use of sympathomimetics.104 105 106 107 d

GI Effects

Use with caution in patients with a history of peptic ulcers; possibility of upper GI hemorrhage in these patients.d 104 105 106 107

Neuroleptic Malignant Syndrome (NMS)

Symptom complex resembling NMS reported following dosage reduction or abrupt withdrawal of levodopa.104 105 106 107 d

Observe closely when dosage is reduced or the drug discontinued; especially important in patients receiving concomitant therapy with an antipsychotic agent.d 104 105 106 107

General Precautions

Evaluate hepatic, hematopoietic, cardiovascular, and renal function periodically.d 104 105 106 107

Use of Fixed Combinations

When the fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo) is used, observe the usual precautions and contraindications associated with all drugs in the preparation.106

Glaucoma

Can be used with caution in patients with well-controlled open-angle glaucoma; monitor IOP.104 105 106 107 d (See Contraindications under Cautions.)

Endocrine Disorders

Use with caution.104 105 106 107

Closely monitor diabetic patients; levodopa may affect glycemic control.d

Somnolence

Possible somnolence and, very rarely, episodes of sudden onset of sleep, sometimes occurring without the patient’s awareness or without warning during daily activities.105 107

Patients must be informed of this risk; advise patients that they should exercise caution while driving or operating machinery and that they must refrain from such activities if they experience somnolence and/or an episode of sudden sleep onset.105 107

Melanoma

Epidemiologic studies indicate patients with parkinsonian syndrome have a twofold to approximately sixfold higher risk of developing melanoma than the general population.105 106 107 Unclear whether increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease).105 106 107

Monitor for melanoma on a frequent and regular basis.105 106 107 Manufacturer recommends periodic skin examinations performed by appropriately qualified individuals (e.g., dermatologists).105 106 107

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including levodopa-carbidopa).105 106 107 Although causal relationship not established, urges stopped in some cases when dosage was reduced or drug was discontinued.105 106 107

Consider reducing dosage or discontinuing levodopa-carbidopa if a patient develops such urges.105 106 107

Phenylketonuria

Levodopa-carbidopa orally disintegrating tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to phenylalanine.104 110 111 112 113 114

Specific Populations Pregnancy

Category C.104 105 106 107

Lactation

Carbidopa is distributed into milk in rats;106 not known whether carbidopa distributes into human milk.108 Distribution of levodopa into human milk reported in at least one nursing woman.105 107 Caution advised.104 105 106 107

Pediatric Use

Safety and efficacy not established in children <18 years of age.104 105 106 107

Common Adverse Effects

Dyskinesias (choreiform, dystonic, other adventitious movements), nausea.104 105 106 107

Interactions for Levodopa/Carbidopa Specific Drugs and Foods

Drug or Food

Interaction

Comments

Anesthetics, general (cyclopropane, halogenated hydrocarbon general anesthetics)

Potential for cardiac arrhythmias with these anesthetic agentsd

Use alternative anesthetic agentsd

Anticholinergic agents

Potential for decreased tremor and/or exacerbation of abnormal involuntary movements104 105 106 107 d

Possible delay in levodopa absorption and increase in gastric metabolism of levodopad

Antidepressants, tricyclic

Potential for hypertension and dyskinesia104 105 106 107

Use concomitantly with cautiond

Antipsychotic agents (phenothiazines, butyrophenones, risperidone)

Possible reduction in the therapeutic effects of levodopa104 105 106 107

Possible increased risk of NMS104 105 106 107 (see Neuroleptic Malignant Syndrome under Cautions)

Observe patient for loss of therapeutic effect104 105 106 107

Benzodiazepines

Possible reduction in the therapeutic effects of levodopa with chlordiazepoxide or diazepamd

Use concomitantly with cautiond

Hypotensive agents

Potential for symptomatic postural hypotension104 105 106 107

Potential for toxic CNS effects such as psychosis with methyldopad

Dosage adjustment of the hypotensive agent may be needed104 105 106 107

Iron preparations

Decreased absorption of levodopa and carbidopa104 105 106 107

Clinical importance unknown104 105 106 107

Isoniazid

Possible reduction in the therapeutic effects of levodopa104 105 106 107

Observe patient for loss of therapeutic effect104 105 106 107

MAO inhibitors

Potential for hypertension, headache, hyperexcitability with nonselective MAO inhibitorse

Possible severe orthostatic hypotension with selegiline104 105 106 107

Contraindicated with nonselective MAO inhibitors;104 105 106 107 discontinue nonselective MAO inhibitor at least 2 weeks prior to initiation of levodopa104 105 106 107

May be administered concomitantly with a selective MAO inhibitor (e.g., selegiline) with caution104 105 106 107

Metoclopramide

Possible increase in bioavailability of levodopa104 105 106 107

Possible reduction in the therapeutic effects of levodopa104 105 106 107

Papaverine

Possible reduction in the therapeutic effects of levodopa104 105 106 107

Observe patient for loss of therapeutic effect104 105 106 107

Phenytoin

Possible reduction in the therapeutic effects of levodopa104 105 106 107

Observe patient for loss of therapeutic effect104 105 106 107

Protein

High protein diet may impair absorption104 105 106 107

Levodopa/Carbidopa Pharmacokinetics Absorption Bioavailability

Well absorbed from the GI tract; peak plasma levodopa concentrations achieved within 0.5 or 2 hours following administration of conventional tablets or extended-release tablets, respectively.105

Bioavailability of levodopa from extended-release tablets 70–75% of that from conventional tablets.105

Extended-release tablets result in less fluctuation in plasma concentrations between doses than conventional tablets.105

Levodopa-carbodopa conventional tablets and orally disintegrating tablets begin to release the drugs within 30 minutes of administration.104 107 109 Pharmacokinetic values for orally disintegrating tablet are similar to those for the conventional tablet.109

Food

High protein diet may interfere with absorption of levodopa.104 105 106 107

Extended-release tablets: Food increases bioavailability and peak plasma concentrations of levodopa.105

Distribution Extent

Widely distributed.d

<1% of levodopa penetrates the CNS;d carbidopa does not cross the blood-brain barrier.104 105 106 107

Plasma Protein Binding

Levodopa: 10–30%.106

Carbidopa: About 36%.106 d

Elimination Metabolism

Levodopa is metabolized in the stomach and intestine and on first pass through the liver; absorbed levodopa decarboxylated to dopamine.d

Carbidopa inhibits peripheral decarboxylation of levodopa, thus increasing availability of levodopa for distribution into the CNS.104 105 106 107

Elimination Route

Levodopa is excreted in urine as metabolites.d

Half-life

Levodopa: 1.5 hours when administered with carbidopa.104 105

Stability Storage Oral Conventional Tablets

25°C (may be exposed to 15–30°C).106 107 108 Protect from light.107

Extended-release Tablets

Tight container; <30°C.105

Orally Disintegrating Tablets

Tight, light-resistant container; 20–25°C (may be exposed to 15–30°C).104

ActionsActions

Manifestations of parkinsonian syndrome related to depletion of dopamine in the corpus striatum.104 105 106 107

Levodopa relieves symptoms of parkinsonism presumably by increasing dopamine concentrations in the brain.104 105 106 107

Advice to Patients

Importance of taking levodopa/carbidopa at regular intervals as scheduled by the clinician.104 105 106 107 Importance of not altering the prescribed dosage regimen or adding other antiparkinsonian drugs.104 105 106 107

Advise patient not to chew or crush extended-release tablets; however, tablets may be halved.105

For patients taking orally disintegrating tablets, advise to gently remove the tablet from the bottle with dry hands just before administering a dose and then placing the tablet on the tongue to dissolve and be swallowed with saliva.104

Importance of informing patients with phenylketonuria that the orally disintegrating tablets contain aspartame.104

Advise patient to notify clinician if abnormal involuntary movements appear or get worse; dosage adjustment may be needed.104 105 106 107

Advise patient of expected onset and duration of effect.104 105 106 107

Possibility that dark color (red, brown, black) may appear in saliva, urine, or sweat; garments may be discolored.104 105 106 107

Advise patient that a change in diet to food high in protein may delay absorption of levodopa and reduce systemic availability.104 105 106 107 Excess acidity may delay absorption.104 105 106 107

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.104 105 106 107

Risk of somnolence and episodes of sudden sleep onset; importance of exercising caution when driving or operating machinery and of refraining from such activities if somnolence and/or an episode of sudden sleep onset occurs.105 107

Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving levodopa-carbidopa and of advising them of the importance of reporting such urges.105 106 107

Importance of frequent monitoring for melanoma and periodic dermatologic examinations by a dermatologist.105 106 107

Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.104 105 106 107

Importance of advising patients of other important precautionary information.104 105 106 107 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Carbidopa

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg (of anhydrous carbidopa)

Lodosyn (scored)

Bristol-Myers Squibb

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Carbidopa-Levodopa (Co-careldopa)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

Carbidopa 10 mg (of anhydrous carbidopa) and Levodopa 100 mg*

Carbidopa and Levodopa Tablets

Sinemet (scored)

Bristol-Myers Squibb

Carbidopa 25 mg (of anhydours carbidopa) and Levodopa 100 mg*

Carbidopa and Levodopa Tablets

Sinemet (scored)

Bristol-Myers Squibb

Carbidopa 25 mg (of anhydrous carbidopa) and Levodopa 250 mg*

Carbidopa and Levodopa Tablets

Sinemet (scored)

Bristol-Myers Squibb

Tablets, extended-release

Carbidopa 50 mg (of anhydrous carbidopa) and Levodopa 200 mg*

Carbidopa and Levodopa Extended-release Tablets

Sinemet CR (scored)

Bristol-Myers Squibb

Carbidopa 25 mg (of anhydrous carbidopa) and Levodopa 100 mg*

Carbidopa and Levodopa Extended-release Tablets (scored)

Sinemet CR

Bristol-Myers Squibb

Tablets, orally disintegrating

Carbidopa 10 mg (of anhydrous carbidopa) and Levodopa 100 mg

Parcopa (scored)

Azur

Carbidopa 25 mg (of anhydrous carbidopa) and Levodopa 100 mg

Parcopa (scored)

Azur

Carbidopa 25 mg (of anhydrous carbidopa) and Levodopa 250 mg

Parcopa (scored)

Azur

Other Carbidopa Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Carbidopa 12.5 mg (of anhydrous carbidopa) with Entacapone 200 mg and Levodopa 50 mg

Stalevo

Novartis

Carbidopa 18.75 mg (of anhydrous carbidopa) Entacapone 200 mg and Levodopa 75 mg

Stalevo

Novartis

Carbidopa 25 mg (of anhydrous carbidopa) with Entacapone 200 mg and Levodopa 100 mg

Stalevo

Novartis

Carbidopa 31.25 mg (of anhydrous carbidopa) Entacapone 200 mg and Levodopa 125 mg

Stalevo

Novartis

Carbidopa 37.5 mg (of anhydrous carbidopa) with Entacapone 200 mg and Levodopa 150 mg

Stalevo

Novartis

Carbidopa 50 mg (of anhydrous carbidopa) Entacapone 200 mg and Levodopa 200 mg

Stalevo

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Carbidopa-Levodopa 10-100MG Tablets (TEVA PHARMACEUTICALS USA): 90/$34.99 or 180/$65.97

Carbidopa-Levodopa 25-100MG Tablets (ACTAVIS ELIZABETH): 90/$39.98 or 270/$101.98

Carbidopa-Levodopa 25-250MG Tablets (TEVA PHARMACEUTICALS USA): 60/$33.99 or 180/$82.98

Carbidopa-Levodopa CR 25-100MG Controlled-release Tablets (MYLAN): 60/$40.99 or 180/$116.98

Carbidopa-Levodopa CR 50-200MG Controlled-release Tablets (MYLAN): 60/$80.99 or 180/$221.98

Parcopa 25-100MG Dispersible Tablets (AZUR PHARMA): 30/$97.64 or 90/$234.33

Sinemet 10-100MG Tablets (MERCK SHARP &amp; DOHME): 90/$91.16 or 270/$256.57

Sinemet 25-100MG Tablets (MERCK SHARP &amp; DOHME): 90/$113.41 or 270/$305.96

Sinemet 25-250MG Tablets (MERCK SHARP &amp; DOHME): 60/$88.99 or 180/$255.97

Sinemet CR 25-100MG Controlled-release Tablets (MERCK SHARP &amp; DOHME): 60/$78.99 or 180/$225.96

Sinemet CR 50-200MG Controlled-release Tablets (MERCK SHARP &amp; DOHME): 60/$145.5 or 180/$417.26

Stalevo 100 25-100-200MG Tablets (NOVARTIS): 90/$318 or 270/$898.92

Stalevo 150 37.5-150-200MG Tablets (NOVARTIS): 30/$113.99 or 90/$334.97

Stalevo 200 50-200-200MG Tablets (NOVARTIS): 100/$363.99 or 300/$1043.97

Stalevo 50 12.5-50-200MG Tablets (NOVARTIS): 30/$110.98 or 90/$317.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 01, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

101. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology. 2001; 56:S1-S88.

102. Chong BS, Mersfelder TL. Entacapone. Ann Pharmacother. 2000; 34:1056-65. [IDIS 452302] [PubMed 10981253]

103. Anon. Initial treatment of Parkinson’s disease: wait just a minute. Med Lett Drugs Ther. 2001; 43:59-60. [PubMed 11445778]

104. Azur Pharma. Parcopa (carbidopa-levodopa) orally disintegrating tablets prescribing information. Philadelphia, PA; 2009 Sep.

105. Bristol-Myers Squibb. Sinemet CR (carbidopa-levodopa) sustained-release tablets prescribing information. Princeton, NJ; 2009 Jan.

106. Novartis. Stalevo 50, Stalevo 75, Stalevo 100, Stalevo 125, Stalevo 150, Stalevo 200 (carbidopa, levodopa and entacapone) tablets prescribing information. East Hanover, NJ; 2009 Mar.

107. Bristol-Myers Squibb. Sinemet (carbidopa-levodopa) tablets prescribing information. Princeton, NJ; 2009 Jan.

108. Bristol-Myers Squibb. Lodosyn (carbidopa) tablets prescribing information. Princeton, NJ; 2006 Sep.

109. Anon. Parcopa: a rapidly dissolving formulation of carbidopa/levodopa. Med Lett Drugs Ther. 2005; 47:12.

110. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA. 1985; 254:400 2. [IDIS 202002] [PubMed 2861297]

111. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm. 1984; 9:26,28 30.

112. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist. 1983; 48:54993 5. (lDIS 178728)

113. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376 82. (IDIS 172957)

114. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. 1982; 24:1 2. [PubMed 7054648]

d. AHFS drug information 2004. McEvoy GK, ed. Levodopa/carbidopa. Bethesda, MD: American Society of Health-System Pharmacists; 2005:2485-90.

e. AHFS drug information 2004. McEvoy GK, ed. Monoamine Oxidase Inhibitors General Statement. Bethesda, MD: American Society of Health-System Pharmacists; 2005:2174-80.

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Cystagon 50 mg hard capsules


1. Name Of The Medicinal Product

CYSTAGON 50 mg hard capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains 50 mg of cysteamine (as mercaptamine bitartrate) .

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard Capsule

White, opaque hard capsules with CYSTA 50 on the body and MYLAN on the cap.

4. Clinical Particulars 4.1 Therapeutic Indications

CYSTAGON is indicated for the treatment of proven nephropathic cystinosis. Cysteamine reduces cystine accumulation in some cells (e.g. leukocytes, muscle and liver cells) of nephropathic cystinosis patients and, when treatment is started early, it delays the development of renal failure.

4.2 Posology And Method Of Administration

CYSTAGON treatment should be initiated under the supervision of a physician experienced in the treatment of cystinosis.

The goal of therapy is to keep leucocyte cystine levels below 1 nmol hemicystine/mg protein. White blood cell (WBC) cystine levels should therefore be monitored to adjust the dose. The WBC levels should be measured 5 to 6 hours after dosing and should be checked frequently when initiating therapy (e.g. monthly) and every 3-4 months when on a stable dose.

For children up to age 12 years, CYSTAGON dosing should be on the basis of body surface area (g/m2/day). The recommended dose is 1.30 g/m2/day of the free base divided four times daily.

For patients over age 12 and over 50 kg weight, the recommended CYSTAGON dose is 2 g/day, divided four times daily.

Starting doses should be 1/4 to 1/6 of the expected maintenance dose, increased gradually over 4-6 weeks to avoid intolerance. The dose should be raised if there is adequate tolerance and the leucocyte cystine level remains>1 nmol hemicystine/mg protein. The maximum dose of CYSTAGON used in clinical trials was 1.95 g/m2/day.

The use of doses higher than 1.95 g/m2/day is not recommended (see section 4.4).

Digestive tolerance of cysteamine is improved when the medicinal product is taken just after or with food.

In children who are at risk of aspiration, aged approximately 6 years and under, the hard capsules should be opened and the content sprinkled on food. Experience suggests that foods such as milk, potatoes and other starch based products seem to be appropriate for mixing with the powder. However, acidic drinks, e.g. orange juice, should generally be avoided as the powder tends not to mix well and may precipitate out.

Patients on dialysis or post-transplantation:

Experience has occasionally shown that some forms of cysteamine are less well tolerated (i.e.leading to more adverse events) when patients are on dialysis. A closer monitoring of the leucocyte cystine levels is recommended in these patients.

Patients with hepatic insufficiency:

Dose adjustment is not normally required; however, leucocyte cystine levels should be monitored.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients

The use of CYSTAGON is contra-indicated during breast-feeding. CYSTAGON should not be used during pregnancy, particularly during the first trimester, unless clearly necessary (see section 4.6 and section 5.3 as it is teratogenic in animals.

CYSTAGON is contraindicated in patients who have developed hypersensitivity to penicillamine.

4.4 Special Warnings And Precautions For Use

CYSTAGON therapy must be initiated promptly after confirmation of the diagnosis of nephropathic cystinosis to achieve maximum benefit.

Nephropathic cystinosis must have been diagnosed by both clinical signs and biochemical investigations (leucocyte cystine measurements).

A few cases of Ehlers-Danlos like syndrome on elbows have been reported in children treated with high doses of different cysteamine preparations (cysteamine chlorhydrate or cystamine or cysteamine bitartrate) mostly above the maximal dose 1.95 g/m2/day. These skin lesions were associated with skin striae and bone lesions first seen during an X-ray examination.

It is therefore recommended to monitor regularly skin and to consider X-ray examinations of the bone as necessary. Self-examination of the skin by the patient or the parents should also be advised. If any similar skin or bone abnormalities appear, it is recommended to decrease the dose of CYSTAGON.

The use of doses higher than 1.95g/m2/day is not recommended (see sections 4.2 and 4.8).

Monitoring of blood cell count is recommended on a regular basis.

Oral cysteamine has not been shown to prevent eye deposition of cystine crystals. Therefore, where cysteamine ophthalmic solution is used for that purpose, its usage should continue.

In contrast to phosphocysteamine, CYSTAGON does not contain phosphate. Most patients will already be receiving phosphate supplements and the dose of these may need to be altered when CYSTAGON is substituted for phosphocysteamine.

Intact CYSTAGON hard capsules should not be administered to children under the age of approximately 6 years due to risk of aspiration (see section 4.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed

CYSTAGON can be administered with electrolyte and mineral replacements necessary for management of the Fanconi syndrome as well as vitamin D and thyroid hormones. Indomethacin and CYSTAGON have been used simultaneously in some patients. In cases of patients with kidney transplants, anti-rejection treatments have been used with cysteamine.

4.6 Pregnancy And Lactation

There are no adequate data from the use of cysteamine bitartrate in pregnant women. Studies in animals have shown reproductive toxicity, including teratogenesis (see section 5.3). The potential risk for humans is unknown. The effect on pregnancy of untreated cystinosis is also unknown.

Therefore, CYSTAGON should not be used during pregnancy, particularly during the first trimester, unless clearly necessary.

If a pregnancy is diagnosed or planned, the treatment should be carefully reconsidered and the patient must be advised of the possible teratogenic risk of cysteamine.

CYSTAGON excretion in human's milk is unknown. However, due to the results of animal studies in breast-feeding mothers and neonates (see section 5.3), breast-feeding is contraindicated in women taking CYSTAGON.

4.7 Effects On Ability To Drive And Use Machines

CYSTAGON has minor or moderate influence on the ability to drive and use machines

CYSTAGON may cause drowsiness. When starting therapy, patients should not engage in potentially hazardous activities until the effects of the medicinal product on each individual are known.

4.8 Undesirable Effects

Approximately 35% of patients can be expected to experience adverse reactions. These mainly involve the gastrointestinal and central nervous systems. When these effects appear at the initiation of cysteamine therapy, temporary suspension and gradual reintroduction of treatment may be effective in improving tolerance.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriouness

Investigations

Common : Liver function tests abnormal

Blood and lymphatic system disorders

Uncommon : Leukopenia

Nervous system disorders

Common : Headache, encephalopathy

Uncommon : Somnolence, convulsions

Gastrointestinal disorders

Very common : Vomiting, nausea, diarrhoea

Common : Abdominal pain, breath odour, dyspepsia, gastroenteritis

Uncommon : Gastrointestinal ulcer

Renal and urinary disorders

Uncommon : Nephrotic syndrome

Skin and subcutaneous tissue disorders

Common : Skin odour abnormal, rash

Uncommon : Hair colour changes, skin striae, skin fragility (molluscoid pseudotumor on elbows)

Musculoskeletal and connective tissue disorders

Uncommon : Joint hyperextension, leg pain, genu valgum, osteopenia, compression fracture, scoliosis.

Metabolism and nutrition disorders

Very common : Anorexia

 

 

 

General disorders and administration site conditions

Very common : Lethargy, pyrexia

Common : Asthenia

Immune system disorders

Uncommon : Anaphylactic reaction

Psychiatric disorders

Uncommon : Nervousness, hallucination

Two cases of nephrotic syndrome have been reported within 6 months of starting therapy with progressive recovery after treatment discontinuation. Histology showed a membranous glomerulonephritis of the renal allograft in one case and hypersensitivity interstitial nephritis in the other.

A few cases of Ehlers-Danlos like syndrome on elbows have been reported in children chronically treated with high doses of different cysteamine preparations (cysteamine chlorhydrate or cystamine or cysteamine bitartrate) mostly above the maximal dose 1.95 g/m2/day.

In some cases, these skin lesions were associated with skin striae and bone lesions first seen during an X-ray examination. Bone disorders reported were genu valgum, leg pain and hyperextensive joints, osteopenia, compression fractures, and scoliosis.

In the few cases where histopathological examination of the skin was performed, the results suggested angioendotheliomatosis.

One patient subsequently died of acute cerebral ischemia with marked vasculopathy.

In some patients, the skin lesions on elbows regressed after CYSTAGON dose reduction.

Cysteamine mechanism of action by interfering with the cross-linking of collagen fibers has been postulated (see section 4.4).

4.9 Overdose

An overdose of cysteamine may cause progressive lethargy.

Should overdosage occur, the respiratory and cardiovascular systems should be supported appropriately. No specific antidote is known. It is not known if cysteamine is removed by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Alimentary tract and metabolism product, ATC code: A16AA04.

Normal individuals and heterozygous subjects for cystinosis have white cell cystine levels of < 0.2, and usually below 1 nmol hemicystine/mg protein, respectively. Individuals with nephropathic cystinosis have elevations of white cell cystine above 2 nmol hemicystine/mg protein

Cysteamine reacts with cystine to form the mixed disulfide of cysteamine and cysteine, and cysteine. The mixed disulfide is then exported from the lysosomes by an intact lysine transport system. The decrease in leucocyte cystine levels is correlated to the cysteamine plasma concentration over the six hours following the administration of CYSTAGON.

The leucocyte cystine level reaches its minimum (mean (± sd) value: 1.8 ± 0.8 hours) slightly later than the peak plasma cysteamine concentration (mean (± sd) value: 1.4 ± 0.4 hours) and returns to its baseline level as the plasma cysteamine concentration decreases at 6 hours post-dose.

In one clinical study, baseline white cell cystine levels were 3.73 (range 0.13 to 19.8) nmol hemicystine/mg protein and were maintained close to 1 nmol hemicystine/mg protein with a cysteamine dose range of 1.3 to 1.95 g/m2/day.

An earlier study treated 94 children with nephropathic cystinosis with increasing doses of cysteamine to attain white cell cystine levels of less than 2 nmol hemicystine/mg protein 5 to 6 hours post-dose, and compared their outcome with an historical control group of 17 children treated with placebo. The principal efficacy measurements were serum creatinine and calculated creatinine clearance and growth (height). The mean white cell cystine level attained during treatment was 1.7 + 0.2 nmol hemicystine/mg protein. Among cysteamine patients, glomerular function was maintained over time. Placebo treated patients, in contrast, experienced a gradual rise in serum creatinine. Patients on treatment maintained growth as compared to untreated patients. However, growth velocity did not increase enough to allow patients to catch up the normal for their age. Renal tubular function was not affected by treatment. Two other studies have shown similar results.

In all studies, patient response was better when treatment was started at an early age with good renal function.

5.2 Pharmacokinetic Properties

Following a single oral dose of cysteamine bitartrate equivalent to 1.05 g of cysteamine free base in healthy volunteers, the mean (± sd) values for the time to peak and peak plasma concentration are 1.4 (± 0.5) hours and 4.0 (± 1.0) µg/ml, respectively. In patients at steady state, these values are 1.4 (± 0.4) hours and 2.6 (± 0.9) µg/ml, respectively, after a dose ranging from 225 to 550 mg.

Cysteamine bitartrate (CYSTAGON) is bioequivalent to cysteamine hydrochloride and phosphocysteamine.

The in vitro plasma protein binding of cysteamine, which is mostly to albumin, is independent of plasma drug concentration over the therapeutic range, with a mean (± sd) value of 54.1 % (± 1.5). The plasma protein binding in patients at steady state is similar: 53.1 % (± 3.6) and 51.1 % (± 4.5) at 1.5 and 6 hours post-dose, respectively.

In a pharmacokinetic study performed in 24 healthy volunteers for 24 hours, the mean estimate (± sd) for the terminal half-life of elimination was 4.8 (± 1.8) hours.

The elimination of unchanged cysteamine in the urine has been shown to range between 0.3 % and 1.7% of the total daily dose in four patients; the bulk of cysteamine is excreted as sulphate.

Very limited data suggest that cysteamine pharmacokinetic parameters may not be significantly modified in patients with mild to moderate renal insufficiency. No information is available for patients with severe renal insufficiency.

5.3 Preclinical Safety Data

Genotoxicity studies have been performed: although in published studies using cysteamine, induction of chromosome aberrations in cultured eukaryotic cell lines has been reported, specific studies with cysteamine bitartrate did not show any mutagenic effects in the Ames test or any clastogenic effect in the mouse micronucleus test.

Reproduction studies showed embryofoetotoxic effects (resorptions and post-implantation losses) in rats at the 100 mg/kg/day dose level and in rabbits receiving cysteamine 50 mg/kg/day. Teratogenic effects have been described in rats when cysteamine is administered over the period of organogenesis at a dose of 100 mg/kg/day.

This is equivalent to 0.6 g/m2/day in the rat, which is less than half the recommended clinical maintenance dose of cysteamine, i.e. 1.30 g/ m2/day. A reduction of fertility was observed in rats at 375 mg/kg/day, a dose at which body weight gain was retarded. At this dose, weight gain and survival of the offspring during lactation was also reduced. High doses of cysteamine impair the ability of lactating mothers to feed their pups. Single doses of the drug inhibit prolactin secretion in animals. Administration of cysteamine in neonate rats induced cataracts.

High doses of cysteamine, either by oral or parenteral routes, produce duodenal ulcers in rats and mice but not in monkeys. Experimental administration of the drug causes depletion of somatostatin in several animal species. The consequence of this for the clinical use of the drug is unknown.

No carcinogenic studies have been conducted with CYSTAGON.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Capsule content:

microcrystalline cellulose,

pregelatinized starch,

magnesium stearate/sodium lauryl sulfate,

colloidal silicon dioxide,

croscarmellose sodium

Capsule shell:

gelatin,

titanium dioxide,

black ink on hard capsules containing E172

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep the container tightly closed in order to protect from light and moisture.

6.5 Nature And Contents Of Container

HDPE bottles of 100 and 500 hard capsules. A desiccant unit containing black activated carbon and silica gel granules is included in the bottle.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Orphan Europe SARL

Immeuble “Le Guillaumet”

F-92046 Paris La D?fense

France

8. Marketing Authorisation Number(S)

EU/1/97/039/001 (100 hard capsules per bottle), EU/1/97/039/002 (500 hard capsules per bottle).

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 23 June 1997.

Date of latest renewal: 23 June 2002.

10. Date Of Revision Of The Text

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu


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Cystagon 150 mg hard capsules


1. Name Of The Medicinal Product

CYSTAGON 150 mg hard capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains 150 mg of cysteamine (as mercaptamine bitartrate)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard Capsule

White, opaque hard capsules with CYSTAGON 150 on the body and MYLAN on the cap.

4. Clinical Particulars 4.1 Therapeutic Indications

CYSTAGON is indicated for the treatment of proven nephropathic cystinosis. Cysteamine reduces cystine accumulation in some cells (e.g. leukocytes, muscle and liver cells) of nephropathic cystinosis patients and, when treatment is started early, it delays the development of renal failure.

4.2 Posology And Method Of Administration

CYSTAGON treatment should be initiated under the supervision of a physician experienced in the treatment of cystinosis.

The goal of therapy is to keep leucocyte cystine levels below 1 nmol hemicystine/mg protein. White blood cell (WBC) cystine levels should therefore be monitored to adjust the dose. The WBC levels should be measured 5 to 6 hours after dosing and should be checked frequently when initiating therapy (e.g. monthly) and every 3-4 months when on a stable dose.

For children up to age 12 years, CYSTAGON dosing should be on the basis of body surface area (g/m2/day). The recommended dose is 1.30 g/m2/day of the free base divided four times daily.

For patients over age 12 and over 50 kg weight, the recommended CYSTAGON dose is 2 g/day, divided four times daily.

Starting doses should be 1/4 to 1/6 of the expected maintenance dose, increased gradually over 4-6 weeks to avoid intolerance. The dose should be raised if there is adequate tolerance and the leucocyte cystine level remains >1 nmol hemicystine/mg protein. The maximum dose of CYSTAGON used in clinical trials was 1.95 g/m2/day.

The use of doses higher than 1.95 g/m2/day is not recommended (see section 4.4).

Digestive tolerance of cysteamine is improved when the medicinal product is taken just after or with food.

In children who are at risk of aspiration, aged approximately 6 years and under, the hard capsules should be opened and the content sprinkled on food. Experience suggests that foods such as milk, potatoes and other starch based products seem to be appropriate for mixing with the powder. However, acidic drinks, e.g. orange juice, should generally be avoided as the powder tends not to mix well and may precipitate out.

Patients on dialysis or post-transplantation:

Experience has occasionally shown that some forms of cysteamine are less well tolerated (i.e. leading to more adverse events) when patients are on dialysis. A closer monitoring of the leucocyte cystine levels is recommended in these patients.

Patients with hepatic insufficiency:

Dose adjustment is not normally required; however, leucocyte cystine levels should be monitored.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients

The use of CYSTAGON is contra-indicated during breast-feeding. CYSTAGON should not be used during pregnancy, particularly during the first trimester, unless clearly necessary (see section 4.6 and section 5.3), as it is teratogenic in animals.

4.4 Special Warnings And Precautions For Use

CYSTAGON therapy must be initiated promptly after confirmation of the diagnosis of nephropathic cystinosis to achieve maximum benefit.

Nephropathic cystinosis must have been diagnosed by both clinical signs and biochemical investigations (leucocyte cystine measurements).

A few cases of Ehlers-Danlos like syndrome on elbows have been reported in children treated with high doses of different cysteamine preparations (cysteamine chlorhydrate or cystamine or cysteamine bitartrate) mostly above the maximal dose 1.95 g/m2/day. These skin lesions were associated with skin striae and bone lesions first seen during an X-ray examination.

It is therefore recommended to monitor regularly skin and to consider X-ray examinations of the bone as necessary. Self-examination of the skin by the patient or the parents should also be advised. If any similar skin or bone abnormalities appear, it is recommended to decrease the dose of CYSTAGON.

The use of doses higher than 1.95g/m2/day is not recommended (see sections 4.2 and 4.8).

Monitoring of blood cell count is recommended on a regular basis.

Oral cysteamine has not been shown to prevent eye deposition of cystine crystals. Therefore, where cysteamine ophthalmic solution is used for that purpose, its usage should continue.

In contrast to phosphocysteamine, CYSTAGON does not contain phosphate. Most patients will already be receiving phosphate supplements and the dose of these may need to be altered when CYSTAGON is substituted for phosphocysteamine.

Intact CYSTAGON hard capsules should not be administered to children under the age of approximately 6 years due to risk of aspiration (see section 4.2).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed

Interactions with other medicines have not been studied. CYSTAGON can be administered with electrolyte and mineral replacements necessary for management of the Fanconi syndrome as well as vitamin D and thyroid hormones. Indomethacin and CYSTAGON have been used simultaneously in some patients. In cases of patients with kidney transplants, anti-rejection treatments have been used with cysteamine.

4.6 Pregnancy And Lactation

There are no adequate data from the use of cysteamine bitartrate in pregnant women. Studies in animals have shown reproductive toxicity, including teratogenesis (see section 5.3). The potential risk for humans is unknown. The effect on pregnancy of untreated cystinosis is also unknown.

Therefore, CYSTAGON should not be used during pregnancy, particularly during the first trimester, unless clearly necessary.

If a pregnancy is diagnosed or planned, the treatment should be carefully reconsidered and the patient must be advised of the possible teratogenic risk of cysteamine.

CYSTAGON excretion in human's milk is unknown. However, due to the results of animal studies in breast-feeding mothers and neonates (see section 5.3), breast-feeding is contra-indicated in women taking CYSTAGON.

4.7 Effects On Ability To Drive And Use Machines

CYSTAGON has minor or moderate influence on the ability to drive ans use machines

CYSTAGON may cause drowsiness. When starting therapy, patients should not engage in potentially hazardous activities until the effects of the medicinal product on each individual are known.

4.8 Undesirable Effects

Approximately 35% of patients can be expected to experience adverse reactions. These mainly involve the gastrointestinal and central nervous systems. When these effects appear at the initiation of cysteamine therapy, temporary suspension and gradual reintroduction of treatment may be effective in improving tolerance.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies are defined as: very common (

Within each frequency grouping, undesirable effects are presented in order of decreasing seriouness

Investigations

Common : Liver function tests abnormal

Blood and lymphatic system disorders

Uncommon : Leukopenia

Nervous system disorders

Common : Headache, encephalopathy

Uncommon : Somnolence, convulsions

Gastrointestinal disorders

Very common : Vomiting, nausea, diarrhoea

Common : Abdominal pain, breath odour, dyspepsia, gastroenteritis

Uncommon : Gastrointestinal ulcer

Renal and urinary disorders

Uncommon : Nephrotic syndrome

Skin and subcutaneous tissue disorders

Common : Skin odour abnormal, rash

Uncommon : Hair colour changes, skin striae, skin fragility (molluscoid pseudotumor on elbows)

Musculoskeletal and connective tissue disorders

Uncommon : Joint hyperextension, leg pain, genu valgum, osteopenia, compression fracture, scoliosis.

Metabolism and nutrition disorders

Very common : Anorexia

 

 

General disorders and administration site conditions

Very common : Lethargy, pyrexia

Common : Asthenia

Immune system disorders

Uncommon : Anaphylactic reaction

Psychiatric disorders

Uncommon : Nervousness, hallucination

Two cases of nephrotic syndrome have been reported within 6 months of starting therapy with progressive recovery after treatment discontinuation. Histology showed a membranous glomerulonephritis of the renal allograft in one case and hypersensitivity interstitial nephritis in the other.

A few cases of Ehlers-Danlos like syndrome on elbows have been reported in children chronically treated with high doses of different cysteamine preparations (cysteamine chlorhydrate or cystamine or cysteamine bitartrate) mostly above the maximal dose 1.95 g/m2/day.

In some cases, these skin lesions were associated with skin striae and bone lesions first seen during an X-ray examination. Bone disorders reported were genu valgum, leg pain and hyperextensive joints, osteopenia, compression fractures, and scoliosis.

In the few cases where histopathological examination of the skin was performed, the results suggested angioendotheliomatosis.

One patient subsequently died of acute cerebral ischemia with marked vasculopathy.

In some the patients, the skin lesions on elbows regressed after CYSTAGON dose reduction.

Cysteamine mechanism of action by interfering with the cross-linking of collagen fibers has been postulated (see section 4.4).

4.9 Overdose

An overdose of cysteamine may cause progressive lethargy.

Should overdosage occur, the respiratory and cardiovascular systems should be supported appropriately. No specific antidote is known. It is not known if cysteamine is removed by haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Alimentary tract and metabolism product, ATC code: A16AA04.

Normal individuals and heterozygous subjects for cystinosis have white cell cystine levels of < 0.2, and usually below 1 nmol hemicystine/mg protein, respectively. Individuals with nephropathic cystinosis have elevations of white cell cystine above 2 nmol hemicystine/mg protein

Cysteamine reacts with cystine to form the mixed disulfide of cysteamine and cysteine, and cysteine. The mixed disulfide is then exported from the lysosomes by an intact lysine transport system. The decrease in leucocyte cystine levels is correlated to the cysteamine plasma concentration over the six hours following the administration of CYSTAGON.

The leucocyte cystine level reaches its minimum (mean (± sd) value: 1.8 ± 0.8 hours) slightly later than the peak plasma cysteamine concentration (mean (± sd) value: 1.4 ± 0.4 hours) and returns to its baseline level as the plasma cysteamine concentration decreases at 6 hours post-dose.

In one clinical study, baseline white cell cystine levels were 3.73 (range 0.13 to 19.8) nmol hemicystine/mg protein and were maintained close to 1 nmol hemicystine/mg protein with a cysteamine dose range of 1.3 to 1.95 g/m2/day.

An earlier study treated 94 children with nephropathic cystinosis with increasing doses of cysteamine to attain white cell cystine levels of less than 2 nmol hemicystine/mg protein 5 to 6 hours post-dose, and compared their outcome with an historical control group of 17 children treated with placebo. The principal efficacy measurements were serum creatinine and calculated creatinine clearance and growth (height). The mean white cell cystine level attained during treatment was 1.7 ± 0.2 nmol hemicystine/mg protein. Among cysteamine patients, glomerular function was maintained over time. Placebo treated patients, in contrast, experienced a gradual rise in serum creatinine. Patients on treatment maintained growth as compared to untreated patients. However, growth velocity did not increase enough to allow patients to catch up the normal for their age. Renal tubular function was not affected by treatment. Two other studies have shown similar results.

In all studies, patient response was better when treatment was started at an early age with good renal function.

5.2 Pharmacokinetic Properties

Following a single oral dose of cysteamine bitartrate equivalent to 1.05 g of cysteamine free base in healthy volunteers, the mean (± sd) values for the time to peak and peak plasma concentration are 1.4 (± 0.5) hours and 4.0 (± 1.0) ?g/ml, respectively. In patients at steady state, these values are 1.4 (± 0.4) hours and 2.6 (± 0.9) ?g/ml, respectively, after a dose ranging from 225 to 550 mg.

Cysteamine bitartrate (CYSTAGON) is bioequivalent to cysteamine hydrochloride and phosphocysteamine.

The in vitro plasma protein binding of cysteamine, which is mostly to albumin, is independent of plasma drug concentration over the therapeutic range, with a mean (± sd) value of 54.1 % (± 1.5). The plasma protein binding in patients at steady state is similar: 53.1 % (± 3.6) and 51.1 % (± 4.5) at 1.5 and 6 hours post-dose, respectively.

In a pharmacokinetic study performed in 24 healthy volunteers for 24 hours, the mean estimate (± sd) for the terminal half-life of elimination was 4.8 (± 1.8) hours.

The elimination of unchanged cysteamine in the urine has been shown to range between 0.3 % and 1.7% of the total daily dose in four patients; the bulk of cysteamine is excreted as sulphate.

Very limited data suggest that cysteamine pharmacokinetic parameters may not be significantly modified in patients with mild to moderate renal insufficiency. No information is available for patients with severe renal insufficiency.

5.3 Preclinical Safety Data

Genotoxicity studies have been performed: although in published studies using cysteamine, induction of chromosome aberrations in cultured eukaryotic cell lines has been reported, specific studies with cysteamine bitartrate did not show any mutagenic effects in the Ames test or any clastogenic effect in the mouse micronucleus test.

Reproduction studies showed embryofoetotoxic effects (resorptions and post-implantation losses) in rats at the 100 mg/kg/day dose level and in rabbits receiving cysteamine 50 mg/kg/day. Teratogenic effects have been described in rats when cysteamine is administered over the period of organogenesis at a dose of 100 mg/kg/day.

This is equivalent to 0.6 g/m2/day in the rat, which is less than half the recommended clinical maintenance dose of cysteamine, i.e. 1.30 g/ m2/day. A reduction of fertility was observed in rats at 375 mg/kg/day, a dose at which body weight gain was retarded. At this dose, weight gain and survival of the offspring during lactation was also reduced. High doses of cysteamine impair the ability of lactating mothers to feed their pups. Single doses of the drug inhibit prolactin secretion in animals. Administration of cysteamine in neonate rats induced cataracts.

High doses of cysteamine, either by oral or parenteral routes, produce duodenal ulcers in rats and mice but not in monkeys. Experimental administration of the drug causes depletion of somatostatin in several animal species. The consequence of this for the clinical use of the drug is unknown.

No carcinogenic studies have been conducted with CYSTAGON.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Capsule content:

microcrystalline cellulose,

pregelatinized starch,

magnesium stearate/sodium lauryl sulfate,

colloidal silicon dioxide,

croscarmellose sodium

Capsule shell:

gelatin,

titanium dioxide,

black ink on hard capsules containing E172

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

Keep the container tightly closed in order to protect from light and moisture.

6.5 Nature And Contents Of Container

HDPE bottles of 100 and 500 hard capsules. A desiccant unit containing black activated carbon and silica gel granules is included in the bottle.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Orphan Europe SARL

Immeuble “Le Guillaumet”

F-92046 Paris La D?fense

France

8. Marketing Authorisation Number(S)

EU/1/97/039/003 (100 hard capsules per bottle), EU/1/97/039/004 (500 hard capsules per bottle).

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 23 June 1997.

Date of latest renewal: 23 June 2007

10. Date Of Revision Of The Text

September 2007

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu


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Lansoprazole



FULL PRESCRIBING INFORMATION Indications and Usage for Lansoprazole Short-Term Treatment of Active Duodenal Ulcer

Lansoprazole delayed-release capsules are indicated for short-term treatment (for 4 weeks) for healing and symptom relief of active duodenal ulcer. [See Clinical Studies (14).]

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy Lansoprazole/amoxicillin/clarithromycin

Lansoprazole delayed-release capsules in combination with amoxicillin plus clarithromycin as triple therapy is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14)].

Please refer to the full prescribing information for amoxicillin and clarithromycin.

Dual Therapy Lansoprazole/amoxicillin

Lansoprazole delayed-release capsules in combination with amoxicillin as dual therapy is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected (see the clarithromycin package insert, MICROBIOLOGY section). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14)].

Please refer to the full prescribing information for amoxicillin.

Maintenance of Healed Duodenal Ulcers

Lansoprazole delayed-release capsules are indicated to maintain healing of duodenal ulcers. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14).]

Short-Term Treatment of Active Benign Gastric Ulcer

Lansoprazole delayed-release capsules are indicated for short-term treatment (up to 8 weeks) for healing and symptom relief of active benign gastric ulcer. [See Clinical Studies (14).]

Healing of NSAID-Associated Gastric Ulcer

Lansoprazole delayed-release capsules are indicated for the treatment of NSAID-associated gastric ulcer in patients who continue NSAID use. Controlled studies did not extend beyond 8 weeks. [See Clinical Studies (14).]

Risk Reduction of NSAID-Associated Gastric Ulcer

Lansoprazole delayed-release capsules are indicated for reducing the risk of NSAID-associated gastric ulcers in patients with a history of a documented gastric ulcer who require the use of an NSAID. Controlled studies did not extend beyond 12 weeks. [See Clinical Studies (14).]

Gastroesophageal Reflux Disease (GERD) Short-Term Treatment of Symptomatic GERD

Lansoprazole delayed-release capsules are indicated for the treatment of heartburn and other symptoms associated with GERD. [See Clinical Studies (14).]

Short-Term Treatment of Erosive Esophagitis

Lansoprazole delayed-release capsules are indicated for short-term treatment (up to 8 weeks) for healing and symptom relief of all grades of erosive esophagitis. For patients who do not heal with Lansoprazole delayed-release capsules for 8 weeks (5% to 10%), it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis an additional 8-week course of Lansoprazole delayed-release capsules may be considered. [See Clinical Studies (14).]

Maintenance of Healing of Erosive Esophagitis (EE)

Lansoprazole delayed-release capsules are indicated to maintain healing of erosive esophagitis. Controlled studies did not extend beyond 12 months. [See Clinical Studies (14).]

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (ZES)

Lansoprazole delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. [See Clinical Studies (14).]

Lansoprazole Dosage and Administration

Lansoprazole delayed-release capsules are available as capsules in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration is presented below. Lansoprazole delayed-release capsules should be taken before eating. Lansoprazole delayed-release capsules SHOULD NOT BE CRUSHED OR CHEWED. In the clinical trials, antacids were used concomitantly with Lansoprazole.

Recommended Dose * Please refer to amoxicillin and clarithromycin full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally-impaired patients. † Controlled studies did not extend beyond indicated duration. ‡ For patients who do not heal with Lansoprazole for 8 weeks (5% to 10%), it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis, an additional 8 week course of Lansoprazole may be considered. § The Lansoprazole dose was increased (up to 30 mg twice daily) in some pediatric patients after 2 or more weeks of treatment if they remained symptomatic. For pediatric patients unable to swallow an intact capsule please see Administration Options. ¶ Varies with individual patient. Recommended adult starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Dosages up to 90 mg twice daily have been administered. Daily dose of greater than 120 mg should be administered in divided doses. Some patients with Zollinger-Ellison Syndrome have been treated continuously with Lansoprazole for more than 4 years. Indication Recommended Frequency Dose Duodenal Ulcers     Short-Term Treatment 15 mg Once daily for 4 weeks      Maintenance of Healed 15 mg Once daily H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence*      Triple Therapy:           Lansoprazole Delayed-release Capsules 30 mg Twice daily (q12h) for 10 or 14 days           Amoxicillin 1 gram Twice daily (q12h) for 10 or 14 days           Clarithromycin 500 mg Twice daily (q12h) for 10 or 14 days      Dual Therapy:           Lansoprazole Delayed-release Capsules 30 mg Three times daily (q8h) for 14 days           Amoxicillin 1 gram Three times daily (q8h) for 14 days Benign Gastric Ulcer      Short-Term Treatment 30 mg Once daily for up to 8 weeks NSAID-associated Gastric Ulcer      Healing 30 mg Once daily for 8 weeks†      Risk Reduction 15 mg Once daily for up to 12 weeks† Gastroesophageal Reflux Disease (GERD)      Short-Term Treatment of Symptomatic GERD 15 mg Once daily for up to 8 weeks      Short -Term Treatment of Erosive Esophagitis 30 mg Once daily for up to 8 weeks‡ Pediatric (1 to 11 years of age) Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of Erosive Esophagitis      ? 30 kg 15 mg Once daily for up to 12 weeks§      > 30 kg 30 mg Once daily for up to 12 weeks§ (12 to 17 years of age) Short-Term Treatment of Symptomatic GERD      Nonerosive GERD 15 mg Once daily for up to 8 weeks      Erosive Esophagitis 30 mg Once daily for up to 8 weeks Maintenance of Healing of Erosive Esophagitis 15 mg Once daily Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 60 mg Once daily¶

Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose and should be instructed to take the next dose on time. Patients should be instructed not to take two doses at one time to make up for a missed dose.

Special Populations

Renal impairment patients and geriatric patients do not require dosage adjustment. However, consider dose adjustment in patients with severe liver impairment. [See Use in Specific Populations (8.5, 8.6 and 8.7).]

Important Administration Information Administration Options

Lansoprazole Delayed-release Capsules -Oral Administration

Lansoprazole delayed-release capsules should be swallowed whole. Alternatively, for patients who have difficulty swallowing capsules, Lansoprazole delayed-release capsules can be opened and administered as follows: Open capsule. Sprinkle intact pellets on one tablespoon of either applesauce, ENSURE® pudding, cottage cheese, yogurt or strained pears. Swallow immediately. Lansoprazole delayed-release capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice and administered as follows: Open capsule. Sprinkle intact pellets into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces). Mix briefly. Swallow immediately. To ensure complete delivery of the dose, the glass should be rinsed with two or more volumes of juice and the contents swallowed immediately.

Lansoprazole Delayed-release Capsules -Nasogastric Tube (? 16 French) Administration

For patients who have a nasogastric tube in place, Lansoprazole delayed-release capsules can be administered as follows: Open capsule. Mix intact pellets into 40 mL of apple juice. DO NOT USE OTHER LIQUIDS. Inject through the nasogastric tube into the stomach. Flush with additional apple juice to clear the tube.

USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.

Dosage Forms and Strengths 15 mg capsules have a green opaque cap, green opaque body, hard-shell gelatin capsule filled with white to off-white pellets. The capsule is axially printed with MYLAN over 8015 in black ink on both the cap and body. 30 mg capsules have a pink opaque cap, pink opaque body, hard-shell gelatin capsule filled with white to off-white pellets. The capsule is axially printed with MYLAN over 8030 in black ink on both the cap and the body. Contraindications

Lansoprazole delayed-release capsules are contraindicated in patients with known severe hypersensitivity to any component of the formulation of Lansoprazole. For information on contraindications for amoxicillin or clarithromycin, refer to their full prescribing information, CONTRAINDICATIONS sections.

Warnings and Precautions Gastric Malignancy

Symptomatic response to therapy with Lansoprazole does not preclude the presence of gastric malignancy.

Bone Fracture

 Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6.2)].

 For information on warnings and precautions for amoxicillin or clarithromycin, refer to their full prescribing information, WARNINGS and PRECAUTIONS sections.

Hypomagnesemia

 Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

 For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].

Adverse Reactions Clinical

Worldwide, over 10,000 patients have been treated with Lansoprazole in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, Lansoprazole treatment has been well tolerated in both short-term and long-term trials.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of Lansoprazole-treated patients and occurred at a greater rate in Lansoprazole-treated patients than placebo-treated patients in Table 1.

Table 1. Incidence of Possibly or Probably Treatment-Related Adverse Reactions in Short-Term, Placebo-Controlled Lansoprazole Studies Lansoprazole Placebo (N = 2,768) (N = 1,023) Body System/Adverse Event % % Body as a Whole      Abdominal Pain 2.1 1.2 Digestive System      Constipation 1 0.4      Diarrhea 3.8 2.3      Nausea 1.3 1.2

 

Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 mg and 30 mg of Lansoprazole, but higher in the patients who received 60 mg of Lansoprazole (2.9%, 1.4%, 4.2% and 7.4%, respectively).

The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.

In the risk reduction study of Lansoprazole for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with Lansoprazole, misoprostol and placebo was 5%, 22% and 3%, respectively.

Another study for the same indication, where patients took either a COX-2 inhibitor or Lansoprazole and naproxen, demonstrated that the safety profile was similar to the prior study. Additional reactions from this study not previously observed in other clinical trials with Lansoprazole included contusion, duodenitis, epigastric discomfort, esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness, impaired gastric emptying, metaplasia and renal impairment.

Additional adverse experiences occurring in less than 1% of patients or subjects who received Lansoprazole in domestic trials are shown below:

Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain

Cardiovascular System: angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation

Digestive System: abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis

Endocrine System: diabetes mellitus, goiter, hypothyroidism

Hemic and Lymphatic System: anemia, hemolysis, lymphadenopathy

Metabolism and Nutritional Disorders: avitaminosis,  gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss

Musculoskeletal System: arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, ptosis, synovitis

Nervous System: abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, dementia, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo

Respiratory System: asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor

Skin and Appendages: acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria

Special Senses: abnormal vision, amblyopia, blepharitis, blurred vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder, eye pain, glaucoma, otitis media, parosmia, photophobia, retinal degeneration/disorder, taste loss, taste perversion, tinnitus, visual field defect

Urogenital System: abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary retention, urinary tract infection, urinary urgency, urination impaired, vaginitis

Post-Marketing Experience

Additional adverse experiences have been reported since Lansoprazole has been marketed. The majority of these cases are foreign-sourced and a relationship to Lansoprazole has not been established. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed below by COSTART body system.

Body as a Whole: anaphylactic/anaphylactoid reactions;

Digestive System: hepatotoxicity, pancreatitis, vomiting;

Hemic and Lymphatic System:  agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura;

Metabolism and Nutritional Disorders: hypomagnesemia;

Musculoskeletal System: bone fracture, myositis;

Skin and Appendages: severe dermatologic reactions including erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis (some fatal);

Special Senses: speech disorder;

Urogenital System: interstitial nephritis, urinary retention

Combination Therapy with Amoxicillin and Clarithromycin

In clinical trials using combination therapy with Lansoprazole plus amoxicillin and clarithromycin, and Lansoprazole plus amoxicillin, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with Lansoprazole, amoxicillin or clarithromycin.

Triple Therapy Lansoprazole/amoxicillin/clarithromycin

The most frequently reported adverse reactions for patients who received triple therapy for 14 days were diarrhea (7%), headache (6%) and taste perversion (5%). There were no statistically significant differences in the frequency of reported adverse reactions between the 10- and 14-day triple therapy regimens. No treatment-emergent adverse reactions were observed at significantly higher rates with triple therapy than with any dual therapy regimen.

Dual Therapy Lansoprazole/amoxicillin

The most frequently reported adverse reactions for patients who received Lansoprazole 3 times daily plus amoxicillin 3 times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse reactions were observed at significantly higher rates with Lansoprazole 3 times daily plus amoxicillin 3 times daily dual therapy than with Lansoprazole alone.

For information on adverse reactions with amoxicillin or clarithromycin, refer to their full prescribing information, ADVERSE REACTIONS sections.

Laboratory Values

The following changes in laboratory parameters in patients who received Lansoprazole were reported as adverse reactions:

Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.

In the placebo controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2,677) patients, who received placebo and Lansoprazole, respectively, had enzyme elevations greater than 3 times the upper limit of normal range at the final treatment visit. None of these patients who received Lansoprazole reported jaundice at any time during the study.

In clinical trials using combination therapy with Lansoprazole plus amoxicillin and clarithromycin, and Lansoprazole plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed.

For information on laboratory value changes with amoxicillin or clarithromycin, refer to their full prescribing information, ADVERSE REACTIONS sections.

Drug Interactions Drugs with pH-Dependent Absorption Kinetics

Lansoprazole causes long-lasting inhibition of gastric acid secretion. Lansoprazole and other PPIs are likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, Lansoprazole and other PPIs should not be coadministered with atazanavir. [See Clinical Pharmacology (12.3).]

Lansoprazole and other PPIs may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). [See Clinical Pharmacology (12.3).] 

Warfarin

In a study of healthy subjects, coadministration of single or multiple 60 mg doses of Lansoprazole and warfarin did not affect the pharmacokinetics of warfarin nor prothrombin time [see Clinical Pharmacology (12.3)]. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. [See Clinical Pharmacology (12.3).] 

Tacrolimus

Concomitant administration of Lansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

Theophylline

A minor increase (10%) in the clearance of theophylline was observed following the administration of Lansoprazole concomitantly with theophylline. Although the magnitude of the effect on theophylline clearance is small, individual patients may require additional titration of their theophylline dosage when Lansoprazole is started or stopped to ensure clinically effective blood levels. [See Clinical Pharmacology (12.3).] 

Clopidogrel

Concomitant administration of Lansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3)]. No dose adjustment of clopidogrel is necessary when administered with an approved dose of Lansoprazole.

For information on drug interactions for amoxicillin or clarithromycin, refer to their full prescribing information, DRUG INTERACTIONS sections.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic effects Pregnancy Category B

Reproduction studies have been performed in pregnant rats at oral doses up to 40 times the recommended human dose and in pregnant rabbits at oral doses up to 16 times the recommended human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Lansoprazole. There are, however, no adequate or well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed [see Nonclinical Toxicology (13.2)].

See full prescribing information for clarithromycin before using in pregnant women.

Nursing Mothers

Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether Lansoprazole is excreted in human milk. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions in nursing infants from Lansoprazole, and because of the potential for tumorigenicity shown for Lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue Lansoprazole, taking into account the importance of Lansoprazole to the mother.

Pediatric Use

The safety and effectiveness of Lansoprazole have been established in pediatric patients 1 to 17 years of age for short-term treatment of symptomatic GERD and erosive esophagitis.

One to 11 Years of Age

In an uncontrolled, open-label, U.S. multicenter study, 66 pediatric patients (1 to 11 years of age) with GERD were assigned, based on body weight, to receive an initial dose of either Lansoprazole 15 mg daily if < 30 kg or Lansoprazole 30 mg daily if greater than 30 kg administered for 8 to 12 weeks. The Lansoprazole dose was increased (up to 30 mg twice daily) in 24 of 66 pediatric patients after 2 or more weeks of treatment if they remained symptomatic. At baseline 85% of patients had mild to moderate overall GERD symptoms (assessed by investigator interview), 58% had non-erosive GERD and 42% had erosive esophagitis (assessed by endoscopy).

After 8 to 12 weeks of Lansoprazole treatment, the intent-to-treat analysis demonstrated an approximate 50% reduction in frequency and severity of GERD symptoms.

Twenty-one of 27 erosive esophagitis patients were healed at 8 weeks and 100% of patients were healed at 12 weeks by endoscopy (Table 2).

Table 2. GERD Symptom Improvement and Erosive Esophagitis Healing Rates in Pediatric Patients Age 1 to 11 * At Week 8 or Week 12 † Symptoms assessed by patients diary kept by caregiver. ‡ No data were available for four pediatric patients. GERD Final Visit* % (n/N) Symptomatic GERD      Improvement in Overall GERD Symptoms† 76% (47/62‡) Erosive Esophagitis      Improvement in Overall GERD Symptoms † 81% (22/27)      Healing Rate 100% (27/27)

 In a study of 66 pediatric patients in the age group 1 year to 11 years old after treatment with Lansoprazole given orally in doses of 15 mg daily to 30 mg twice daily, increases in serum gastrin levels were similar to those observed in adult studies. Median fasting serum gastrin levels increased 89% from 51 pg/mL at baseline to 97 pg/mL [interquartile range (25th to 75th   percentile) of 71 to 130 pg/mL] at the final visit.

The pediatric safety of Lansoprazole delayed-release capsules has been assessed in 66 pediatric patients aged 1 to 11 years of age. Of the 66 patients with GERD 85% (56/66) took Lansoprazole for 8 weeks and 15% (10/66) took it for 12 weeks.

The most frequently reported (two or more patients) treatment-related adverse reactions in patients 1 to 11 years of age (N = 66) were constipation (5%) and headache (3%).

Twelve to 17 Years of Age

In an uncontrolled, open-label, U.S. multicenter study, 87 adolescent patients (12 to 17 years of age) with symptomatic GERD were treated with Lansoprazole for 8 to 12 weeks. Baseline upper endoscopies classified these patients into two groups: 64 (74%) nonerosive GERD and 23 (26%) erosive esophagitis (EE). The nonerosive GERD patients received Lansoprazole 15 mg daily for 8 weeks and the EE patients received Lansoprazole 30 mg daily for 8 to 12 weeks. At baseline, 89% of these patients had mild to moderate overall GERD symptoms (assessed by investigator interviews). During 8 weeks of Lansoprazole treatment, adolescent patients experienced a 63% reduction in frequency and a 69% reduction in severity of GERD symptoms based on diary results.

Twenty-one of 22 (95.5%) adolescent erosive esophagitis patients were healed after 8 weeks of Lansoprazole treatment. One patient remained unhealed after 12 weeks of treatment (Table 3).

Table 3. GERD Symptom Improvement and Erosive Esophagitis Healing Rates in Pediatric Patients Age 12 to 17 * Symptoms assessed by patient diary (parents/caregivers as necessary). † No data available for five patients. ‡ Data from one healed patient was excluded from this analysis due to timing of final endoscopy. GERD Final Visit % (n/N) Symptomatic GERD (All Patients)      Improvement in Overall GERD Symptoms* 73.2% (60/82)† Nonerosive GERD      Improvement in Overall GERD Symptoms* 71.2% (42/59) † Erosive Esophagitis      Improvement in Overall GERD Symptoms* 78.3% (18/23)      Healing Rate‡ 95.5% (21/22)‡

 

In these 87 adolescent patients, increases in serum gastrin levels were similar to those observed in adult studies, median fasting serum gastrin levels increased 42% from 45 pg/mL at baseline to 64 pg/mL [interquartile range (25th   to 75th   percentile) of 44 to 88 pg/mL] at the final visit. (Normal serum gastrin levels are 25 to 111 pg/mL).

The safety of Lansoprazole delayed-release capsules has been assessed in these 87 adolescent patients. Of the 87 adolescent patients with GERD, 6% (5/87) took Lansoprazole for less than 6 weeks, 93% (81/87) for 6 to 10 weeks, and 1% (1/87) for greater than 10 weeks.

The most frequently reported (at least 3%) treatment-related adverse reactions in these patients were headache (7%), abdominal pain (5%), nausea (3%) and dizziness (3%). Treatment-related dizziness, reported in this package insert as occurring in less than 1% of adult patients, was reported in this study by three adolescent patients with nonerosive GERD, who had dizziness concurrently with other reactions (such as migraine, dyspnea and vomiting).

Geriatric Use

No dosage adjustment of Lansoprazole is necessary in geriatric patients. The incidence rates of Lansoprazole-associated adverse reactions and laboratory test abnormalities are similar to those seen in younger patients. [See Clinical Pharmacology (12.3).]

Renal Impairment

No dosage adjustment of Lansoprazole is necessary in patients with renal impairment. The pharmacokinetics of Lansoprazole in patients with various degrees of renal impairment were not substantially different compared to those in subjects with normal renal function. [See Clinical Pharmacology (12.3).]

Hepatic Impairment

In patients with various degrees of chronic hepatic impairment, an increase in the mean AUC of up to 500% was observed at steady-state compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment. [See Clinical Pharmacology (12.3).]

Gender

Over 4,000 women were treated with Lansoprazole. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse reactions in females were similar to those seen in males. [See Clinical Pharmacology (12.3).]

Race

The pooled mean pharmacokinetic parameters of Lansoprazole from 12 U.S. Phase 1 studies (N = 513) were compared to the mean pharmacokinetic parameters from two Asian studies (N = 20). The mean AUCs of Lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.


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Comtan


Generic Name: Entacapone
Class: Catechol-O-Methyltransferase (COMT) Inhibitors
VA Class: CN500
Chemical Name: (E)-?-Cyano-N,N-diethyl-1,3,4-dihydroxy-5-nitrocinnamamide
Molecular Formula: C14H15N3O5
CAS Number: 130929-57-6

Introduction

Selective, reversible inhibitor of catechol-O-methyltransferase (COMT).1 2 3 7

Uses for Comtan Parkinsonian Syndrome

Adjunct to levodopa-carbidopa in the symptomatic treatment of idiopathic parkinsonian syndrome in patients with manifestations of end-of-dose “wearing-off.”1 4

Not evaluated systematically in patients without manifestations of end-of-dose “wearing-off.”1

Comtan Dosage and Administration Administration Oral Administration

Administer orally without regard to meals.1

Administer in conjunction with levodopa-carbidopa (conventional tablets, orally disintegrating tablets, or extended-release preparations) or as a fixed-combination preparation containing levodopa, carbidopa, and entacapone (Stalevo).1 8

Administer one tablet of the fixed-combination preparation (Stalevo) per dosing interval; do not divide the tablets.8

Dosage Adults Parkinsonian Syndrome Oral

200 mg with each levodopa-carbidopa dose.1

May need to reduce daily levodopa dosage or administration frequency to optimize patient response.1 In clinical studies, most patients receiving ?800 mg of levodopa daily or experiencing moderate or severe dyskinesias before initiating entacapone therapy required a reduction (average 25%) in levodopa dosage.1

Transferring to the Fixed-combination Preparation (Stalevo) Oral

Patients receiving levodopa-carbidopa conventional tablets containing a 1:4 ratio of carbidopa to levodopa: Switch to the corresponding strength of Stalevo.8

No information on transferring patients receiving extended-release levodopa-carbidopa preparation or levodopa-carbidopa preparations containing a 1:10 ratio of carbidopa to levodopa.8

Initiating Entacapone Using the Fixed-combination Preparation (Stalevo) Oral

Patients receiving levodopa >600 mg daily or with history of moderate or severe dyskinesias: Administer levodopa-carbidopa (1:4 ratio) and entacapone as separate preparations to determine optimum maintenance dosage and then switch to corresponding strength of Stalevo.8

Patients receiving levodopa <600 mg daily (conventional tablet, 1:4 ratio) with no dyskinesias: Switch to the strength of Stalevo that corresponds to the dosage of levodopa-carbidopa being taken.8 Further adjustment may be needed.8

Prescribing Limits Adults Parkinsonian Syndrome Oral

Entacapone: Maximum of 8 doses (1.6 g) daily; clinical experience with dosages >1.6 g daily is limited.1 8

Fixed-combination preparations containing levodopa 50–150 mg, carbidopa 12.5–37.5 mg, and entacapone 200 mg (Stalevo 50, 75, 100, 125, and 150): Maximum of 8 tablets daily; clinical experience with entacapone dosages >1.6 g daily is limited.8

Fixed-combination preparation containing levodopa 200 mg, carbidopa 50 mg, and entacapone 200 mg (Stalevo 200): Maximum of 6 tablets daily; clinical experience with carbidopa dosages >300 mg daily is limited.8

Cautions for Comtan Contraindications

Known hypersensitivity to entacapone or any ingredient in the formulation.1

When entacapone is used in fixed combination with levodopa-carbidopa, consider the contraindications associated with levodopa-carbidopa.8

Warnings/Precautions Warnings Concomitant Use with MAO Inhibitors

Possible inhibition of principal pathways involved in the metabolism of catecholamines if used concomitantly with a nonselective MAO inhibitor (e.g., phenelzine, tranylcypromine); concomitant use not recommended.1 (See Specific Drugs under Interactions.)

Concomitant Use with Drugs Metabolized by Catechol-O-methyltransferase

Possible increased heart rate, arrhythmias, and excessive changes in BP when used concomitantly with drugs metabolized by catechol-O-methyltransferase (COMT).1 (See Specific Drugs under Interactions.)

Potential Risk of Prostate Cancer

Higher incidence of prostate cancer was observed in one long-term, randomized, controlled study in patients initiating levodopa therapy with levodopa, carbidopa, and entacapone (Stalevo) compared with those initiating therapy with conventional levodopa-carbidopa formulation.11 13 Increased risk of prostate cancer not observed in other shorter-term controlled studies evaluating entacapone as an adjunct to levodopa-carbidopa.11 13 FDA is continuing to review available data related to this safety concern.11

FDA advises patients receiving entacapone as an adjunct to levodopa-carbidopa (either separately or as a fixed-combination preparation) to continue taking the drugs as prescribed unless otherwise instructed by a clinician.11 Men receiving such therapy should continue to be monitored for development of prostate cancer according to current prostate cancer screening guidelines.11

Major Toxicities Cardiovascular Effects

Enhances levodopa availability; possible increased occurrence of orthostatic hypotension or syncope when administered with levodopa-carbidopa.1

Findings from an FDA-conducted meta-analysis suggest that patients receiving combined therapy with levodopa, carbidopa, and entacapone may be at increased risk of adverse cardiovascular events (i.e., MI, stroke, cardiovascular death) compared with those receiving levodopa-carbidopa.12 However, several limitations of the meta-analysis preclude definite conclusions.12 FDA is continuing to review available data related to this safety concern.12 FDA advises patients receiving entacapone as an adjunct to levodopa-carbidopa (either separately or as a fixed-combination preparation) to continue taking the drugs as prescribed unless otherwise instructed by a clinician.12 Clinicians should monitor cardiac function regularly, particularly in patients with a history of cardiovascular disease.12

GI Effects

Possible mild to moderate diarrhea; rarely may be severe.1 Generally occurs during first 4–12 weeks of therapy; may occur as early as first week or as late as several months following initiation and resolves following discontinuance.1

Hallucinations

Possible hallucinations, sometimes resulting in hospitalization.1

Dyskinesia

May potentiate adverse dopaminergic effects of levodopa and may cause or exacerbate dyskinesias.1 3 4

Reduction of levodopa dosage may ameliorate dyskinesias; however, many patients in clinical studies continued to experience frequent dyskinesias.1 Discontinuance of therapy may be required.1

Rhabdomyolysis

Severe rhabdomyolysis reported rarely.1 4 7

Nervous System and Muscular Effects

Symptom complex resembling neuroleptic malignant syndrome (NMS) (elevated temperature, muscular rigidity, altered consciousness, elevated CPK) reported in association with abrupt withdrawal or dosage lowering of other dopaminergic agents.1 Similar episodes possible with entacapone.1 4 7 (See Withdrawal of Therapy under Cautions.)

Respiratory Effects

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and thickening of the pleura reported with ergot-derivative dopamine receptor agonists (e.g., bromocriptine, pergolide); possibility exists that nonergot-derived drugs that increase dopaminergic activity (e.g., entacapone) may induce similar pulmonary changes.1

General Precautions Use of Fixed Combination

When the fixed combination containing levodopa, carbidopa, and entacapone (Stalevo) is used, observe the usual precautions and contraindications associated with all the drugs in the preparation.8

Withdrawal of Therapy

Slow withdrawal is recommended.1

If entacapone therapy is discontinued, closely monitor patient and adjust dosage of dopaminergic therapy accordingly.1

If hyperpyrexia or severe rigidity occurs, consider possibility of symptom complex resembling NMS.1

Melanoma

Epidemiologic studies indicate patients with parkinsonian syndrome have a twofold to approximately sixfold higher risk of developing melanoma than the general population.1 8 Unclear whether increased risk is due to parkinsonian syndrome or other factors (e.g., drugs used to treat the disease).1 8

Monitor for melanoma on a frequent and regular basis.1 8 Manufacturer recommends periodic skin examinations performed by appropriately qualified individuals (e.g., dermatologists).1 8

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including entacapone).1 8 Although causal relationship not established, urges stopped in some cases when dosage was reduced or drug was discontinued.1 8

Consider reducing dosage or discontinuing entacapone if a patient develops such urges.1 8

Specific Populations Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Caution if used in nursing women.1

Pediatric Use

Not indicated.1

Geriatric Use

No substantial differences in safety or pharmacokinetics relative to younger adults.1 3 7

Hepatic Impairment

Use with caution.1 (See Special Populations under Pharmacokinetics.)

Biliary Obstruction

Use with caution.1

Common Adverse Effects

Dyskinesia, nausea, hyperkinesia, diarrhea, urine discoloration, hypokinesia, dizziness, abdominal pain, constipation, fatigue.1

Interactions for Comtan

Inhibits CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A only at very high concentrations.1 Inhibition of these isoenzymes not expected during clinical use.1

Drugs Metabolized by Catechol-O-methyltransferase

Possible increased heart rate, arrhythmias, and excessive changes in BP.1

Drugs Interfering with Biliary Excretion, Glucuronidation, and Intestinal ?-Glucuronidase

Decreased entacapone excretion.1 7

Protein-bound Drugs

No binding displacement between entacapone and other highly protein bound drugs (e.g., warfarin, salicylic acid, phenylbutazone, diazepam).1

Specific Drugs

Drug

Interaction

Comments

Anti-infective agents (e.g., ampicillin, chloramphenicol, erythromycin, rifampin)

Possible decreased entacapone excretion1 7

Use with caution1

Apomorphine

Possible increased heart rate, arrhythmias, and excessive changes in BP1

Cholestyramine

Possible decreased entacapone excretion1

Use with caution1

CNS depressants

Additive sedative effects1

Imipramine

Pharmacologic interaction unlikely1

Levodopa

Increased plasma levodopa concentrations, resulting in enhanced therapeutic effects1

Increased risk of levodopa-induced cardiovascular effects and dyskinesia1

MAO inhibitors

Potential inhibition of catecholamine metabolism when used concomitantly with nonselective MAO inhibitors (e.g., phenelzine, tranylcypromine)1

Pharmacologic interaction unlikely with selective MAO-B inhibitors (e.g., selegiline)1

Avoid concomitant use with nonselective MAO inhibitors1

Methyldopa

Possible increased heart rate, arrhythmias, and excessive changes in BP1

Probenecid

Possible decreased entacapone excretion1

Use with caution1

Sympathomimetic (adrenergic) agents (e.g., dobutamine, dopamine, epinephrine, isoetharine, isoproterenol, norepinephrine)

Possible increased heart rate, arrhythmias, and excessive changes in BP1

Comtan Pharmacokinetics Absorption Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentrations attained within approximately 1 hour.1

Absolute bioavailability is 35%.1 a

Food

Food does not affect pharmacokinetics.1

Special Populations

Increased peak plasma concentrations and AUC in patients with mild to moderate hepatic impairment.1

Distribution Extent

Does not distribute widely into tissues.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

98% (mainly albumin).1

Elimination Metabolism

Almost completely metabolized, principally by isomerization followed by glucuronidation to an inactive conjugate.1

Elimination Route

Entacapone and its metabolites are eliminated principally in feces (90%) via biliary excretion and to a lesser extent in urine (10%).1 3 4

Half-life

Approximately 2.4 hours.1 a

Stability Storage Oral Tablets

25°C (may be exposed to 15–30°C).1

ActionsActions

Structurally and pharmacologically related to tolcapone;1 3 7 however, unlike tolcapone, not associated with hepatotoxicity (e.g., drug-induced hepatitis, fatal liver failure).1 3 4 7

Inhibits catechol-O-methyltransferase (COMT) enzyme in peripheral tissues;1 3 4 effects on central COMT activity in humans not studied.1

Concomitant administration with levodopa and a decarboxylase inhibitor (e.g., carbidopa) results in increased and more sustained plasma levodopa concentrations compared with administration of levodopa and a decarboxylase inhibitor.1 3 4

Lacks antiparkinsonian activity when administered alone.1

Advice to Patients

Importance of taking entacapone as prescribed and not discontinuing abruptly.1

Necessity of exercising caution when driving or operating machinery when entacapone is initiated.1 Caution when taking other CNS depressants.1

Advise that entacapone may cause brownish orange discoloration of urine; not clinically important.1

Advise that hallucinations, nausea, and increased dyskinesia can occur.1

Advise patients not to rise rapidly after prolonged sitting or lying down, especially during first few weeks of therapy.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

Importance of asking patients whether they have developed any new or increased gambling urges, sexual urges, or other urges while receiving entacapone and of advising them of the importance of reporting such urges.1 8

Importance of frequent monitoring for melanoma and periodic dermatologic examinations by a dermatologist.1 8

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Entacapone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg

Comtan

Novartis

Entacapone Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg with Carbidopa 12.5 mg (of anhydrous carbidopa) and Levodopa 50 mg

Stalevo

Novartis

200 mg with Carbidopa 18.75 mg (of anhydrous carbidopa) and Levodopa 75 mg

Stalevo

Novartis

200 mg with Carbidopa 25 mg (of anhydrous carbidopa) and Levodopa 100 mg

Stalevo

Novartis

200 mg with Carbidopa 31.25 mg (of anhydrous carbidopa) and Levodopa 125 mg

Stalevo

Novartis

200 mg with Carbidopa 37.5 mg (of anhydrous carbidopa) and Levodopa 150 mg

Stalevo

Novartis

200 mg with Carbidopa 50 mg (of anhydrous carbidopa) and Levodopa 200 mg

Stalevo

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Comtan 200MG Tablets (NOVARTIS): 30/$112.99 or 90/$310.97

Stalevo 100 25-100-200MG Tablets (NOVARTIS): 90/$318 or 270/$898.92

Stalevo 150 37.5-150-200MG Tablets (NOVARTIS): 30/$113.99 or 90/$334.97

Stalevo 200 50-200-200MG Tablets (NOVARTIS): 100/$363.99 or 300/$1043.97

Stalevo 50 12.5-50-200MG Tablets (NOVARTIS): 30/$110.98 or 90/$317.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals Corporation. Comtan (entacapone) tablets prescribing information. East Hanover, NJ; 2009 Mar.

2. LeWitt PA. New drugs for the treatment of Parkinson’s disease. Pharmacotherapy. 2000; 20:26S-32S.

3. Holm KJ, Spencer CM. Entacapone: a review of its use in Parkinson’s disease. Drugs. 1999; 58:159-77.

4. Anon. Entacapone for Parkinson’s disease. Med Lett Drugs Ther. 2000; 42:7-8.

5. Rinne UK, Larsen JP, Siden A et al. Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Neurology. 1998; 51:1309-14.

6. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol. 1997; 42:747-55.

7. Novartis, East Hanover, NJ: Personal communication.

8. Novartis. Stalevo 50, Stalevo 75, Stalevo 100, Stalevo 125, Stalevo 150, Stalevo 200 (carbidopa, levodopa, and entacapone) tablets prescribing information. East Hanover, NJ; 2009 Mar.

9. Mylan Bertek Pharmaceuticals Inc. Apokyn (apomorphine hydrochloride) injection prescribing information. Research Triangle Park, NC; 2004 Apr.

10. van der Geest R, van Laar T, Kruger PP et al. Pharmacokinetics, enantiomer interconversion, and metabolism of R-apomorphine in patients with idiopathic Parkinson’s disease. Clin Neuropharmacol. 1998; 21:159-68. [PubMed 9617507]

11. Food and Drug Administration. FDA drug safety communication: ongoing safety review of Stalevo (entacapone/carbidopa/levodopa) and possible development of prostate cancer. Rockville, MD; 2010 Mar 31. From FDA website ().

12. Food and Drug Administration. FDA drug safety communication: ongoing safety review of Stalevo and possible increased cardiovascular risk. Rockville, MD; 2010 Aug 20. From FDA website ().

13. Stocchi F, Rascol O, Kieburtz K et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann Neurol. 2010; 68:18-27. [PubMed 20582993]

a. Heikkinen H, Saraheimo M, Antila S et al. Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man. A study using a stable isotope technique. Eur J Clin Pharmacol. 2001; 56: 821-6. [PubMed 11294372]

More Comtan resources Comtan Side Effects (in more detail) Comtan Dosage Comtan Use in Pregnancy & Breastfeeding Drug Images Comtan Drug Interactions Comtan Support Group 2 Reviews for Comtan - Add your own review/rating Comtan Prescribing Information (FDA) Comtan MedFacts Consumer Leaflet (Wolters Kluwer) Comtan Concise Consumer Information (Cerner Multum) Comtan Advanced Consumer (Micromedex) - Includes Dosage Information Entacapone Professional Patient Advice (Wolters Kluwer) Compare Comtan with other medications Parkinson's Disease
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Tamoxifen Citrate


Class: Antineoplastic Agents
VA Class: AN500
Chemical Name: 2-Hydroxy-1,2,3-propanetricarboxylate-(Z)-2-[4-(1,2-diphyl-1-butenyl)phenoxy]-N,Ndimethyl ethanamine
Molecular Formula: C26H29NO•C6H8O7
CAS Number: 54965-24-1
Brands: Nolvadex

For women with ductal carcinoma in situ (DCIS) and women at high risk for breast cancer: serious and life-threatening events associated with tamoxifen in the risk reduction setting include uterine malignancies, stroke, and pulmonary embolism.a Incidence rates for these events have been estimated from the NSABP P-1 trial (median length of follow-up 6.9 years).a

Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1000 women-years of 2.2 for tamoxifen versus 0.71 for placebo) and uterine sarcoma (incidence rate per 1000 women-years of 0.17 for tamoxifen versus 0 for placebo).

For stroke, the incidence rate per 1000 women-years was 1.43 for tamoxifen versus 1 for placebo.a

For pulmonary embolism, the incidence rate per 1000 women-years was 0.75 for tamoxifen versus 0.25 for placebo.a

Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer.a

The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer.a

Introduction

A nonsteroidal estrogen agonist-antagonist; an antineoplastic agent.128

Uses for Tamoxifen Citrate Breast Cancer

An adjuvant to surgery and radiation therapy for the treatment of breast cancer in women with negative axillary lymph nodes and in postmenopausal women with positive axillary lymph nodes.110 121 128 130 133 136 194 195 196 198 204 205 253 254 258 Also reduces the occurrence of contralateral breast cancer in these women.128 253 254 258

Reduction of risk of invasive breast cancer in patients with DCIS following surgery and radiation therapy.a

Palliative treatment of metastatic breast cancer in men and women.128 An alternative to ovarian ablative therapy (oopherectomy or radiation) in premenopausal women.128 133 158 159 160 161 162 163 164 165 166 167 168 169 183

Reduction in the incidence of breast cancer in women at high risk for developing the disease.128 293

Albright’s Syndrome

Has been used to reduce the frequency of vaginal bleeding episodes and to reduce the rate of increase in bone age in girls with Albright’s syndrome (McCune-Albright syndrome†) and precocious puberty.a

Long-term effects not established.a

Tamoxifen Citrate Dosage and Administration General

Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.

Administration

Administered orally as a single daily dose or in divided doses; dosages exceeding 20 mg daily should be given in divided doses (morning and evening).128

Initiate therapy during menstruation when used to reduce the incidence of breast cancer in sexually active women.a In women with menstrual irregularity, a negative ?-human chorionic gonadotropin test immediately prior to therapy is sufficient.a

Dosage

Available as tamoxifen citrate; dosage expressed in terms of tamoxifen.128

Adults Breast Cancer Adjuvant Therapy Oral

20–40 mg daily.100 102 110 121 128 129 130 194 195 196 205 Current data from clinical studies support 5 years of adjuvant therapy.128 194 195 196 253 254 256 257 291 328

Ductal Carcinoma in Situ Oral

20 mg daily for 5 years.a

Metastatic Breast Cancer Oral

20–40 mg daily.128

Reduction in the Incidence of Breast Cancer in Women at High Risk Oral

20 mg daily for 5 years.128 270 284 291

Prescribing Limits Adults Breast Cancer Adjuvant Therapy Oral

No evidence that dosages >20 mg daily are more effective.112 128

Cautions for Tamoxifen Citrate Contraindications

Known hypersensitivity to tamoxifen or any ingredient in the formulation.128

When used in women with DCIS and women at high risk for breast cancer, history of DVT or pulmonary embolism.a

When used in women with DCIS and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative.a 278 293 309

Warnings/Precautions Warnings Hypercalcemia

Hypercalcemia reported in patients with metastatic breast cancer who have bone metastases.128 129 If hypercalcemia occurs, take appropriate measures; if severe, discontinue tamoxifen.128

Effects on the Uterus

Increased incidence of uterine malignancies, sometimes fatal, reported.128 330 Most uterine malignancies have been classified as adenocarcinoma of the endometrium; rare uterine sarcomas also reported.128 330 (See Boxed Warning.) Gynecologic symptoms (i.e., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, pelvic pain or pressure) should be promptly evaluated.128 163 183

Endometrial changes, including hyperplasias and polyps, endometriosis and uterine fibroids reported.128 180 258 259 274 Ovarian cysts reported in a small number of premenopausal women with advanced breast cancer.128

Cardiovascular Effects

Increased incidence of thromboembolic events, including DVT128 293 and pulmonary embolism; 269 270 293 stroke also reported.128 269 277 293 Some cases of stroke and pulmonary emboli have been fatal.128 (See Boxed Warning.) Concomitant use with chemotherapy may increase incidence of these events.128

Hepatic Effects

Liver cancer reported.128

Changes in AST, ALT, bilirubin and/or alkaline phosphatase concentrations reported; severe hepatic abnormalities including fatty changes in the liver, cholestasis, hepatitis, and hepatic necrosis (some fatal) reported rarely.128

Ocular Effects

Visual disturbances, decrement in color vision perception, corneal changes, cataracts, optic neuritis, retinal vein thrombosis, intraretinal crystals, posterior subcapsular opacities, and/or retinopathy reported.128 190 191 192 193 258 268 326

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.128 If inadvertently used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard, including possible long-term risk of a diethylstilbestrol-like syndrome.128

General Precautions Hematologic Effects

Thrombocytopenia, neutropenia, pancytopenia, and leukopenia reported; caution in patients with leukopenia or thrombocytopenia.128 Periodic CBCs, including platelet count recommended.128

Specific Populations Pregnancy

Category D.128 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether tamoxifen is distributed into milk.128 Discontinue nursing or the drug because of potential risk to nursing infant.128

Pediatric Use

Safety and efficacy in girls 2–10 years of age with Albright’s syndrome and precocious puberty not studied beyond 1 year; long-term effects not established and continued monitoring recommended.a (See Special Populations under Pharmacokinetics.)

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.a

Common Adverse Effects

Hot flashes, vaginal discharge, menstrual irregularities, weight loss.128

Interactions for Tamoxifen Citrate

A substrate of CYP3A, 2C9, 2D6.a

Effect of tamoxifen on drugs that require mixed function oxidases for activation unknown.a

Cytotoxic Agents

Increased risk of thromboembolic events.128

Specific Drugs

Drug

Interaction

Comments

Aminoglutethimide

Decreased plasma tamoxifen and N-desmethyltamoxifen concentrations128

Anticoagulants (e.g., warfarin)

Enhanced warfarin effects128 170 171 172

Careful monitoring of PT is recommended128 170 171 172

When used in women with DCIS or at high risk for breast cancer, concomitant use contraindicateda

Bromocriptine

Increased plasma tamoxifen and N-desmethyltamoxifen concentrations128

Cyclosporine

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Diltiazem

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Erythromycin

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Letrozole

Decreased plasma letrozole concentrationsa

Medroxyprogesterone

Decreased plasma N-desmethyltamoxifen concentrations but did not reduce plasma tamoxifen concentrationsa

Nifedipine

Competitively inhibited formation of N-desmethyltamoxifen in vitroa

Clinicial importance unknowna

Phenobarbital

Decreased plasma tamoxifen concentrations128

Clinical importance unknown128

Rifampin

Decreased plasma tamoxifen and N-desmethyltamoxifen concentrationsa

Tamoxifen Citrate Pharmacokinetics Absorption Bioavailability

Absorbed slowly following oral administration; peak serum concentrations of tamoxifen occur about 3–6 hours after a single dose.128 137 138 139 140 141

Plasma Concentrations

Steady-state concentrations of tamoxifen are attained after 3–4 weeks and those of N-desmethyltamoxifen, an active metabolite, are attained after 3–8 weeks.128 137 140 143 145

Distribution Extent

Not fully characterized.128

Not known whether tamoxifen is distributed into milk.128

Elimination Metabolism

Rapidly and extensively metabolized.26 28 140 142 143 144 145 146 148 149 150 151 The major metabolite, N-desmethyltamoxifen,128 140 143 144 145 146 148 150 151 has biologic activity similar to that of the parent drug.128

Elimination Route

Excreted principally in feces as polar conjugates.128

Half-life

Tamoxifen: 5–7 days.28 137 139 145

N-Desmethyltamoxifen: 9–14 days.128 139 145

Special Populations

Clearance higher in female children 2–10 years of age than in women; exposure to N-desmethyltamoxifen in these pediatric patients similar to adults.a

Stability Storage Oral Tablets

Well-closed, light-resistant containers 20–25°C.128

ActionsActions

Acts as an estrogen antagonist on breast tissue and in the CNS and as an estrogen agonist on endometrium, bone, and lipids.311

In breast epithelial tissue, increases production of inhibitory factors and decreases production of stimulatory factors that influence breast cell growth.271 286 287 323

Reduces bone resorption and bone turnover.265 266 267 316

Decreases total and LDL-cholesterol concentrations.318 319 320 Less favorably, decreases HDL-cholesterol concentrations and increases triglyceride concentrations.318 319 320

Acts as an estrogen agonist on the uterus and exhibits proliferative and tumor-promoting effects on the endometrium.311

Advice to Patients

Importance of receiving routine gynecologic care and of immediately informing clinician if any new breast lumps or abnormal gynecologic symptoms, including abnormal vaginal bleeding, change in vaginal discharge, menstrual irregularities, or pelvic pain/pressure occur.128 163 183

Importance of informing clinician of any changes in vision.128 190 191 192 193 258 268

Importance of immediately informing clinician of unexplained shortness of breath or leg swelling/tenderness.128

Importance of periodic monitoring, including liver function test monitoring and blood counts.128

Advise patients at high risk of breast cancer that tamoxifen may decrease the incidence of breast cancer, but may not eliminate the risk of the disease.128

Importance of women informing clinicians immediately if they are or plan to become pregnant; importance of avoiding pregnancy during therapy;119 128 243 importance of using effective nonhormonal contraception while receiving tamoxifen and for 2 months after discontinuing the drug.a Necessity of advising pregnant patients of the risk to the fetus.128

Importance of reading the medication guide; the guide is for women using tamoxifen to lower their risk of breast cancer or with DCIS.128

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.128

Importance of women informing clinicians if they are or plan to breast-feed.128

Importance of informing patients of other important precautionary information.128 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Tamoxifen Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

10 mg (of tamoxifen)*

Nolvadex

AstraZeneca

Tamoxifen Citrate Tablets

Aegis, Andrx, Barr, Mylan, Roxane, Teva

20 mg (of tamoxifen)*

Nolvadex

AstraZeneca

Tamoxifen Citrate Tablets

Aegis, Andrx, Barr, Mylan, Roxane, Teva

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nolvadex 20MG Tablets (ASTRAZENECA): 30/$120.99 or 60/$239.98

Tamoxifen Citrate 20MG Tablets (TEVA PHARMACEUTICALS USA): 30/$21.99 or 90/$49.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

26. Fromson JM, Sharp DS. The selective uptake of tamoxifen by human uterine tissue. J Obstet Gynaecol Br Comm. 1974; 81:321-3.

28. Fromson JM, Pearson S. The metabolism of tamoxifen (I.C.I. 46,474). Part II: in female patients. Xenobiotica. 1973; 3:711-4. [PubMed 4783632]

100. Nolvadex Adjuvant Trial Organisation. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer: interim analysis at four years. Lancet. 1983; 1:257-61. [IDIS 164603] [PubMed 6130291]

101. Nolvadex Adjuvant Trial Organisation. Improved survival amongst patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. Lancet. 1983; 2:450.

102. Ribeiro G, Palmer MK. Adjuvant tamoxifen for operable carcinoma of the breast: report of clinical trial by the Christie Hospital and Holt Radium Institute. BMJ. 1983; 286:827-30. [IDIS 168605] [PubMed 6403101]

103. Brinkley D. Adjuvant questions. BMJ. 1984; 288:1709-10. [PubMed 6428507]

104. Patterson JS, Battersby LA, Bach BK. Use of tamoxifen in advanced male breast cancer. Cancer Treat Rep. 1980; 64:801-4. [PubMed 7427964]

105. Becher R, H?ffken K, Pape H et al. Tamoxifen treatment before orchiectomy in advanced breast cancer in men. N Engl J Med. 1981; 305:169-70. [IDIS 133415] [PubMed 7242589]

106. Hortobagyi GN, Distefano A, Legha SS et al. Hormonal therapy with tamoxifen in male breast cancer. Cancer Treat Rep. 1979; 63:539-41. [IDIS 112371] [PubMed 221118]

107. Stathopoulos GP, Karvountzis GG, Yiotis J. Tamoxifen in carcinoid syndrome. N Engl J Med. 1981; 305:52. [IDIS 133352] [PubMed 7231519]

108. Myers CF, Ershler WB, Tannenbaum MA et al. Tamoxifen and carcinoid tumor. Ann Intern Med. 1982; 96:383. [IDIS 146199] [PubMed 7059114]

109. Moertel CG, Engstrom PF, Schutt AJ. Tamoxifen therapy for metastatic carcinoid tumor: a negative study. Ann Intern Med. 1984; 100:531-2. [IDIS 183832] [PubMed 6200021]

110. Nolvadex Adjuvant Trial Organisation. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer: analysis at six years. Lancet. 1985; 1:836-40. [IDIS 199145] [PubMed 2858709]

111. Rose C, Thorpe SM, Andersen KW et al. Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet. 1985; 1:16-9. [PubMed 2856949]

112. National Institutes of Health Office of Medical Applications of Research. Consensus conference: adjuvant chemotherapy for breast cancer. JAMA. 1985; 254:3461-3. [IDIS 207936] [PubMed 4068189]

113. Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984; 1:1256-60. [IDIS 186376] [PubMed 6144974]

114. Fisher B, Fisher ER, Redmond C. A brief overview of findings from NSABP trials of adjuvant therapy. Recent Results Cancer Res. 1984; 96:55-65. [PubMed 6101262]

115. Hubay CA, Gordon NH, Crowe JP et al. Antiestrogen-cytotoxic chemotherapy and Bacillus Calmette-Guerin vaccination in stage II breast cancer: seventy-two-month follow-up. Surgery. 1984; 96:61-72. [PubMed 6740497]

116. Cummings FJ, Gray R, Davis TE et al. Adjuvant tamoxifen treatment of elderly women with Stage II breast cancer: a double-blind comparison with placebo. Ann Intern Med. 1985; 103:324-9. [IDIS 205815] [PubMed 3896085]

117. Gau T (Stuart Pharmaceuticals, Wilmington, DE): Personal communication; 1986 Jan 13.

118. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep. 1978; 62:315-20. [PubMed 647693]

119. Diver JMJ, Jackson IM, Fitzgerald JD. Tamoxifen and non-malignant indications. Lancet. 1986; 1:733. [IDIS 213703] [PubMed 2870236]

120. Kaiser-Kupfer MI, Kupfer C, Rodrigues MM. Tamoxifen retinopathy: a clinicopathologic report. Ophthalmology. 1981; 88:89-93. [PubMed 7243233]

121. Report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish trial. Lancet. 1987; 2:171-5. [IDIS 233071] [PubMed 2885637]

122. Fisher B, Brown A, Wolmark N et al. Prolonging tamoxifen therapy for primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project Clinical Trial. Ann Intern Med. 1987; 106:649-54. [IDIS 229430] [PubMed 3551710]

123. Tormey DC. Long-term adjuvant therapy with tamoxifen in breast cancer: how long is long? Ann Intern Med. 1987; 106:762-4. Editorial.

124. Zielinski CC, Kubista E, Salzer H et al. Adjuvant chemotherapy combined with tamoxifen in postmenopausal patients with stage II breast cancer. Lancet. 1986; 2:1164. [IDIS 223328] [PubMed 2877314]

125. Fentiman IS, Caleffi M, Brame E et al. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet. 1986; 1:287-8. [IDIS 211071] [PubMed 2868162]

126. Fentiman IS. Tamoxifen and mastalgia: an emerging indication. Drugs. 1986; 32:477-80. [IDIS 223766] [PubMed 3539572]

127. Fisher B, Redmond C, Brown A et al. Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol. 1983; 1:227-41. [PubMed 6366135]

128. Zeneca Pharmaceuticals. Nolvadex (tamoxifen citrate) prescribing information. Wilmington, DE; 1998 Oct 28.

129. Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med. 1988; 109:219-28. [IDIS 244745] [PubMed 3291659]

130. National Cancer Institute. Clinical alert on breast cancer. Bethesda, MD: National Cancer Institute; 1988 May 18.

131. Bradbeer JW, Kyngdon J. Primary treatment of breast cancer in elderly women with tamoxifen. Clin Oncol. 1983; 9:31-4. [PubMed 6851305]

132. Taylor SG IV, Gelman RS, Falkson G et al. Combination chemotherapy compared to tamoxifen as initial therapy for stage IV breast cancer in elderly women. Ann Intern Med. 1986; 104:455-61. [IDIS 213853] [PubMed 3513684]

133. Glick JH. Meeting highlights: adjuvant therapy for breast cancer. J Natl Cancer Inst. 1988; 80:471-5. [PubMed 3367387]

134. Delozier T, Julien JP, Juret P et al. Adjuvant tamoxifen in postmenopausal breast cancer: preliminary results of a randomized trial. Breast Cancer Res Treat. 1986; 7:105-10. [PubMed 3521767]

135. Fisher B, Redmond C, Brown A et al. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol. 1986; 4:459-71. [PubMed 2856857]

136. Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 randomized trials among 28,896 women. N Engl J Med. 1988; 319:1681-92. [IDIS 248808] [PubMed 3205265]

137. Fabian C, Sternson L, Barnett M. Clinical pharmacology of tamoxifen in patients with breast cancer: comparison of traditional and loading dose schedules. Cancer Treat Rep. 1980; 64:765-73. [PubMed 7427961]

138. Adam HK, Gay MA, Moore RH. Measurement of tamoxifen in serum by thin-layer densitometry. J Endocrinol. 1980; 84:35-42. [PubMed 7359080]

139. Adam HK, Patterson JS, Kemp JV. Studies on the metabolism and pharmacokinetics of tamoxifen in normal volunteers. Cancer Treat Rep. 1980; 64:761-4. [PubMed 7427960]

140. McVie JG, Simonetti GPC, Stevenson D et al. The bioavailability of Tamoplex(tamoxifen). Part 1: a pilot study. Methods Find Exp Clin Pharmacol. 1986; 8:505-12. [PubMed 3747644]

141. Wilkinson P, Ribeiro G, Adam H et al. Clinical pharmacology of tamoxifen and N-desmethyltamoxifen in patients with advanced breast cancer. Cancer Chemother Pharmacol. 1980; 5:109-11. [PubMed 7471314]

142. Fromson JM, Pearson S, Bramah S. The metabolism of tamoxifen (I.C.I. 46,474). Part I: in laboratory animals. Xenobiotica. 1973; 3:693-709. [PubMed 4361333]

143. Milano G, Etienne MC, Frenay M et al. Optimised analysis of tamoxifen and its main metabolites in the plasma and cytosol of mammary tumours. Br J Cancer. 1987; 55:509-12. [PubMed 3606944]

144. Daniel P, Gaskell SJ, Bishop H et al. Determination of tamoxifen and biologically active metabolites in human breast tumours and plasma. Eur J Cancer Clin Oncol. 1981; 17:1183-9. [PubMed 7199465]

145. Jordan VC. Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance. Breast Cancer Res Treat. 1982; 2:123-38. [PubMed 6184101]

146. Soininen K, Kleimola T, Elomaa I et al. The steady-state pharmacokinetics of tamoxifen and its metabolites in breast cancer patients. J Int Med Res. 1986; 14:162-5. [PubMed 3522312]

147. Ribeiro GG, Wilkinson PM. A clinical assessment of loading dose tamoxifen for advanced breast carcinoma. Clin Oncol. 1984; 10:363-7. [PubMed 6509818]

148. Adam HK, Douglas EJ, Kemp JV. The metabolism of tamoxifen in humans. Biochem Pharmacol. 1979; 27:145-7.

149. Bain RR, Jordan VC. Identification of a new metabolite of tamoxifen in patient serum during breast cancer therapy. Biochem Pharmacol. 1983; 32:373-5. [PubMed 6870963]

150. Jordan VC, Bain RR, Brown RR et al. Determination and pharmacology of a new hydroxylated metabolite of tamoxifen observed in patient sera during therapy for advanced breast cancer. Cancer Res. 1983; 43:1446-50. [IDIS 165659] [PubMed 6825112]

151. Murphy C, Fotsis T, Pantzar P et al. Analysis of tamoxifen and its metabolites in human plasma by gas chromatography-mass spectrometry (GC-MS) using selected ion monitoring (SIM). J Steroid Biochem. 1987; 26:547-55. [PubMed 3586671]

152. Kemp JV, Adam HK, Wakeling AE et al. Identification and biological activity of tamoxifen and metabolites in human serum. Biochem Pharmacol. 1983; 32:2045-52. [PubMed 6870933]

153. Jordan VC, Collins MM, Rowsby L et al. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977; 75:305-16. [PubMed 591813]

154. Wakeling AE, Slater SR. Estrogen-receptor binding and biologic activity of tamoxifen and its metabolites. Cancer Treat Rep. 1980; 64:741-4. [PubMed 7427959]

155. Fabian C, Tilzer L, Sternson L. Comparative binding affinities of tamoxifen, 4-hydroxytamoxifen, and desmethyltamoxifen for estrogen receptors isolated from human breast carcinoma: correlation with blood levels in patients with metastatic breast cancer. Biopharm Drug Dispos. 1981; 2:381-90. [IDIS 143191] [PubMed 7317574]

156. Borgna JL, Rochefort H. Hydroxylated metabolites of tamoxifen are formed in vivo and bound to estrogen receptor in target tissues. J Biol Chem. 1981; 256:859-68. [PubMed 7451477]

157. Coezy E, Borgna JL, Rochefort H. Tamoxifen and metabolites in MCF, cells: correlation between binding to estrogen receptor and inhibition of cell growth. Cancer Res. 1982; 42:317-23. [PubMed 7053859]

158. Pritchard KI, Thomson DB, Myers RE et al. Tamoxifen therapy in premenopausal patients with metastatic breast cancer. Cancer Treat Rep. 1980; 64:787-96. [PubMed 7427962]

159. Manni A, Pearson OH. Antiestrogen-induced remissions in premenopausal women with stage IV breast cancer: effects on ovarian function. Cancer Treat Rep. 1980; 64:779-85. [PubMed 6775808]

160. Sawka CA, Pritchard KI, Paterson AH et al. Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma. Cancer Res. 1986; 46:3152-6. [IDIS 217168] [PubMed 3084082]

161. Ingle JN, Krook JE, Green SJ et al. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol. 1986; 4:178-85. [PubMed 3511184]

162. Buchanan RB, Blamey RW, Durrant KR et al. A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol. 1986; 4:1326-30. [PubMed 3528402]

163. Legha SS. Tamoxifen in the treatment of breast cancer. Ann Intern Med. 1988; 109:219-28. [IDIS 244745] [PubMed 3291659]

164. Hoogstraten B, Fletcher WS, Gad-el-Mawla N et al. Tamoxifen and oophorectomy in the treatment of recurrent breast cancer. A Southwest Oncology Group study. Cancer Res. 1982; 42:4788-91. [IDIS 159551] [PubMed 7127314]

165. Yoshida M, Murai H, Miura S. Tamoxifen therapy for premenopausal and postmenopausal Japanese females with advanced breast cancer. Jpn J Clin Oncol. 1982; 12:57-63.

166. Margreiter R, Wiegele J. Tamoxifen (Nolvadex) for premenopausal patients with advanced breast cancer. Breast Cancer Res Treat. 1984; 4:45-8. [PubMed 6365211]

167. Planting AS, Alexieva-Figusch J, Blonk-VdWijst J et al. Tamoxifen therapy in premenopausal women with metastatic breast cancer. Cancer Treat Res. 1985; 69:363-8.

168. Wada T, Koyama H, Terasawa T. Effect of tamoxifen in premenopausal Japanese women with advanced breast cancer. Cancer Treat Rep. 1981; 65:728-9. [IDIS 137005] [PubMed 7248991]

169. Hoogstraten B, Gad-el-Mawla N, Maloney TR et al. Combined modality therapy for first recurrence of breast cancer. A Southwest Oncology Group study. Cancer. 1984; 54:2248-56. [IDIS 193333] [PubMed 6488144]

170. Lodwick R, McConkey B, Brown AM. Life threatening interaction between tamoxifen and warfarin. BMJ. 1987; 295:1141. [IDIS 235136] [PubMed 3120919]

171. Tenni P, Lalich DL, Byrne MJ. Life threatening interaction between tamoxifen and warfarin. BMJ. 1989; 298:93. [IDIS 249683] [PubMed 2493305]

172. Ritchie LD, Grant SMT. Tamoxifen–Warfarin interaction: the Aberdeen hospitals drug file. BMJ. 1989; 298:1253.

173. Fornander T, Rutquist LE, Cedermark B et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet. 1989; 1:117-20. [IDIS 249801] [PubMed 2563046]

174. Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet. 1988; 2:563. [IDIS 245548] [PubMed 2900934]

175. Killackey MA, Hakes TB, Pierce VK. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep. 1985; 69:237-8. [IDIS 196903] [PubMed 3971394]

176. Jordan VC. Tamoxifen and endometrial cancer. Lancet. 1989; 1:733-4. [IDIS 254039] [PubMed 2564550]

177. Gottardis MM, Robinson SP, Satyaswaroop PG et al. Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res. 1988; 48:812-5. [PubMed 3338079]

178. Neven P, De Muylder X, Van Belle Y et al. Tamoxifen and the uterus and endometrium. Lancet. 1989; 1:375. [IDIS 250800] [PubMed 2563519]

179. Stewart HJ, Knight GM. Tamoxifen and the uterus and endometrium. Lancet. 1989; 1:375-6. [PubMed 18446929]

180. Cano A, Matallin P, Legua V et al. Tamoxifen and the uterus and endometrium. Lancet. 1989; 1:376. [PubMed 18446930]

181. Boccardo F, Bruzzi P, Rubagotti A et al. Estrogen-like action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology. 1981; 38:281-5. [PubMed 7266969]

182. Boccardo F, Guarneri D, Rubagotti A et al. Endocrine effects of tamoxifen in postmenopausal breast cancer patients. Tumori. 1984; 70:61-8. [PubMed 6538707]

183. Buckley MMT, Goa KL. Tamoxifen: a reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use. Drugs. 1989; 37:451-90. [IDIS 257967] [PubMed 2661195]

184. Cuzick J, Baum M. Tamoxifen and contralateral breast cancer. Lancet. 1985; 2:282. [IDIS 203072] [PubMed 2862460]

185. Brun LD, Gagne C, Rousseau C et al. Severe lipemia induced by tamoxifen. Cancer. 1986; 57:2123-6. [IDIS 216127] [PubMed 3697911]

186. Noguchi M, Taniya T, Tajiri K et al. Fatal hyperlipaemia in a case of metastatic breast cancer treated by tamoxifen. Br J Surg. 1987; 74:586-7. [PubMed 3620865]

187. Taniya T, Noguchi M, Tajiri K et al. [A case report of hyperlipemia with giant fatty liver during adjuvant endocrine therapy by tamoxifen]. Gan No Rinsho. 1987; 33:300-4. [PubMed 3108557]

188. Rossner S, Wallgren A. Serum lipoproteins and proteins after breast cancer surgery and effects of tamoxifen. Atherosclerosis. 1984; 52:339-46. [PubMed 6497936]

189. McKeown CA, Swartz M, Blom J et al. Tamoxifen retinopathy. Br J Ophthalmol. 1981; 65:177-9. [PubMed 7225310]

190. Vinding T, Nielsen NV. Retinopathy caused by treatment with tamoxifen in low dosage. Acta Ophthalmol. 1983; 61:45-50.

191. Griffiths MF. Tamoxifen retinopathy at low dosage. Am J Ophthalmol. 1987; 104:185-6. [IDIS 232920] [PubMed 3039846]

192. Ashford AR, Donev I, Tiwari RP et al. Reversible ocular toxicity related to tamoxifen therapy. Cancer. 1988; 61:33-5. [IDIS 237645] [PubMed 3334951]

193. Pugesgaard T, Von Eyben FE. Bilateral optic neuritis evolved during tamoxifen treatment. Cancer. 1986; 58:383-6. [IDIS 218074] [PubMed 3719532]

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Probenecid


Class: Uricosuric Agents
VA Class: MS400
CAS Number: 57-66-9
Brands: Col-Probenecid

Introduction

Uricosuric and renal tubular transport blocking agent.b

Uses for Probenecid Hyperuricemia Associated with Gout

Reduction of serum uric acid concentrations in chronic gouty arthritis and tophaceous gout in patients with frequent disabling gout attacks.a b

Management of gout when there are visible tophi or when serum urate concentrations exceed 8.5–9 mg/dL and patient has family history of tophi or low urate excretion.b

Not usually recommended for management of asymptomatic hyperuricemia; however, some clinicians have suggested that therapy be initiated when serum urate concentrations exceed 9 mg/dL (by colorimetric method) because these concentrations often are associated with increased joint changes and renal complications.b

Of no value in the treatment of acute gout attacks (due to lack of analgesic or anti-inflammatory activity).b

Probenecid/colchicine fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.b

Hyperuricemia Secondary to Other Causes

Has been used effectively to promote uric acid excretion in hyperuricemia secondary to the administration of thiazide and related diuretics†, furosemide†, ethacrynic acid†, pyrazinamide†, or ethambutol†.b

Not recommended to treat hyperuricemia secondary to cancer chemotherapy, radiation, or myeloproliferative neoplastic diseases because of increased risk of uric acid nephropathy.b

Infections

Used for therapeutic advantage to increase concentrations of certain ?-lactam anti-infectives in the treatment of gonorrhea, neurosyphilis, or pelvic inflammatory disease (PID); do not use alone for treatment of gonorrhea, neurosyphilis, or PID.a c

Used as an adjunct to IM cefoxitin for treatment of uncomplicated urogenital and anorectal gonorrhea† in adults and adolescents;c considered an alternative regimen by CDC.c

Used as an adjunct to IM penicillin G procaine for treatment of neurosyphilis if compliance can be ensured; considered an alternative regimen by CDC.c

Used as an adjunct to IM cefoxitin for treatment of PID†; considered a regimen of choice by CDC.c

Diagnostic Agent

Has been used in diagnosis of parkinsonian syndrome† and mental depression†.b

Probenecid Dosage and Administration General

Adjust dosage according to individual response and tolerance.a b

Maintain fluid intake to yield daily urine output of ?2–3 L; alkalinization of urine is desirable.a b (See Renal Effects under Cautions.)

Hyperuricemia Associated with Gout

Administer prophylactic doses of colchicine concurrently during the first 3–6 months of probenecid therapy because probenecid may increase the frequency of acute gout attacks during the first 6–12 months of therapy.b Initiate colchicine prior to uricosuric therapy since sudden changes in serum urate concentrations may precipitate acute attacks.

Initially, low probenecid doses are recommended to reduce the possibility of flare-up of acute gouty attacks and to prevent massive uricosuria.b If acute attack occurs during therapy, continue probenecid without changing dosage and administer full therapeutic doses of colchicine or other anti-inflammatory agents.b (See Acute Gout Attacks under Cautions.)

Serum urate concentrations usually reach a minimum within a few days after beginning therapy.b

Infections

The 15-minute IV phenolsulfonphthalein (PSP) excretion test can be used to determine effectiveness of probenecid in decreasing penicillin secretion.a b Probenecid dosage is adequate when renal clearance of the dye is reduced to approximately 20% of the normal rate.a b

Administration Oral Administration

Administer with food or antacids to minimize GI effects.a b (See Common Adverse Effects under Cautions.)

Dosage Pediatric Patients Infections General Dosage (Probenecid and Penicillin Therapy) Oral

Children 2–14 years of age: Initial dose of 25 mg/kg (or 700 mg/m2); subsequently, 40 mg/kg (or 1.2 g/m2) daily, given in 4 divided doses daily (given as an adjunct with a penicillin).a b

Children weighing >50 kg: 500 mg 4 times daily (given as an adjunct with a penicillin).a b

Uncomplicated Gonorrhea† Oral

Adolescents: 1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose).c

Neurosyphilis Oral

Adolescents: 500 mg 4 times daily for 10–14 days as an adjunct to IM penicillin G procaine (2.4 million units once daily for 10–14 days); some clinicians recommend that this regimen be followed by a regimen of IM penicillin G benzathine (2.4 million units once weekly for up to 3 weeks).c

PID† Oral

Adolescents: 1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose); followed by a 14-day regimen of oral doxycycline (100 mg twice daily) with or without oral metronidazole (500 mg twice daily).c

Adults Hyperuricemia Associated with Gout Oral

Initially, 250 mg twice daily for one week, initiated 2–3 weeks after an acute gout attack.a b Subsequently, increase to 500 mg twice daily.a b

Patients previously controlled with other uricosuric therapy: Initially, 500 mg twice daily.b

If gouty arthritis is not controlled or if 24-hour uric acid excretion is <700 mg, increase daily dosage by 500 mg every 4 weeks as tolerated to a maximum of 2–3 g daily.a b

If acute attacks have been absent ?6 months and serum urate concentrations are controlled, consider decreasing daily dosage by 500 mg every 6 months.a b

Continue therapy indefinitely; irregular dosage schedules may lead to increased serum urate concentrations.b

Probenecid/Colchicine Fixed-Combination Therapy Oral

Fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.b

Manufacturer recommends initial dosage of probenecid 500 mg in fixed combination with colchicine 0.5 mg (1 tablet) daily for 1 week, then 1 tablet twice daily.e If gouty arthritis is not controlled or if 24-hour uric acid excretion is ?700 mg, increase daily dosage by 1 tablet every 4 weeks as tolerated (generally not exceeding 4 tablets [probenecid 2 g and colchicine 2 mg] daily).e

If acute attacks have been absent ?6 months and serum urate concentrations are controlled, manufacturer recommends reducing dosage by 1 tablet every 6 months as long as serum urate concentrations remain controlled.e

Infections General Dosage (Probenecid and Penicillin Therapy) Oral

500 mg 4 times daily as an adjunct to a penicillin.a b

Uncomplicated Gonorrhea† Oral

1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose).c

Neurosyphilis Oral

500 mg 4 times daily for 10–14 days as an adjunct to IM penicillin G procaine (2.4 million units once daily for 10–14 days); some clinicians recommend that this regimen be followed by a regimen of IM penicillin G benzathine (2.4 million units once weekly for up to 3 weeks).c

PID† Oral

1 g as a single dose as an adjunct to IM cefoxitin (2 g as a single dose); followed by a 14-day regimen of oral doxycycline (100 mg twice daily) with or without oral metronidazole (500 mg twice daily).c

Diagnosis of Parkinson’s Disease† or Mental Depression† Oral

500 mg every 12 hours for 5 doses.b Obtain CSF levels for homovanillic acid (HVA)(Parkinson’s disease) or 5-hydroxyindoleacetic acid (5-HIAA) (mental depression) 12 hours after last dose.b

Prescribing Limits Adults Hyperuricemia Associated with Gout Oral

Maximum 2–3 g daily.a b

Special Populations Hepatic Impairment

No specific dosage recommendations at this time.a

Renal Impairment

Dosage requirements may be increased in patients with mild renal impairment (Clcr ?50 mL/minute).a b Use not recommended in patients with moderate to severe renal impairment (Clcr <50 mL/minute). b (See Renal Impairment under Cautions.)

Geriatric Patients

No dosage adjustments except those related to renal impairment. a

Cautions for Probenecid Contraindications

Known blood dyscrasias.a b

Uric acid kidney stones.a b

Initiation of therapy during acute gout attack.a b (See Acute Gout Attacks under Cautions.)

Children <2 years of age.a b

Known hypersensitivity to probenecid or any ingredient in the formulation.a b

Warnings/Precautions Warnings Acute Gout Attacks

May exacerbate and prolong inflammation during acute gout attacks.b Initiate therapy 2–3 weeks after acute gout attack subsides.a b

Possible increased frequency of acute gout attacks during the first 6–12 months of therapy.a b If acute attacks occur during therapy, continue probenecid and administer colchicine or other anti-inflammatory agents.a b

Interactions

Methotrexate toxicity reported during concomitant probenecid therapy. a (See Specific Drugs under Interactions.)

Concomitant use with salicylates is not recommended.a (See Specific Drugs under Interactions.)

Sensitivity Reactions Hypersensitivity Reactions

Severe allergic reactions (e.g., dermatitis, pruritus, fever, sweating, hypotension) and anaphylaxis reported rarely; typically occurs within several hours after administration in patients who previously received the drug.a If hypersensitivity reaction occurs, discontinue therapy.a

If rash occurs during concomitant administration with a penicillin and causative agent cannot be determined, discontinuance of both drugs may be necessary.b

General Precautions Renal Effects

Possible development of uric acid stones due to increased concentration of uric acid in renal tubules; may result in hematuria, renal colic, costovertebral pain.a b Usually occurs when therapy is initiated.b

May be prevented by alkalinization of the urine and adequate hydration.a b (See General under Dosage and Administration.) Monitor acid-base balance if alkali is administered.a

Peptic Ulcer

Use with caution in patients with history of peptic ulcer.a b

Use of Fixed Combinations

When used in fixed combination with colchicine, consider the cautions, precautions, and contraindications associated with colchicine.e

Specific Populations Pregnancy

Category C.d

Lactation

Distribution into human milk is expected; however, effects on nursing infant not known.d Caution advised if probenecid is used because of potential risk to nursing infants.d

Pediatric Use

Use contraindicated in children <2 years of age.a

Geriatric Use

Consider age-related decreases in renal function when selecting dosage; adjust dosage if necessary.a b

Renal Impairment

Not effective in gouty patients with moderate to severe renal impairment (Clcr <50 mL/minute); avoid use in these patients.b May be effective in gouty patients with mild renal impairment (Clcr ?50 mL/minute), but increased dosages may be required.a b

Concomitant use with a penicillin or other ?-lactams not recommended in patients with known renal impairment.a

Common Adverse Effects

Headache, a b vomiting, a b nausea, a b anorexia.a b

Interactions for Probenecid Weak Organic Acids

Probenecid inhibits renal tubular secretion of many weak organic acids, thereby increasing plasma concentrations of weak organic acids.b

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Acetaminophen

Possible increased peak plasma concentrations of acetaminophen102

Select and adjust acetaminophen dosage with care; lower dosages may be adequatea

Alcohol

Potential for increased serum urate concentrationsa b

May need to increase probenecid dosageb

Allopurinol

Probenecid increases excretion of allopurinol’s active metabolite

Used concomitantly for additive therapeutic effectb

Antidiabetic agents, oral (sulfonylureas)

Possible increased plasma concentrations of oral sulfonylurea antidiabetic agents resulting in hypoglycemiaa b

Antineoplastic agents

Increased serum urate concentrations; possible uric acid nephropathyb

Avoid concomitant useb

?-Lactam antibiotics

Decreased renal excretion of ?-lactam antibiotics and increased concentrations of ?-lactam antibioticsa

Psychic disturbances reported with concomitant use101

Used concomitantly for additive therapeutic effecta

Consider adverse effects of increased antibiotic concentrationsa

Diazoxide

Potential for increased serum urate concentrationsa b

May need to increase probenecid dosageb

Diuretics, loop (furosemide, ethacrynic acid)

Potential for increased serum urate concentrationsa b

Inhibits furosemide and ethacrynic acid naturesisb

May need to increase probenecid dosageb

Diuretics, thiazide

Increased excretion of calcium, magnesium, and citrate; does not antagonize thiazide-induced naturesisb

Ganciclovir

Possible increase in AUC and decrease in renal excretion of ganciclovir

107 108

Ketamine

Possible prolonged anesthesiaa

Reported in animal studiesa

Lorazepam

Possible increased peak plasma concentrations of lorazepam102

Select and adjust lorazepam dosage with care; lower dosage may be adequatea

Methotrexate

Increased serum concentrations of methotrexate and methotrexate toxicitya b

Reduce methotrexate dosage and monitor carefullya

NSAIAs (indomethacin, ketoprofen, meclofenamate, naproxen, sulindac)

Increased plasma concentrations of NSAIAsa 102 103 104 105

Sulindac: Possible decreased uricosuric action of probenecid102 103

Select and adjust NSAIA dosage with care; lower dosage may be adequatea

Changes in uricosuric action unlikely to be clinically important102 103

Concomitant use of ketoprofen and probenecid not recommended104

Nitrofurantoin

Possible inhibition of renal excretion of nitrofurantoin resulting in increased risk of adverse effects and decreased efficacy in treatment of UTIsb

Avoid concomitant useb

Pyrazinamide

Pyrazinamide antagonizes uricosuric action of probenecid; potential for increased serum urate concentrationsa b

May need to increase probenecid dosageb

Rifampin

Possible inhibition of tubular secretion and hepatic uptake of rifampin resulting in small increases in plasma concentrations of rifampinb

Not considered clinically importantb

Salicylates

Reduced uricosuric effect of probenecida b

Concomitant use not recommendeda

Sulfinpyrazone

Probenecid inhibits the renal secretion of sulfinpyrazoneb

May be administered concurrently without adverse interactionb

Sulfonamides (i.e., sulfa antibiotics)

Increased serum concentrations of total sulfonamidea

Free sulfonamide concentrations not altered; concomitant use not therapeutically usefula

Tests for theophylline

Possible interference with Schack and Waxler assay resulting in falsely elevated theophylline concentrationsa

Tests for urinary glucose

Possible interference with tests using cupric sulfate reagent (Benedict’s Qualitative Reagent, Clinitest, Fehling’s Solution) resulting in false-positive glycosuriaa b

May be caused by a reducing substance in the urine which disappears with discontinuance of therapya b

Use glucose oxidase reagent (Clinistix, Tes-Tape)a b

Thiopental

Possible increased serum concentrations of thiopentala 101

Reduced thiopental dosages may be requireda

Probenecid Pharmacokinetics Absorption Bioavailability

Rapidly and completely absorbed following oral administration, with peak plasma concentration attained within 2–4 hours.b

Onset

Following oral administration, maximal renal clearance of uric acid is reached after 30 minutes; exerts its effect on plasma penicillin concentrations after 2 hours.b

Distribution Extent

CSF concentrations of the drug are about 2% of plasma concentrations.b Crosses the placenta; not known whether distributed into milk; however, distribution into milk is expected.b d

Plasma Protein Binding

Approximately 75%.b

Elimination Metabolism

Slowly metabolized, principally by the liver, to metabolites that may possess some uricosuric activity.b

Elimination Route

Excreted principally in the urine as monoacyl glucuronide and unchanged drug.b Alkalinization of urine increases renal probenecid excretion.b

Half-life

Dose dependent; 4–17 hours.b

Stability Storage Oral Tablets

15–30°C.a

ActionsActions

Competitively inhibits active reabsorption of urate at the proximal convoluted tubule, increasing urinary excretion of uric acid and reducing serum urate concentrations.a b

Competitively inhibits tubular secretion of weak organic acids (e.g., penicillins, most cephalosporins, other ?-lactam antibiotics) and substantially increases plasma concentrations of acidic drugs eliminated principally by renal secretion.a b

Mechanism(s) of action responsible for inhibition of renal tubular transport not known; may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules.b

Advice to Patients

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses.a

Potential for drug to increase incidence of gouty arthritis attacks during therapy initiation.a b Continue probenecid during acute attacks, without changing dose, and add therapeutic dosages of colchicine or other anti-inflammatory agents.b

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a

Importance of informing patients of other important precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Probenecid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

500 mg*

Tablets, film-coated

500 mg*

Probenecid Tablets

Lannett, Mylan, Watson

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Probenecid and Colchicine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

500 mg Probenecid and Colchicine 0.5 mg*

Col-Probenecid

Watson

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Colchicine-Probenecid 0.5-500MG Tablets (WATSON LABS): 30/$35.99 or 90/$95.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Centers for Disease Control. Sexually transmitted diseases treatment guidelines 1989. MMWR Morb Mortal Wkly Rep. 1989; 38(Suppl 8S):1-43.

101. Merck Sharp & Dohme. Benemid (probenecid) prescribing information. In: Huff BB, ed. Physicians’ desk reference. 40th ed. Oradell, NJ: Medical Economics Company, Inc; 1986(Suppl A):A22.

102. Benemid (probenecid) tablets prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987 (Suppl B):B10-1.

103. Clinoril (sulindac) tablets prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987:1251-3.

104. Orudis (ketoprofen) capsules prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987:2179-81.

105. Naprosyn (naproxen) prescribing information. In: Huff BB, ed. Physicians’ desk reference. 41st ed. Oradell, NJ: Medical Economics Company Inc; 1987(Suppl B):B22-4.

106. Upton RA, Williams RL, Buskin JN et al. Effects of probenecid on ketoprofen kinetics. Clin Pharmacol Ther. 1982; 31:705-12. [IDIS 152190] [PubMed 7075118]

107. Roche. Valcyte (valganciclovir hydrochloride) tablets prescribing information. Nutley, NJ; 2001 Mar.

108. Roche. Cytovene-IV (ganciclovir sodium for injection) and Cytovene (ganciclovir capsules) prescribing information. Nutley, NJ; 2000 Sep.

a. Watson Laboratories, Inc. Probenecid prescribing information. Corona, CA; 2003 Jul.

b. AHFS drug information 2008. McEvoy GK, ed. Probenecid. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2792-5.

c. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR. 2006; 55(RR11):1-94.

d. Probenecid. In: Briggs GG, Freeman RK, Yaffe SJ. Drug in pregnancy and lactation: a reference guide to fetal and neonatal risk. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:1342-3

e. Watson Laboratories, Inc. Probenecid and colchicine tablets prescribing information. Corona, CA. 2006 Mar.

More Probenecid resources Probenecid Side Effects (in more detail) Probenecid Dosage Probenecid Use in Pregnancy & Breastfeeding Drug Images Probenecid Drug Interactions Probenecid Support Group 1 Review for Probenecid - Add your own review/rating Probenecid MedFacts Consumer Leaflet (Wolters Kluwer) Probenecid Prescribing Information (FDA) Probenecid Professional Patient Advice (Wolters Kluwer) probenecid Concise Consumer Information (Cerner Multum) probenecid Advanced Consumer (Micromedex) - Includes Dosage Information Compare Probenecid with other medications Adjunct to Antibiotic Therapy Gout
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Valacyclovir Hydrochloride


Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: 2-[(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxyl]ethyl ester-l-valine monohydrochloride
Molecular Formula: C13H20N6O4•ClH
CAS Number: 124832-27-5
Brands: Valtrex

Introduction

Antiviral; prodrug of acyclovir, a nucleoside.1

Uses for Valacyclovir Hydrochloride Genital Herpes

Treatment of initial episodes of genital herpes in immunocompetent1 24 29 30 or HIV-infected†24 adults and adolescents.

Episodic treatment of recurrent episodes of genital herpes in immunocompetent1 24 29 30 or HIV-infected†24 adults and adolescents.

Chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent or HIV-infected adults and adolescents.1 24 29 30 33 When used for suppressive therapy in immunocompetent individuals, the risk of heterosexual transmission of genital herpes to susceptible partners is reduced;1 35 efficacy for reducing transmission not established in those with multiple partners or in non-heterosexual couples.1

CDC and others recommend oral acyclovir, oral famciclovir, or oral valacyclovir as drug of choice for treatment of initial episodes of genital herpes and for episodic treatment or chronic suppressive therapy of recurrent genital herpes.24 29 30

Herpes Labialis

Treatment of herpes labialis (perioral herpes, cold sores, fever blisters) in adults and adolescents.1 34

Safety and efficacy not established in immunocompromised patients.1

Mucocutaneous Herpes Simplex Virus (HSV) Infections

Treatment of recurrent mucocutaneous HSV infections in HIV-infected adults†.26

Chronic suppressive or maintenance therapy (secondary prophylaxis) against recurrence of HSV infections† in HIV-infected individuals who have frequent or severe recurrences.25 26

Herpes Zoster

Treatment of acute, localized herpes zoster (shingles, zoster) in adults and adolescents.1 4 10 11

Treatment of localized dermatomal herpes zoster in HIV-infected adults or adolescents†.38 If cutaneous lesions are extensive or there is clinical evidence of visceral involvement, IV acyclovir should be used for initial treatment.38

Safety and efficacy not established in immunocompromised patients.1

Safety and efficacy not established for treatment of disseminated herpes zoster.1

Prevention of Cytomegalovirus (CMV) Disease in Transplant Recipients

Prevention of CMV disease in kidney transplant recipients† at high risk (CMV-seropositive donor).27

Not recommended for prevention of CMV disease in hematopoietic stem cell transplant (HSCT) recipients because the drug is presumed to be less effective than ganciclovir.31

Not recommended for primary prevention of CMV disease in HIV-infected individuals because of an unexplained trend toward increased mortality in clinical studies.25 28

Valacyclovir Hydrochloride Dosage and Administration Administration Oral Administration

Administer orally without regard to meals.1

Patients should maintain adequate hydration during treatment.1

Dosage

Available as valacyclovir hydrochloride;1 dosage expressed in terms of valacyclovir.1

Pediatric Patients Genital Herpes, Herpes Labialis, Mucocutaneous Herpes Simplex Virus (HSV) Infections, and Herpes Zoster Oral

Adolescents should receive dosage recommended for adults.24 (See Adults under Dosage and Administration.)

Adults Genital Herpes Treatment of First Episodes Oral

Immunocompetent adults: 1 g twice daily for 7–10 days.1 24 29 30 CDC suggests duration of treatment may be extended if healing is incomplete after 10 days.24

HIV-infected adults: 1 g twice daily for 7–14 days recommended by CDC and others.38

Initiate therapy within 48 hours of onset of signs and symptoms;1 efficacy not established if initiated >72 hours after onset of signs or symptoms.1

Episodic Treatment of Recurrent Episodes Oral

Immunocompetent adults: 500 mg twice daily for 3 days.1 24 29 30 Alternatively, CDC recommends 1 g once daily for 5 days†.24

HIV-infected adults: CDC recommends 1 g twice daily for 5–10 days;24 may be continued for 7–14 days.38

Initiate therapy at first sign or symptom of an episode;1 efficacy not established if initiated >24 hours after onset of signs or symptoms.1

Suppressive Therapy of Recurrent Episodes Oral

Immunocompetent adults: 1 g once daily.1 24 30 Alternatively, 500 mg once daily for those with a history of ?9 recurrences per year.1 24 30

HIV-infected adults: 500 mg twice daily.1 24

Manufacturer states safety and efficacy not established beyond a duration of 1 year in immunocompetent or 6 months in HIV-infected individuals.1

Because frequency of recurrent episodes diminishes over time in many patients, CDC and others recommend suppressive antiviral therapy be discontinued periodically (e.g., once yearly) to assess the need for continued therapy.24 29 30

Reduction of Transmission Oral

500 mg once daily in source partner with a history of ?9 recurrences per year.1

Efficacy for reducing transmission not established beyond a duration of 8 months in discordant couples.1

Herpes Labialis Oral

Immunocompetent adults: 2 g every 12 hours for 1 day;1 treatment for cold sores should not exceed 1 day.1

Initiate treatment at earliest symptom of cold sore (e.g., tingling, itching, burning);1 efficacy not established if initiated after development of clinical signs of cold sore (e.g., papule, vesicle, ulcer).1

Mucocutaneous Herpes Simplex Virus (HSV) Infections Chronic Suppression of Recurrent Episodes Oral

HIV-infected adults: 500 mg twice daily for chronic suppressive or maintenance therapy (secondary prophylaxis) of HSV infections in those who have frequent or severe recurrences.25

Herpes Zoster Oral

Immunocompetent adults: 1 g 3 times daily for 7 days.1

Local dermatomal herpes zoster in HIV-infected adults or adolescents†: 1 g 3 times daily for 7–10 days recommended by CDC and others.38

Initiate therapy at earliest sign or symptom (preferably within 48 hours of rash onset);1 efficacy not established if initiated >72 hours after rash onset.1

Special Populations Hepatic Impairment

Dosage adjustments not recommended for patients with cirrhosis.1

Renal Impairment Genital Herpes Oral Table 1. Dosage for Treatment of Genital Herpes in Renal Impairment1

Clcr (mL/min)

Daily Dosage

First Episodes

 

?50

1 g every 12 hours

30–49

1 g every 12 hours

10–29

1 g once every 24 hours

<10

500 mg once every 24 hours

Episodic Treatment of Recurrent Episodes

 

?50

500 mg every 12 hours

30–49

500 mg every 12 hours

10–29

500 mg once every 24 hours

<10

500 mg once every 24 hours

Suppressive Therapy of Recurrent Episodes (Immunocompetent with >9 Episodes/Year)

 

?50

1 g once every 24 hours

30–49

1 g once every 24 hours

10–29

500 mg once every 24 hours

<10

500 mg once every 24 hours

Suppressive Therapy of Recurrent Episodes (Immunocompetent with <9 Episodes/Year)

 

?50

500 mg once every 24 hours

30–49

500 mg once every 24 hours

10–29

500 mg once every 48 hours

<10

500 mg once every 48 hours

Suppressive Therapy of Recurrent Episodes (HIV-infected Individuals)

 

?50

500 mg every 12 hours

30–49

500 mg every 12 hours

10–29

500 mg once every 24 hours

<10

500 mg once every 24 hours

Herpes Labialis Oral Table 2. Dosage for Treatment of Herpes Labialis in Renal Impairment1

Clcr (mL/min)

Daily Dosage

?50

2 g every 12 hours for 1 day

30–49

1 g every 12 hours for 1 day

10–29

500 mg every 12 hours for 1 day

<10

A single dose of 500 mg

Herpes Zoster Oral Table 3. Dosage for Treatment of Herpes Zoster in Renal Impairment1

Clcr (mL/min)

Daily Dosage

?50

1 g every 8 hours

30–49

1 g every 12 hours

10–29

1 g once every 24 hours

<10

500 mg once every 24 hours

Hemodialysis

Usual dose should be administered after hemodialysis.23

Peritoneal Dialysis

Supplemental doses unnecessary following CAPD or CAVHD.1

Geriatric Patients

No dosage adjustments except those related to renal impairment.1 23

Cautions for Valacyclovir Hydrochloride Contraindications

Known hypersensitivity or intolerance to valacyclovir, acyclovir, or any component of the formulation.1

Warnings/Precautions Warnings Hematologic Effects

Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (sometimes fatal) reported in patients with advanced HIV infection and in allogeneic bone marrow or renal transplant recipients receiving high dosages (8 g daily).1 23

General Precautions Renal Effects

Use of inappropriately high dosage for the level of renal function has resulted in acute renal failure in patients with underlying renal disease.1

Acyclovir may precipitate in renal tubules if solubility (2.5 mg/mL) is exceeded in intratubular fluid.1 Maintain adequate hydration.1

If acute renal failure and anuria occur, hemodialysis recommended until normal renal function returns.1

CNS Effects

Use of inappropriately high dosage for the level of renal function has resulted in CNS symptoms in patients with underlying renal disease.1

Genital Herpes

Valacyclovir is not a cure for genital herpes.1

Avoid sexual contact while lesions and/or symptoms are present due to risk of infecting sexual partners.1 Infection can be transmitted in the absence of symptoms through asymptomatic viral shedding.1

Although use for suppressive therapy in immunocompetent individuals with genital herpes decreases the risk for heterosexual transmission, safer sex practices also should be used.1 Efficacy for reducing transmission not established in individuals with multiple partners or in non-heterosexual couples.1

Type-specific serologic testing of asymptomatic partners of individuals with genital herpes can determine whether risk for HSV-2 acquisition exists.1

Valacyclovir has not been shown to reduce transmission of sexually transmitted infections other than HSV-2.1

Recommended by CDC and others for episodic treatment of genital herpes or chronic suppressive therapy of recurrent episodes in HIV-infected adults and adolescents,1 25 26 but manufacturer says efficacy not established for treatment of genital herpes in HIV-infected individuals and safety and efficacy not established for chronic suppressive therapy in those with advanced HIV disease (CD4+ T-cell count <100/mm3).1

Herpes Labialis

Valacyclovir is not a cure for cold sores.1

Treatment should not exceed a single day;1 therapy beyond 1 day does not provide additional clinical benefits.1

Because of high dosage, use caution when prescribing valacyclovir for treatment of cold sores in geriatric individuals or those with renal impairment.1 (See Special Populations under Dosage and Administration.)

Safety and efficacy not established for treatment of cold sores in immunocompromised individuals.1

Herpes Zoster

Safety and efficacy not established for treatment of disseminated herpes zoster or for treatment of herpes zoster in immunocompromised individuals.1

Specific Populations Pregnancy

Category B.1

Lactation

Acyclovir distributed into human milk following oral administration of valacyclovir.1 Use valacyclovir with caution.1

Pediatric Use

Safety and efficacy not established in prepubertal children.1

Geriatric Use

Increased risk of adverse renal or CNS effects.1 CNS effects reported more frequently in geriatric adults than in younger adults include agitation, hallucinations, confusion, delirium, and encephalopathy.1

In herpes zoster, longer duration of pain after healing (post-herpetic neuralgia) than in younger adults.1

Consider age-related decreases in renal function when selecting dosage and adjust dosage if necessary.1 23 (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Decreased clearance; increased risk of adverse renal and CNS effects in patients with underlying renal disease receiving high dosages.1

Adjust dosage as necessary.1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, nausea, vomiting.1

Interactions for Valacyclovir Hydrochloride

Neither valacyclovir nor acyclovir metabolized by CYP isoenzymes.1

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum- or magnesium-containing)

No effect on acyclovir pharmacokinetics1

Use usual dosages1

Cimetidine

Potential increased peak plasma concentrations and AUC of acyclovir1

Not considered clinically important if renal function normal;1 use usual dosages1

Digoxin

No effect on pharmacokinetics of acyclovir or digoxin1

Use usual dosages1

Probenecid

Potential increased peak plasma concentrations and AUC of acyclovir1

Not considered clinically important if renal function normal;1 use usual dosage1

Thiazide diuretics

No effect on acyclovir pharmacokinetics1

Use usual dosages1

Valacyclovir Hydrochloride Pharmacokinetics Absorption Bioavailability

Valacyclovir hydrochloride, a prodrug of acyclovir, is rapidly absorbed following oral administration and almost completely converted to acyclovir andl-valine by first-pass intestinal and/or hepatic metabolism.1 36

Absolute bioavailability of acyclovir approximately 54% following oral administration of valacyclovir hydrochloride;1 36 peak acyclovir plasma concentrations attained within 1.7 hours.36

Food

Administration of valacyclovir with food does not alter acyclovir bioavailability.1

Distribution Extent

Although there are no adequate studies using valacyclovir, acyclovir crosses the placenta.1

Following oral administration of valacyclovir to the mother, acyclovir is distributed into milk.1

Plasma Protein Binding

13.5–17.9% bound to plasma proteins.1

Elimination Metabolism

Valacyclovir hydrochloride rapidly converted to acyclovir and l-valine by first-pass intestinal and/or hepatic metabolism.1 Acyclovir converted to acyclovir monophosphate, diphosphate, and triphosphate in cells infected with herpesviruses.1

Neither valacyclovir nor acyclovir metabolized by CYP enzymes.1

Elimination Route

Valacyclovir principally eliminated as acyclovir;1 46 and 47% of an oral dose eliminated in urine and feces, respectively.1 36

Half-life

Plasma elimination half-life of acyclovir after oral administration of valacyclovir averages 2.5–3.3 hours.1 36

Special Populations

Renal clearance and elimination half-life decreased in patients with renal impairment;1 half-life averages 14 hours in end-stage renal disease.1

Pharmacokinetics in geriatric patients vary depending on renal function.1

Stability Storage Oral Tablets

15–25°C.1

Actions and SpectrumActions

Valacyclovir is thel-valine ester of acyclovir.1 2 3 4 5 6 7 8 9 Prodrug with no antiviral activity until converted in vivo to acyclovir and subsequently to the active acyclovir triphosphate.1 2 5 6 7

GI absorption of valacyclovir substantially greater than absorption of oral acyclovir resulting in plasma acyclovir concentrations comparable to those achieved with IV acyclovir.36

Active against Herpesviridae including herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), and cytomegalovirus (CMV).1

Acyclovir highly selective for thymidine kinase encoded by HSV and VZV, which converts acyclovir into acyclovir monophosphate, which is further converted to the diphosphate and then to the active triphosphate via other cellular enzymes.1 Also exhibits activity against viruses that do not code for this enzyme.12 13 14 15 16 17 18 19 20

Inhibits viral DNA replication by competitive inhibition of viral DNA polymerase, incorporation and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.1

Resistant strains of HSV and VZV reported.1

Advice to Patients

Advise patients that valacyclovir is not a cure for genital herpes or herpes labialis (cold sores).1

Importance of avoiding sexual contact with uninfected partners while genital herpes lesions and/or symptoms are present since there is a risk of transmission.1 Genital herpes can be transmitted in the absence of symptoms.1

Importance of using safer sex practices in conjunction with use of valacyclovir for suppressive therapy of genital herpes.1

Importance of initiating treatment of genital herpes recurrence as soon as possible following onset of signs and symptoms.1

For treatment of herpes labialis, importance of initiating treatment immediately following onset of symptoms (tingling, itching, burning) and importance of not using valacyclovir for longer than 1 day.1

Importance of maintaining adequate hydration during treatment.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Valacyclovir Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

500 mg (of valacyclovir)

Valtrex Caplets (with povidone)

GlaxoSmithKline

1 g (of valacyclovir)

Valtrex Caplets (with povidone)

GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Valacyclovir HCl 1GM Tablets (AUROBINDO PHARMA): 30/$315.99 or 90/$899.97

Valacyclovir HCl 500MG Tablets (MYLAN): 30/$185.99 or 90/$525.97

Valtrex 1GM Tablets (GLAXO SMITH KLINE): 30/$365.87 or 90/$1050.46

Valtrex 500MG Tablets (GLAXO SMITH KLINE): 30/$233.81 or 90/$657.9

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. GlaxoSmithKline. Valtrex (valacyclovir hydrochloride) caplets prescribing information. Research Triangle Park, NC; 2006 Jul.

2. Jacobson MA, Gallant J, Wang LH et al. Phase I trial of valaciclovir, the l-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother. 1994; 38:1534-40. [IDIS 332383] [PubMed 7979285]

3. Darby G. Acyclovir—and beyond. J Int Med Res. 1994; 22(Suppl 1):33-42A. [PubMed 8187942]

4. Beutner KR, Friedman DJ, Forszpaniak C et al. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother. 1995; 39:1546-53. [IDIS 350497] [PubMed 7492102]

5. Gnann JW Jr. New antivirals with activity against varicella-zoster virus. Ann Neurol. 1994; 34(Suppl):S69-72.

6. Easterbrook P, Wood MJ. Successors to acyclovir. J Antimicrob Chemother. 1994; 34:307-11. [IDIS 336425] [PubMed 7829405]

7. Weller S, Blum MR, Doucette M et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin Pharmacol Ther. 1993; 54:595-605. [IDIS 324231] [PubMed 8275615]

8. Lampkin TA. Valacyclovir HCl (Valtrex) administration achieves increased acyclovir concentration in multiple populations. Int Pharm Abst. 1994; 31:2291.

9. Shaefer MS. Valacyclovir HCl (Valtrex) provides simplified dosing and increased efficacy in the treatment of herpes virus infections. Int Pharm Abst. 1994; 31:2244-5.

10. The International Valaciclovir Zoster Study Group, Smiley ML. The efficacy and safety of valaciclovir for the treatment of herpes zoster. Proceedings of ICAAC New Orleans 1993. Abstract No. 1203.

11. The International Valaciclovir Zoster Study Group, Smiley ML. Valaciclovir and acyclovir for the treatment of recurrent genital herpes simplex virus infections. Proceedings of ICAAC New Orleans 1993. Abstract No. 1210.

12. Koch-Weser J, Hirsch MS, Swartz MN. Drug therapy: antiviral agents (second of two parts). N Engl J Med. 1980; 302:949-53. [IDIS 113597] [PubMed 6244492]

13. Lerner AM. Acyclovir reaches clinical trial. Ann Intern Med. 1982; 96:370-2. [IDIS 146189] [PubMed 7036819]

14. Weller IV, Carreno V, Fowler MJ et al. Acyclovir inhibits hepatitis B virus replication in man. Lancet. 1982; 1:273. [IDIS 144926] [PubMed 6120286]

15. Colby BM, Furman PA, Shaw JE et al. Phosphorylation of acyclovir [9-(2-hydroxyethoxymethyl)-guanine] in Epstein-Barr virus infected lymphoblastoid cell lines. J Virol. 1981; 38:606-11. [PubMed 6264131]

16. St. Clair MH, Furman PA, Lubbers CM et al. Inhibition of cellular ? and virally induced deoxyribonucleic acid polymerases by the triphosphate of acyclovir. Antimicrob Agents Chemother. 1980; 18:741-5. [PubMed 7192534]

17. Tyms AS, Scamans EM, Naim HM. The in vitro activity of acyclovir and related compounds against cytomegalovirus infections. J Antimicrob Chemother. 1981; 8:65-72. [PubMed 6265430]

18. Burns WH, Wingard JR, Bender WJ et al. Thymidine kinase not required for antiviral activity of acyclovir against mouse cytomegalovirus. J Virol. 1981; 30:889-93.

19. McCarthy P (Burroughs Wellcome Co, Research Triangle Park, NC): Personal communication; 1982 Aug.

20. Mar E, Patel PC, Huang E. Effect of 9-(2-hydroxyethoxymethyl) guanine on viral-specific polypeptide synthesis in human cytomegalovirus-infected cell. Am J Med. 1982; 73(Acyclovir symposium):82-5. [IDIS 154027] [PubMed 6285739]

21. Lang DJ, Cheung K. Effectiveness of acycloguanosine and trifluorothymidine as inhibitors of cytomegalovirus infection in vitro. Am J Med. 1982; 73(Acyclovir symposium):49-53. [IDIS 154025] [PubMed 6285732]

22. Pagano JS, Datta AK. Perspectives on interactions of acyclovir with Epstein-Barr and other herpes viruses. Am J Med. 1982; 73(Acyclovir symposium):18-26. [IDIS 156729] [PubMed 6285710]

23. Glaxo Wellcome, Inc, Research Triangle Park, NC: Personal communication.

24. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006; 55(RR-11):1-95.

25. US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) Prevention of Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of opportunistic infections in persons with human immunodeficiency virus. From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ().

26. Balfour HH. Antiviral drugs. N Engl J Med. 1999; 340:1255-68. [IDIS 423356] [PubMed 10210711]

27. Lowance D, Neumayer HH, Legendre CM et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N Engl J Med. 1999; 340:1462-70. [IDIS 427339] [PubMed 10320384]

28. Feinberg JE, Hurwitz S, Cooper D et al. A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. J Infect Dis. 1998; 177:48-56. [IDIS 399239] [PubMed 9419169]

29. Anon. Drugs for sexually transmitted infections. Treat Guidel Med Lett. 2004; 2:67-74. [PubMed 15529116]

30. Anon. Drugs for non-HIV viral infections. Treat Guidel Med Lett. 2005; 3:23-32.

31. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Recomm Rep. 2000; 49(RR-10):1-125.

32. Leone P, Trottier S, Miller JM. Valacyclovir for episodic treatment of genital herpes: a shorter 3-day treatment course compared with 5-day treatment. Clin Infect Dis. 2002; 34:958-62. [IDIS 480416] [PubMed 11880962]

33. DeJesus E, Wald A, Warren T et al. Valacyclovir for suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis. 2003; 188:1009-16. [IDIS 516503] [PubMed 14513421]

34. Spruance SL, Jones TM, Blatter MM et al. High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrob Agents Chemother. 2003; 47:1072-80. [IDIS 495732] [PubMed 12604544]

35. Corey L, Wald A, Patel R et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004; 350:11-20. [IDIS 508984] [PubMed 14702423]

36. Soul-Lawton J, Seaber E, On N et al. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother. 1995; 39:2759-64. [IDIS 358708] [PubMed 8593015]

37. Soul-Lawton J, Seaber E, On N et al. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrobial Agents and Chemotherapy. 1995; 39:2759-64. [IDIS 358708] [PubMed 8593015]

38. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-15):1-112.

39. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53( RR-14):1-92.

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Minipress


Generic Name: Prazosin Hydrochloride
Class: alpha-Adrenergic Blocking Agents
VA Class: CV150
CAS Number: 19237-84-4

Introduction

Postsynaptic ?1-adrenergic blocking agent; quinazoline derivative.101 b

Uses for Minipress Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).101 153 161

Current antihypertensive and urology guidelines (e.g., JNC 7) no longer recommend ?1-blockers as preferred first-line therapy for patients with hypertension.b

Acute management of severe hypertension in patients with increased concentrations of circulating catecholamines.b

Benign Prostatic Hyperplasia (BPH)

Has been used to reduce urinary obstruction and relieve associated manifestations in patients with symptomatic BPH†; efficacy relative to other ?1-adrenergic blockers remains to be established.112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133

Posttraumatic Stress Disorder (PTSD)

Has been used in the management of PTSD†, particularly in combat veterans and in patients experiencing nighttime PTSD symptoms (e.g., nightmares, sleep disturbances).200 201 202 203 204 205 206 207 208 209 210 211 212 215 216 217 221 222 225

Some clinicians currently recommend prazosin as first-line or alternative therapy when treating PTSD patients with prominent nighttime symptoms, particularly in combat veterans.201 204 212 215 217 222 225 Further studies necessary in civilians with noncombat trauma-related PTSD and in treatment of daytime PTSD symptoms.200 201 203 204 208 216

Minipress Dosage and Administration Administration Oral Administration

Administer orally in divided doses 2 or 3 times daily.101

Manufacturers make no specific recommendations regarding administration with meals.101 221

Dosage

Available as prazosin hydrochloride; dosage expressed in terms of prazosin.101 b

Individualize dosage according to patient response and tolerance.101 b Initiate at low dosage to minimize frequency of postural hypotension and syncope.101 b

Postural effects are most likely to occur 2–6 hours after a dose; monitor BP during this period after first dose and with any dosage increases.161 179

If therapy is interrupted for a few days, restart using initial dosage regimen.

Pediatric Patients Hypertension† Oral

Initially, 0.05–0.1 mg/kg daily given in 3 divided doses.195 Increase dosage as necessary up to a maximum of 0.5 mg/kg daily given in 3 divided doses.195

Adults Hypertension Monotherapy Oral

Initially, 1 mg 2 or 3 times daily.101 b Do not initiate with higher dosages.101 b May increase dosage gradually to 20 mg daily given in divided doses.101 b

Usual maintenance dosage: 6–15 mg daily given in divided doses.101 b

Careful monitoring of BP is recommended during initial titration or subsequent upward dosage adjustment;161 avoid large or abrupt reductions in BP.161 179

For the acute management of severe hypertension, initially, 1–2 mg; dosage may be repeated after 1 hour, if necessary.b

Combination Therapy Oral

When other hypotensive agents or diuretics are added to existing prazosin therapy, reduce dosage to 1 or 2 mg 3 times daily; gradually increase according to patient's response and tolerance.101 b

Posttraumatic Stress Disorder†

Optimum dosage not established.200 201 212 In clinical studies, usual initial dosage was 1 mg at bedtime; dosage was then gradually increased based on patient's response and tolerance.200 201 202 203 204 205 206 207 208 209 210 211 212 217 220 Maintenance dosages ranging from 1 to 25 mg daily (given once daily at bedtime or in 2 divided doses) have been use.200 203 206 210 212 217 220 225 Some experts recommend a target maintenance dosage of 1–10 mg daily; others recommend a higher target dosage of 2–20 mg daily.224 225

Prescribing Limits Pediatric Patients Hypertension† Oral

Maximum 0.5 mg/kg daily.195

Adults Hypertension Oral

Maximum 20 mg daily.101 b Although higher dosages usually do not increase efficacy, a few patients may benefit from ?40 mg daily.101 b

Special Populations Hepatic Impairment

No specific dosage recommendations at this time.b

Renal Impairment

Initially, 1 mg twice daily.b Patients with chronic renal failure may require only small dosages.b

Geriatric Patients

No specific dosage recommendations at this time;b generally increase dosage more slowly in geriatric hypertensive patients than in younger adults.

Cautions for Minipress Contraindications

Known hypersensitivity to prazosin, quinazolines (e.g., alfuzosin, doxazosin, terazosin), or any ingredient in the formulation.101

Warnings/Precautions Warnings Postural Hypotension

Like other ?-adrenergic blocking agents, marked hypotension, especially in the upright position, can occur; may be accompanied by syncope, palpitations, and other postural effects (e.g., dizziness, lightheadedness, vertigo).101

Postural effects are most common after an initial dose, shortly after dosing (e.g., within 90 minutes), when dosage is rapidly increased, or when other antihypertensive agents are added to therapy.101 b

To decrease risk of excessive hypotension and syncope, initiate therapy at a low dosage (i.e., 1 mg) and titrate slowly; initiate concomitant antihypertensive agents with caution.101 b

If syncope or hypotension occurs, place patient in a recumbent position and institute supportive therapy as necessary.101 b

General Precautions Intraoperative Floppy Iris Syndrome (IFIS)

IFIS observed during cataract surgery in some patients currently receiving or previously treated with ?1-adrenergic blocking agents.101 218

If patient has received ?1-blockers, ophthalmologist should be prepared to modify the surgical technique (e.g., through use of iris hooks, iris dilator rings, viscoelastic substances) to minimize complications of IFIS.101 218

Benefit of discontinuing ?1-blockers, including prazosin, prior to cataract surgery not established.101 218

Prostate Cancer

Exclude possibility of prostate cancer before initiation of therapy for BPH.155 156

Specific Populations Pregnancy

Category C.101

Lactation

Distributed into milk in small amounts.101 Caution if used in nursing women.101 b

Pediatric Use

Safety and efficacy not established in children <18 years of age.101 b

Geriatric Use

Geriatric patients may be particularly susceptible to postural effects and other adverse effects.153 161

Common Adverse Effects

Dizziness, lightheadedness, headache, drowsiness, lack of energy, weakness, palpitation, nausea.101 b

Interactions for Minipress Protein-bound Drugs

Potential pharmacokinetic interaction (displacement of prazosin or other protein-bound drug).b

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Analgesic agents (aspirin, indomethacin, phenylbutazone [no longer commercially available in the US], propoxyphene)

No interaction observed101

Antiarrhythmic agents (procainamide, quinidine)

No interaction observed101

Antigout agents (allopurinol, colchicine, probenecid)

No interaction observed101

Antihypertensive agents (e.g., propranolol)

Possible additive hypotensive effects and symptomatic hypotension101

Initiate additional antihypertensive agents with caution; may reduce prazosin dosage and gradually increase dosage based on clinical response101

Benzodiazepines (chlordiazepoxide, diazepam)

No interaction observed101

Digoxin

No interaction observed101

Diuretics

Possible additive hypotensive effects and symptomatic hypotension101 b

Effect usually used to therapeutic advantageb

Initiate diuretics with caution; may reduce prazosin dosage and gradually increase dosage based on clinical response101

Hypoglycemic agents (insulin, chlorpropramide, phenformin [no longer commercially available in the US], tolazamide, tolbutamide)

No interaction observed101

Phenobarbital

No interaction observed101

Phosphodiesterase (PDE) type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)

Possible additive hypotensive effects and symptomatic hypotension101

Initiate PDE type 5 inhibitor at lowest possible dosage101

Test for pheochromocytoma

Possible increase in urinary metabolite of norepinephrine and VMA; false positive results may occur in pheochromocytoma screening tests101

If elevated VMA is observed, discontinue prazosin and repeat test after 1 month101

Minipress Pharmacokinetics Absorption Bioavailability

Peak plasma concentrations attained within about 2–3 hours.b

Bioavailability is approximately 60%.b

Onset

In patients with hypertension, maximum reduction in BP usually occurs 2–4 hours after administration.b

Food

Food does not affect the extent of absorption; however, absorption may be delayed.b

Distribution Extent

Not known whether prazosin crosses the placenta;b distributed into milk in small amounts.b Crosses the blood-brain barrier.200 204 205 206 208 210

Plasma Protein Binding

Approximately 97%.b

Elimination Metabolism

Extensively metabolized, principally in the liver by demethylation and conjugation.101 b

Elimination Route

Excreted principally in feces via biliary excretion and to a lesser extent in urine (6–10%).101 b

Half-life

2–4 hours.b

Stability Storage Oral Capsules

20-25°C; protect from moisture and light.221

ActionsActions

Reduces peripheral vascular resistance and BP as a result of vasodilating effects;101 b produces both arterial and venous dilation.101

Effects appear to result from selective, competitive inhibition of ?1-adrenergic receptors.b

Generally causes no change in heart rate, cardiac output, renal blood flow, and GFR.101 b

Binds to ?-adrenergic receptors on the prostate capsule, prostate adenoma, and bladder trigone, resulting in decreased urinary outflow resistance in men.

May improve to limited extent the serum lipid profile (e.g., small increases in HDL and HDL/total cholesterol ratio; small decreases in LDL, total cholesterol, and triglyceride concentrations).153 161 c

Precise mechanism of action in PTSD not fully elucidated; however, norepinephrine and ?1-adrenergic receptors play an important role in the pathophysiology of PTSD-associated nightmares, arousal, selective attention and vigilance.200 201 203 204 205 206 207 208 209 210 216 217 220 Prazosin is believed to help correct the effects of ?1-adrenergic receptor hyperstimulation in PTSD and has also been shown to normalize the sleep cycle.200 203 205 206 211 220

Advice to Patients

Possible dizziness, lightheadedness or fainting, especially at initiation of therapy;101 b importance of avoiding driving or other hazardous tasks where injury could occur for 24 hours after the first dose or when dosage is increased.101

Importance of advising patient that alcohol use, hot weather, exercise, and standing for long periods of time may precipitate or exacerbate symptoms of dizziness, lightheadedness, or fainting, and to use caution during these situations.101

Importance of sitting or lying down when symptoms of lowered BP occur, and of rising carefully from a sitting or lying position.101 b

Possible drowsiness or somnolence; use caution when operating machinery or driving a motor vehicle until effects on individual are known.b

Importance of advising patients being considered for cataract surgery that they should inform their ophthalmologist of current or prior ?1-blocker therapy, including prazosin.101 218

Importance of advising patients receiving prazosin for PTSD† that the drug may help reduce nightmares and improve sleep and other symptoms; however, it does not cure PTSD and their nightmares, anxiety, and other PTSD-related symptoms may return if therapy is stopped.201 203 219

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.101

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.101

Importance of informing patients of other important precautionary information.101 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Prazosin Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

1 mg (of prazosin)*

Minipress

Pfizer

Prazosin Hydrochloride Capsules

2 mg (of prazosin)*

Minipress

Pfizer

Prazosin Hydrochloride Capsules

5 mg (of prazosin)*

Minipress

Pfizer

Prazosin Hydrochloride Capsules

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Minipress 1MG Capsules (PFIZER U.S.): 60/$51.99 or 180/$149.97

Minipress 2MG Capsules (PFIZER U.S.): 60/$69.99 or 180/$199.98

Minipress 5MG Capsules (PFIZER U.S.): 60/$123.99 or 180/$347.96

Prazosin HCl 1MG Capsules (MYLAN): 60/$17.99 or 180/$37.97

Prazosin HCl 2MG Capsules (TEVA PHARMACEUTICALS USA): 60/$22.99 or 180/$49.97

Prazosin HCl 5MG Capsules (TEVA PHARMACEUTICALS USA): 60/$33.99 or 180/$93.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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101. Pfizer Labs. Minipress (prazosin hydrochloride) capsules prescribing information. New York, NY; 2009 Jul.

102. Waldo R. Prazosin relieves Raynaud’s vasospasm. JAMA. 1979; 241:1037. [IDIS 101504] [PubMed 762741]

103. Nielsen SL, Vitting K, Rasmussen K. Prazosin treatment of primary Raynaud’s phenomenon. Eur J Clin Pharmacol. 1983; 24:421-3. [IDIS 170153] [PubMed 6345178]

104. Wollersheim H, Thien T, Fennis J et al. Double-blind, placebo-controlled study of prazosin in Raynaud’s phenomenon. Clin Pharmacol Ther. 1986; 40:219-25. [IDIS 219933] [PubMed 3731684]

105. Cobaugh DS. Prazosin treatment of ergotamine-induced peripheral ischemia. JAMA. 1980; 244:1360. [IDIS 125518] [PubMed 7411811]

106. 1988 Joint National Committee. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988; 148:1023-38. [IDIS 242588] [PubMed 3365073]

107. Guilleminault C, Mignot E, Aldrich M et al. Prazosin contraindicated in patients with narcolepsy. Lancet. 1988; 2:511. [IDIS 245751] [PubMed 2900433]

108. Aldrich MS, Rogers AE. Exacerbation of human cataplexy by prazosin. Sleep. 1989; 12:254-6. [PubMed 2740697]

109. Mignot E, Guilleminault C, Bowersox S et al. Central alpha 1 adrenoceptor subtypes in narcolepsy-cataplexy: a disorder of REM sleep. Brain Res. 1989; 490:186-91. [PubMed 2569353]

110. Mignot E, Guilleminault C, Bowersox S et al. Role of central alpha-1 adrenoceptors in canine narcolepsy. J Clin Invest. 1988; 82:885-94. [PubMed 2843574]

111. Mignot E, Guilleminault C, Bowersox S et al. Effect of central alpha 1-adrenoceptors blockade with prazosin in canine narcolepsy. Brain Res. 1988; 444:184-8. [PubMed 2834022]

112. Milroy E. Clinical overview of prazosin in the treatment of prostatic obstruction. Urol Int. 1990; 45(Suppl 1):1-3. [PubMed 1690474]

113. Kondo A, Gotoh M, Saito M et al. The efficacy of prazosin HCl in the treatment of urinary flow obstruction due to prostatic hypertrophy. Urol Int. 1990; 45(Suppl 1):4-17. [PubMed 1690480]

114. Aoki H, Ohninata M, Tsuzuki T et al. Clinical studies on the effectiveness of prazosin HCl (Minipress tablets) in the treatment of dysuria accompanying benign prostatic hyperplasia. Urol Int. 1990; 45(Suppl 1):18-25. [PubMed 1690476]

115. Kohama Y, Watanabe H, Sen Y et al. Effects of prazosin HCl on micturition disturbance associated with benign prostatic hypertrophy and bladder neck contracture. Urol Int. 1990; 45(Suppl 1):26-9. [PubMed 1690477]

116. Nakamura K, Kawashita E, Osumi Y et al. Effects of prazosin HCl on the urethral pressure profile in patients with benign prostatic hyperplasia. Urol Int. 1990; 45(Suppl 1):30-5. [PubMed 1690478]

117. Shimizu K, Nakai K, Imai K et al. Effects of an alpha 1-adrenergic blocker (prazosin HCl) on micturition disturbances associated with benign prostatic hypertrophy. Urol Int. 1990; 45(Suppl 1):36-9. [PubMed 1690479]

118. Yamaguchi O, Shiraiwa Y, Kobayashi M et al. Clinical evaluation of effects of prazosin in patients with benign prostatic obstruction; a double-blind, multi-institutional, Paraprost-controlled study. Urol Int. 1990; 45(Suppl 1):40-6. [PubMed 1690481]

119. Chapple CR, Christmas TJ, Milroy EJ. A twelve-week placebo-controlled study of prazosin in the treatment of prostatic obstruction. Urol Int. 1990; 45(Suppl 1):47-55. [PubMed 1690482]

120. Le Duc A, Cariou G, Baron C. A multicenter, double-blind, placebo-controlled trial of the efficacy of prazosin in the treatment of dysuria associated with benign prostatic hypertrophy. Urol Int. 1990; 45(Suppl 1):56-62. [PubMed 1690483]

121. Andersson KE. Current concepts in the treatment of disorders of micturition. Drugs. 1988; 35:477-94. [IDIS 240964] [PubMed 3292211]

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126. Ruutu ML, Hansson E, Juusela HE et al. Efficacy and side-effects of prazosin as a symptomatic treatment of benign prostatic obstruction. Scand J Urol Nephrol. 1991; 25:15-9. [PubMed 1710823]

127. Rowden AM, Mowers RM. Prazosin in benign prostatic hypertrophy. DICP Ann Pharmacother. 1989; 23:474-5.

128. Brendler CB. Diseases of the prostate. In: Wyngaarden JB, Smith LH Jr, Bennett JC, eds. Cecil textbook of medicine. 19th ed. Philadelphia: WB Saunders Company; 1992:1351-5.

129. Kirby RS. Alpha-adrenoceptor inhibitors in the treatment of benign prostatic hyperplasia. Am J Med. 1989; 87(Suppl 2A):26-30S.

130. Lepor H. Alpha adrenergic antagonists for the treatment of symptomatic BPH. Int J Clin Pharmacol Ther Toxicol. 1989; 27:151-5. [PubMed 2469658]

131. Chisholm GD. Benign prostatic hyperplasia: the best treatment. BMJ. 1989; 299:215-6. [IDIS 257552] [PubMed 2475197]

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133. Chapple C. Medical treatment for benign prostatic hyperplasia. BMJ. 1992; 304:1198-9. [IDIS 296671] [PubMed 1381250]

134. Caine M. Alpha-adrenergic blockers for the treatment of benign prostatic hyperplasia. Urol Clin North Am. 1990; 17:641-9. [PubMed 1695784]

135. Geller J. Nonsurgical treatment of prostatic hyperplasia. Cancer. 1992; 70(Suppl 1):339-45. [IDIS 298353] [PubMed 1376202]

136. Chapple CR, Aubry ML, James S et al. Characterisation of human prostatic adrenoceptors using pharmacology receptor binding and localisation. Br J Urol. 1989; 63:487-96. [PubMed 2471572]

137. Staub WR, Staub JS. Phenoxybenzamine in benign prostatic obstruction. JAMA. 1988; 260:2220. [IDIS 246399] [PubMed 2459421]

138. Hieble JP, Caine M, Zalaznik E. In vitro characterization of the alpha-adrenoceptors in human prostate. Eur J Pharmacol. 1985; 107:111-7. [PubMed 2579826]

139. Caine M. Alpha-adrenergic mechanisms in dynamics of benign prostatic hypertrophy. Urology. 1988; 32(Suppl 6):16-20. [PubMed 2462300]

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