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Acne Medications


Definition of Acne: An inflammatory skin condition characterized by superficial skin eruptions around hair follicles. More...

Drugs associated with Acne

The following drugs and medications are in some way related to, or used in the treatment of Acne. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.

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Topics under Acne Rosacea (77 drugs) Learn more about Acne

Medical Encyclopedia:

Acne Blackheads Comedones Teenagers and acne medicine Whitehead

Harvard Health Guide:

Symptoms and treatment for Acne
Drug List: A-T-S Acanya Accutane Acetoxyl-10-Topical Acne-Treatment-Cream Acne-10-Gel-Topical Acne-Clear Acnex-Topical Acnomel-Skin-Tone-Topical Acnomel-Acne-Mask-Topical Acnomel-Bp-5-Topical Acnotex Aczone Adoxa Adoxa-Ck-Kit Adoxa-Tt-Kit Akne-Mycin-Ointment Akurza-Topical Ala-Tet Aldactone Aliclen-Topical Alquam-X-Acne-Therapy-Gel-Topical Altabax Altinac Amnesteem Atralin Avar-Cream Avar-Cleanser Avar-Gel Avar-Green Avar-Ls-Cleanser Avar-E Avar-E-Emollient Avar-E-Green Avar-E-Ls Avidoxy Avita-Cream Azelex-Cream Bactrim Bactrim-Ds Bencort-Lotion Benprox Benzac-Topical Benzac-Ac-Wash Benzac-W Benzaclin Benzagel-5 5-Benzagel-Acne-Wash-Topical Benzamycin-Gel Benzamycin-Pak-Gel Benzashave-10 Benzefoam-Foam Benzefoam-Ultra-Topical Benziq Benziq-Ls Benziq-Wash Beyaz Binora-Topical Bio-Cef Bioelements-Active-Astringent Bp-10-Wash Bp-Wash Bpo-3-Foaming-Cloths Bpo-6-Foaming-Cloths Bpo-9-Foaming-Cloths Bpo-Foaming-Cloths Bpo-4-Gel-Topical Bps-Gel Brevicon Brevoxyl-Gel Brevoxyl-Acne-Wash-Kit Brevoxyl-Creamy-Wash-Complete-Pack-Wash-And-Cleansing-Bar Brevoxyl-4-Wash Brevoxyl-8-Wash Breze Briellyn Cerisa-Wash Claravis Clarifoam-Ef-Foam Cleanse-Treat Clear-Away-Wart-Removal-System-Topical Clearplex Clearskin-Cream Clenia-Emollient-Cream Clenia-Foaming-Wash Cleocin-T-Gel Clinac-Bpo Clinda-Derm-Topical Clindacin-P Clindagel Clindareach-Pledget Clindets-Swab Co-Trimoxazole Compound-W Cotrim Cyclafem-1-35 Cyclafem-7-7-7 Del-Aqua-Topical Delos-Liquid Dermalzone Dermarest-Psoriasis-Skin-Treatment Desquam-E Desquam-X-10 Desquam-X-5 Desquam-X-Wash Dhs-Sal-Topical Differin Doryx-Delayed-Release-Capsules Doxy-100 Doxy-200 Dr-Scholl-S-Callus-Removers Dr-Scholl-S-Clear-Away-Wart-Remover Dr-Scholl-S-Corn-Removers Dr-Scholl-S-Corn-Callous-Remover-Solution Dr-Scholl-S-Zino-Soft-Corn-Remover-Pads Duac-Cs-Kit-Gel Dulcolax-Milk-Of-Magnesia-Suspension Duofilm-Solution Duoplant-Gel Durasal-Topical Dynacin Emcin-Clear-Pad Emgel-Gel Epiduo Ery-Pads-Pad Erycette Eryderm-Solution Erygel Erymax Erythra-Derm Estrostep-Fe Ethexderm Ethexderm-Bpw-Wash Evoclin Ex-Lax-Milk-Of-Magnesia Femcon-Fe-Chewable-Tablets Femhrt Finacea Finevin Fostex-Cream Fostex-Bar-10 Fostex-Bpo-Bar Fostex-Gel-10 Fostex-Medicated-Soap Fostex-Cream-Topical Fostex-Wash-10 Fostril Freezone-One-Step-Callus-Remover-Pad-Topical Freezone-Liquid Freezone-Corn-Remover Genora-1-35 Gianvi Gildess-Fe-1-5-0-03 Gildess-Fe-1-0-2 Gordofilm-Topical Hydrisalic-Gel Inova-Pads Inova-4-1-Acne-Control-Therapy-Pads Inova-8-2 Ionil-Plus-Shampoo Jenest Jevantique Junel-1-5-30 Junel-1-20 Junel-Fe-1-5-30 Junel-Fe-1-20 Keflex Keralyt-Scalp-Shampoo Keralyt-Shampoo Keralyt-Gel Lavoclen-4 Lavoclen-4-Creamy-Wash Lavoclen-8 Lavoclen-8-Creamy-Wash Leena Liquimat-Light Liquimat-Medium Loestrin-1-20 Loestrin-21-1-5-30 Loestrin-21-1-20 Loestrin_24_Fe Loestrin-Fe-1-5-30 Loestrin-Fe-1-20 Loroxide Loryna Mediplast Meted-Shampoo Microgestin-1-5-30 Microgestin-1-20 Microgestin-Fe-1-5-30 Microgestin-Fe-1-20 Milk-Of-Magnesia Minocin Modicon Monodox Mosco-Corn-Callus-Remover-Topical Myrac Necon-0-5-35 Necon-1-35 Necon-10-11 Necon-7-7-7 Nelova-0-5-35 Neobenz-Micro Neobenz-Micro-Sd Neobenz-Micro-Wash-Plus-Pack-Cream Neutrogena-Acne-Mask Neutrogena-Healthy-Scalp-Shampoo Neutrogena-On-Spot-Acne-Treatment Norethin-1-35-E Norinyl-1-35 Nortrel-0-5-35 Nortrel-1-35 Nortrel-7-7-7 Novacet Nuox-Gel Occlusal-Hp-Liquid Ocella Ocudox-Convenience-Kit Oraxyl Ortho-Tri-Cyclen Ortho-Novum-1-35 Ortho-Novum-7-7-7 Oscion Oscion-Cleanser Ovcon-35 Ovcon-35-Fe Ovcon-50 Oxy-10-Balance Oxy-Balance Oxy-Balance-Deep-Pore-Cleanser-Liquid Oxy-Daily-Wash-Chill-Factor Oxy-Face-Scrub Oxy-10 P-S-Topical Pacnex Panixine Panoxyl-Bar Panoxyl-10 Panoxyl-5 Panoxyl-Aqua-Gel Panoxyl-Maximum-Strength-Foaming-Acne-Wash Pernox-Lotion Peroderm-7-Wash Persa-Gel Phillips-Milk-Of-Magnesia-Suspension Plexion Plexion-Cleanser Plexion-Cleansing-Cloths Plexion-Sct-Cream Plexion-Ts-Emulsion Prascion Prascion-Cleanser Prascion-Fc-Cloths Prascion-Ra Propa-P-H Propa-Ph-Acne-Med-Cleansing-Pads Propa-Ph-Acne-Med-Maximum-Strength-Liquid R-A-Acne-Topical Resinol-Topical Retin-A-Micro-Gel Retin-A-Cream Rezamid Romycin Rosac-Cream Rosac-Wash Rosaderm-Cleanser Rosanil Rosula-Foam Rosula-Cleanser Rosula-Clk-Kit Sal-Acid-Plaster-Topical Sal-Plant-Gel Salac Salactic-Film-Topical Salacyn-Lotion Salex-Lotion Salitop-Lotion Salkera-Foam Salvax-Foam Sastid-Soap Scalpicin-Scalp-Relief Se-10-5-Ss Se-Bpo-Wash Seba-Gel Sebucare Sebulex-Shampoo Septra Septra-Ds Smz-Tmp-Ds Solodyn Soluclenz-Rx Sotret Staticin-Topical Stieva-A-Cream-Forte-Topical Stieva-A-Cream-Topical Stri-Dex Stridex-Body-Focus-Cream Stridex-Maximum-Strength-Pads Sulfacet-R Sulfatol-10-4-Cleansing-Pads Sulfatol-C Sulfatol-Ss Sulfatrim-Suspension Sulfo-Lo Sulfoam Sulforcin Sulfoxyl-Regular-Lotion Sulfoxyl-Strong-Lotion Sulmasque Sulpho-Lac Sulpho-Lac-Soap Sulzee-Wash Sumadan Sumaxin-Wash Sumaxin-Ts-Emulsion Sumycin Suphera Syeda T-Stat Tazorac-Cream Thera-Sal-Topical Theramycin-Z Tilia-Fe Tinamed-Plantar-Pads Topicycline Topisulf Tretin-X-Cream Tri-Legest Tri-Legest-Fe Tri-Norinyl Tri-Previfem Tri-Sprintec Triaz-Cloths Trinessa Trinessa-Lo Vanoxide-Hc-Lotion Veltin Vestura Vibra-Tabs Vibramycin Wart-Off-Treatment Yasmin Yaz Z-Clinz-10 Z-Clinz-5 Zacare-4-Kit-Lotion Zaclir Zenchent-Fe Zencia-Wash Zeosa Zetacet-Emulsion Zetacet-Wash Ziana Zoderm-Cleanser
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GelTears (Bausch & Lomb U.K Limited)


1. Name Of The Medicinal Product

GelTears.

2. Qualitative And Quantitative Composition

Clear, colourless gel containing 0.2% w/w carbomer 980 Ph.Eur.

3. Pharmaceutical Form

Eye gel.

4. Clinical Particulars 4.1 Therapeutic Indications

Substitution of tear fluid in the management of dry eye conditions, including keratoconjunctivitis sicca and unstable tear film.

4.2 Posology And Method Of Administration

Adults (including the elderly) and children:

One drop to be instilled into the conjunctival fold of each affected eye 3 - 4 times daily or as required, depending on the degree of discomfort.

4.3 Contraindications

Use in patients with a known hypersensitivity to any component of the preparation.

4.4 Special Warnings And Precautions For Use

Blurred vision can occur if too much gel is instilled at one time, or if the gel is used too frequently. This effect can last for up to an hour. Recovery can be aided by blinking vigorously for a few seconds. If this fails, the lower eyelid should be manipulated until the gel returns to the lower fornix and normal vision is restored.

Contact lenses should be removed during treatment with GelTears.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No significant interactions have been reported.

4.6 Pregnancy And Lactation

Safety for use in pregnancy and lactation has not been established, therefore, Geltears should not be used in these circumstances.

4.7 Effects On Ability To Drive And Use Machines

As with other ophthalmic preparations, transient blurring of vision may occur on instillation. If affected, the patient should be advised not to drive or operate hazardous machinery until normal vision is restored.

4.8 Undesirable Effects

Corneal irritation due to benzalkonium chloride could possibly occur with prolonged use.

4.9 Overdose

Not applicable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

GelTears contains Carbomer 980, a hydrophilic, high molecular weight polymer of carboxyvinylic acid. The gel forms a transparent lubricating and moistening film on the surface of the eye. The preparation has a pH similar to that found in the normal tear film and is slightly hypotonic with respect to tears. GelTears relieves the symptoms of irritation linked with dry eye syndromes and protects the cornea against drying out.

The use of vital stains has provided objective evidence that the corneal and conjunctival epithelial lesions associated with dry eye syndromes show improvement on treatment with GelTears. The gel remains on the surface of the eye for longer than low viscosity artificial tears and hence, less frequent application is required.

5.2 Pharmacokinetic Properties

No human pharmacokinetic studies are available, however, absorption or accumulation in ocular tissues is likely to be negligible due to the high molecular weight of the active ingredient.

5.3 Preclinical Safety Data

No adverse safety issues were detected during the development of this formulation. The ingredients are well established in clinical ophthalmology.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Benzalkonium chloride 0.01% w/w (as a preservative)

Purified water

Sorbitol

Sodium hydroxide

6.2 Incompatibilities

None known.

6.3 Shelf Life

The shelf life expiry date shall not exceed 3 years from the date of its manufacture when stored below 25°C. Any remaining gel should be discarded 28 days after first opening the tube.

6.4 Special Precautions For Storage

The product should be transported in the original packaging. It should be stored below 25°C.

6.5 Nature And Contents Of Container

Sterile ophthalmic gel presented in 5g and 10g plasticised, lacquered aluminium tubes, closed with a tamper evident polyethylene cap. Each tube is individually cartonned with a patient information leaflet.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Chauvin Pharmaceuticals Ltd

106 London Road

Kingston-Upon-Thames

Surrey

KT2 6TN

8. Marketing Authorisation Number(S)

PL 0033/0149

9. Date Of First Authorisation/Renewal Of The Authorisation

05 August 1996.

10. Date Of Revision Of The Text

September 2002

November 2002


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Temgesic 400 microgram Sublingual tablets


1. Name Of The Medicinal Product

Temgesic 400 microgram Sublingual Tablets

2. Qualitative And Quantitative Composition

Buprenorphine hydrochloride 432 µg/tablet, equivalent to 400 µg buprenorphine base.

3. Pharmaceutical Form

Sublingual tablet

4. Clinical Particulars 4.1 Therapeutic Indications

As a strong analgesic for the relief of moderate to severe pain.

4.2 Posology And Method Of Administration

Administration by the sublingual route.

Adults and children over 12:

200-400 micrograms to be dissolved under the tongue every 6-8 hours or as required. The recommended starting dose for moderate to severe pain of the type typically presenting in general practice is 200 to 400 microgram tablets, 8 hourly. The tablet should not be chewed or swallowed whole as this will reduce efficacy.

Elderly :

There is no evidence that dosage needs to be modified for the elderly.

Children under 12 years :

Temgesic Sublingual is suitable for use in children under 12 as follows:

16-25 kg (35-55 lb)

100 micrograms

25-37.5 kg (55-82.5 lb)

100-200 micrograms

37.5-50 kg (82.5-110 lb)

200-300 micrograms

The recommended dose should be administered every 6-8 hours.

Sublingual administration is not suitable for children under the age of six years.

Temgesic sublingual may be used in balanced anaesthetic techniques at a dose of 400 micrograms.

4.3 Contraindications

Not to be given to patients who are known to be allergic to Temgesic or other opiates. Hypersensitivity to any of the constituents.

4.4 Special Warnings And Precautions For Use

Temgesic occasionally causes significant respiratory depression and, as with other strong centrally acting analgesics, care should be taken when treating patients with impaired respiratory function or patients who are receiving drugs which can cause respiratory depression. Although volunteer studies have indicated that opiate antagonists may not fully reverse the effects of Temgesic, clinical experience has shown that Naloxone may be of benefit in reversing a reduced respiratory rate. Respiratory stimulants such as Doxapram are also effective. The intensity and duration of action may be affected in patients with impaired liver failure.

Controlled human and animal studies indicate that buprenorphine has a substantially lower dependence liability than pure agonist analgesics. In patients abusing opioids in moderate doses substitution with buprenorphine may prevent withdrawal symptoms. In man limited euphorigenic effects have been observed. This has resulted in some abuse of the same product and caution should be exercised when prescribing it to patients known to have, or suspected of having, problems with drug abuse.

Diversion:

Diversion of Temgesic has been reported. Diversion refers to the introduction of buprenorphine into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients of pharmacies. This diversion may lead to new addicts using buprenorphine as the primary drug of abuse, with the risks of overdose, spread of blood borne viral infections and respiratory depression.

Athletes must be aware that this medicine may cause a positive reaction to 'anti-doping' tests.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There is evidence to indicate that therapeutic doses of buprenorphine do not reduce the analgesic efficacy of standard doses of an opioid agonist and that when buprenorphine is employed within the normal therapeutic range, standard doses of opioid agonist may be administered before the effects of the former have ended without compromising analgesia. However, in individuals on high doses of opioids buprenorphine may precipitate abstinence effects due to its properties as a partial agonist.

Temgesic may cause some drowsiness which may be potentiated by other centrally acting agents, including alcohol, tranquillisers, sedatives and hypnotics. Temgesic should be used with caution in patients receiving monoamine oxidase inhibitors, although animal studies have given no evidence of interactions.

Although interaction studies have not been performed, since this drug is metabolised by CYP3A4 (see section 5.2 pharmacokinetic properties), it is expected that gestodene, troleandomycin, ketoconazoles, norfluoxetine, ritonavir, indinavir and saquinavir inhibit its metabolism. Alternatively, inducers of this enzyme such as phenobarbital, carbamazepine, phenytoin and rifampicin may reduce the levels of the drug. Since the magnitude of an inducing or inhibitory effect is unknown, such drug combinations should be avoided.

Temgesic has no know effects on diagnostic laboratory tests.

4.6 Pregnancy And Lactation

Temgesic is not recommended for use during pregnancy. Animal studies indicate that the amounts of buprenorphine excreted in milk are very low in human use are unlikely to be of clinical significance to the baby. There is indirect evidence in animal studies to suggest that Temgesic may cause a reduction in milk flow during lactation. Although this occurred only at doses well in excess of the human dose, it should be borne in mind when treating lactating women.

4.7 Effects On Ability To Drive And Use Machines

Ambulant patients should be warned not to drive or operate machinery until they are certain they can tolerate Temgesic.

4.8 Undesirable Effects

Nausea, vomiting, dizziness, sweating and drowsiness have been reported and may be more frequent in ambulant patients. Hallucinations and other psychotomimetic effects have occurred although more rarely than with other agonists/antagonists. Elderly patients would be expected to be more susceptible to these effects. Hypotension leading to syncope may occur. Rashes, headache, urinary retention and blurring of vision have occasionally been reported. Rarely, a serious allergic reaction may occur following a single dose. Temgesic occasionally causes significant respiratory depression (see section 4.4 special warnings and precautions before use).

Cases of bronchospasm, angioneurotic oedema and anaphylactic shock have also been reported.

During use of buprenorphine as substitution treatment the following adverse reactions have also been observed: hepatic necrosis and hepatitis.

4.9 Overdose

Supportive measures should be instituted and if appropriate Naloxone or respiratory stimulants can be used. The expected symptoms of overdose would be drowsiness, nausea and vomiting; marked miosis may occur.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Buprenorphine is a µ (mu) opioid partial agonist and k (kappa) antagonist. It is a strong analgesic of the partial agonist (mixed agonist/antagonist) class.

5.2 Pharmacokinetic Properties

Absorption

When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjungation in the small intestine. The use of this medication by oral route is therefore inappropriate.

Peak plasma concentrations are achieved 90 minutes after sublingual administration.

Distribution

The absorption of buprenorphine is followed by a rapid distribution phase and a half - life of 2 to 5 hours.

Metabolism and elimination

Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is µ (mu) agonist with weak intrinsic activity.

Elimination of buprenorphine is bi- or tri- exponential, with long terminal elimination phase4 of 20-25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.

Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (80%), the rest being eliminated in the urine.

5.3 Preclinical Safety Data

None stated

6. Pharmaceutical Particulars 6.1 List Of Excipients

Lactose

Mannitol

Maize starch

Povidone k30

Citric acid anhydrous

Magnesium stearate

Sodium citrate

Purified water

Alcohol (96%)

6.2 Incompatibilities

None stated

6.3 Shelf Life

3 years – Nylon/aluminium/uPVC blister strip

3 years – HDPE bottle

6.4 Special Precautions For Storage

Do not store above 30°C. Store in the original package- Nylon/aluminium/uPVC blister strip

Do not store above 30°C –HDPE bottle.

6.5 Nature And Contents Of Container

Nylon/aluminium/uPVC blister strips of 10 tablets each, packed in cartons of 50 tablets.

HDPE bottle consisting of 50 tablets.

6.6 Special Precautions For Disposal And Other Handling

To be dissolved under the tongue and not to be chewed or swallowed.

7. Marketing Authorisation Holder

RB Pharmaceuticals Ltd

103 – 105 Bath Road, Slough, Berkshire

SL1 3UH

8. Marketing Authorisation Number(S)

PL36699/0005

9. Date Of First Authorisation/Renewal Of The Authorisation

May 1998

10. Date Of Revision Of The Text

29th September 2010

11. LEGAL CATEGORY

CD (Sch 3), POM


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Maxalt Tablets


MAXALT 10 mg Tablets/5 mg Tablets

(rizatriptan)

Read all of this leaflet carefully before you start taking this medicine, Keep this leaflet. You may need to read it again. If you have further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What MAXALT is and what it is used for 2. Before you take MAXALT 3. How to take MAXALT 4. Possible side effects 5. How to store MAXALT 6. Further information What Maxalt Is And What It Is Used For

MAXALT belongs to a class of medicines called selective serotonin 5-HT1B/1D receptor agonists.

Your doctor has prescribed MAXALT to treat the headache phase of your migraine attack.

Treatment with MAXALT:

Reduces swelling of blood vessels surrounding the brain. This swelling results in the headache pain of a migraine attack.

Before You Take Maxalt Do not take MAXALT if: you are allergic (hypersensitive) to rizatriptan benzoate or any of the other ingredients of MAXALT you have moderately severe or severe high blood pressure or mild high blood pressure that is not controlled by medication you have or have ever had heart problems including heart attack or pain on the chest (angina) or you have experienced heart disease related signs you have severe liver or severe kidney problems you have had a stroke (cerebrovascular accident CVA) or mini stroke (transient ischaemic attack TIA) you have blockage problems with your arteries (peripheral vascular disease) you are taking monoamine oxidase (MAO) inhibitors such as moclobemide, phenelzine, tranylcypromine, or pargyline, (drugs against depression), or linezolid (an antibiotic), or if it has been less than two weeks since you stopped taking MAO inhibitors you are now taking ergotamine-type medications, such as ergotamine or dihydro-ergotamine to treat your migraine or methysergide to prevent a migraine attack you are taking any other drug in the same class, such as sumatriptan, naratriptan, or zolmitriptan to treat your migraine (see Taking with other medicines below).

If you are not sure if any of the above apply to you talk to your doctor or pharmacist before taking MAXALT.

Take special care with MAXALT if you:

Before you take MAXALT, tell your doctor or pharmacist, if:

you have any of the following risk factors for heart disease: high blood pressure, diabetes, you smoke or you are using nicotine substitution, your family has a history of heart disease, you are a man over 40 years of age, or you are a post-menopausal woman you have kidney or liver problems you have a particular problem with the way your heart beats (bundle branch block) you have or have had any allergies. your headache is associated with dizziness, difficulty in walking, lack of co-ordination or weakness in the leg or arm you use herbal preparation containing St. John's wort you have had allergic reaction like swelling of face, lips, tongue and/or throat which may cause difficulty breathing and/or swallowing (angioedema). you are taking selective serotonin reuptake inhibitors (SSRIs) such as sertraline, escitalopram oxalate, and fluoxetine or serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, and duloxetine for depression you have had short lived symptoms including chest pain and tightness

If you take MAXALT too often this may result in you getting a chronic headache. In such cases you should contact your doctor as you may have to stop taking MAXALT.

Please tell your doctor or pharmacist about your symptoms. Your doctor will decide if you have migraine. You should take MAXALT only for a migraine attack. MAXALT should not be used to treat headaches that might be caused by other, more serious conditions.

Please tell your doctor if you are taking or have recently taken, or plan to take, any other medicines including medicines obtained without a prescription. This includes herbal medicines and those you normally take for a migraine. This is because MAXALT can affect the way some medicines work. Also other medicines can affect MAXALT.

Taking with other medicines

Do not take MAXALT

if you are already taking a 5HT1B/1D agonist (sometimes referred to as ‘triptans’), such as sumatriptan, naratriptan or zolmitriptan. if you are taking a monoamine oxidase (MAO) inhibitor such as moclobemide, phenelzine, tranylcypromine, linezolid, or pargyline or if it has been less than two weeks since you stopped taking an MAO inhibitor. if you use ergotamine-type medications such as ergotamine or dihydro-ergotamine to treat your migraine. if you use methysergide to prevent a migraine attack.

The above listed medicines when taken with MAXALT may increase the risk of side-effects.

You should wait at least 6 hours after taking MAXALT before you take ergotamine-type medications such as ergotamine or dihydro-ergotamine or methysergide.

You should wait at least 24 hours after taking ergotamine-type medications before taking MAXALT.

Ask your doctor for instructions and the risks about taking MAXALT

if you are taking propranolol (see section 3: How to take MAXALT) if you are taking SSRIs such as sertraline, escitalopram oxalate, and fluoxetine or SNRIs such as venlafaxine, and duloxetine for depression.

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Taking MAXALT with food and drink:

MAXALT can take longer to work if it is taken after food. Although it is better to take it on an empty stomach, you can still take it if you have eaten.

Pregnancy and breast feeding

It is not known whether MAXALT is harmful to an unborn baby when taken by a pregnant woman.

Talk to your doctor before taking this medicine if you are pregnant, planning to get pregnant or are breastfeeding. Breastfeeding should be avoided for 24 hours after treatment.

Ask your doctor or pharmacist for advise before taking any medicine.

Use in children

There is no experience with the use of MAXALT in children under 18 years of age, therefore children should not be given MAXALT.

Use in patients older than 65 years

There have been no full studies to look at how safe and effective MAXALT is amongst patients older than 65 years.

Driving or using machines

You may feel sleepy or dizzy while taking MAXALT. If this happens, do not drive or use any tools or machines.

Important information about some of the ingredients of MAXALT

The 5-mg tablet contains 30.25 mg of lactose and the 10-mg tablet contains 60.50 mg of lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

How To Take Maxalt

MAXALT is used to treat migraine attacks. Take MAXALT as soon as possible after your migraine headache has started. Do not use it to prevent an attack.

Always take MAXALT exactly as your doctor has told you. You should check with your doctor or your pharmacist if you are not sure.

The usual dose is 10 mg.

If you are currently taking propranolol or have kidney or liver problems you should use the 5-mg dose of MAXALT. You should leave at least 2 hours between taking propranolol and MAXALT up to a maximum of 2 doses in a 24-hour period.

MAXALT (rizatriptan benzoate) tablets should be taken by mouth and swallowed whole with liquid.

MAXALT is also available as a 10-mg wafer (referred to technically as an oral lyophilisate) that dissolves in the mouth. The wafer can be used in situations in which liquids are not available, or to avoid the nausea and vomiting that may accompany the ingestion of tablets with liquids.

If migraine returns within 24 hours

In some patients, migraine symptoms can return within a 24-hour period. If your migraine does return you can take an additional dose of MAXALT. You should always wait at least 2 hours between doses.

If after 2 hours you still have migraine

If you do not respond to the first dose of MAXALT during an attack, you should not take a second dose of MAXALT for treatment of the same attack. It is still likely, however, that you will respond to MAXALT during the next attack.

Do not take more than 2 doses of MAXALT in a 24-hour period, (for example, do not take more than two 10-mg or 5 mg tablets or wafers in a 24-hour period). You should always wait at least 2 hours between doses.

If your condition worsens, seek medical attention.

If you take more MAXALT than you should:

If you take more MAXALT than you should, talk to your doctor or pharmacist straight away. Take the medicine pack with you.

Signs of overdosage can include dizziness, drowsiness, vomiting, fainting and slow heart rate.

If you have any further questions on the use of this product ask your doctor or pharmacist.

Maxalt Tablets Side Effects

Like all medicines, MAXALT can cause side effects, although not everybody gets them. The following side effects may happen with this medicine.

In studies, the most common side effects reported were dizziness, sleepiness and tiredness.

Common (affects less than 1 in 10 people) tingling (paraesthesia), headache, decreased sensitivity of skin (hypaesthesia), decreased mental sharpness, tremor, fast or irregular heart beat (palpitation), very fast heartbeat (tachycardia), flushing (redness of the face lasting a short time), hot flushes sweating, throat discomfort, difficulty breathing (dyspnoea), feeling sick (nausea), dry mouth, vomiting, diarrhoea, feeling of heaviness in parts of the body, pain in abdomen or chest Uncommon (affects less than 1 in 100 people) unsteadiness when walking (ataxia), dizziness (vertigo), blurred vision, confusion, insomnia, nervousness, high blood pressure (hypertension); thirst, indigestion (dyspepsia), itching and lumpy rash (hives), neck pain, feeling of tightness in parts of the body, stiffness, muscle weakness Rare (affects less than 1 in 1000 people) bad taste in your mouth, fainting (syncope), a syndrome called "serotonin syndrome", that may cause side effects like coma, unstable blood pressure, extremely high body temperature, lack of muscle co-ordination, agitation and hallucinations facial pain, wheezing allergic reaction like swelling of face, lips, tongue and/or throat which may cause difficulty breathing and/or swallowing (angioedema); rash, severe shedding of the skin including accompanied by fever (toxic epidermal necrolysis). heart attack, spasm of blood vessels of the heart, stroke. They generally occur in patients with risk factors for heart and blood vessel disease (high blood pressure, diabetes, smoking, use of nicotine substitution, family history of heart disease or stroke, man over 40 years of age, post-menopausal women, particular problem with the way your heart beats [bundle branch block]). Not known how often this occurs: seizure (convulsions/fits) spasm of blood vessels of the extremities including coldness and numbness of the hands or feet.

Tell your doctor right away if you have symptoms of allergic reactions, serotonin syndrome, heart attack or stroke.

In addition, tell your doctor if you experience any symptoms that suggest an allergic reaction (such as a rash or itching) after taking MAXALT.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How To Store Maxalt

Keep MAXALT out of the reach and sight of children.

Do not use MAXALT after the expiry date which is stated on the container after EXP. The expiry date refers to the last day of the month.

Do not store MAXALT above 30?C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose medicines no longer required. These measures will help to protect the environment.

Further Information What MAXALT contains

The active substance of MAXALT is rizatriptan. One tablet contains 5/10 mg rizatriptan as 7.265 or 14.53 mg of rizatriptan benzoate.

The other ingredients of MAXALT tablets are lactose monohydrate, microcrystalline cellulose (E460a), pregelatinized corn starch, iron oxide (E172) and magnesium stearate (E572).

What MAXALT looks like and contents of pack

5 mg tablets are pale pink, capsule shaped, coded MSD on one side and 266 on the other.

10 mg tablets are pale pink, capsule-shaped, coded MAXALT on one side and MSD 267 on the other.

Pack sizes: Packs with 2, 3, 6, 12 or 18 tablets.

Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Merck Sharp & Dohme Limited Hertford Road Hoddesdon Hertfordshire EN11 9BU UK

Manufacturer

MERCK SHARP & DOHME B.V. Waarderweg 39 2031 BN Haarlem The Netherlands

This medicinal product is authorised in the Member States of the EEA under the following names:

Maxalt 10 mg Tablets

Austria, Finland, France, Greece, The Netherlands, Portugal, Sweden and the United Kingdom: MAXALT

Belgium, Luxemburg and Spain: MAXALT 10 mg

Denmark: MAXALT, tabletter

Germany: MAXALT 10mg Tabletten

Italy: MAXALT 10 mg compresse

Maxalt 5 mg Tablets

Austria, Finland, France, Greece, The Netherlands, Portugal, Sweden and the United Kingdom: MAXALT

Belgium, Luxemburg and Spain: MAXALT 5 mg

Denmark: MAXALT, tabletter

Germany: MAXALT 5mg Tabletten

Italy: MAXALT 5 mg compresse

This leaflet was last approved in April 2010

How can you obtain more information about MAXALT?

This leaflet gives you some of the most important information about MAXALT. If you have any questions after you have read it, ask your doctor or pharmacist who can give you further information.

Further information about migraine is available from the following organisations:

Migraine Action Association 27 East Street Leicester LE1 6NB Tel:0116 275 8317 Fax:0116 254 2023 E-mail: info@migraine.org.uk

and

The Migraine Trust 55-56 Russell Square London WC1B 4HP Tel:020 7436 1336 Fax:020 7436 2880 Email: info@migrainetrust.org Helpline:020 7462 6601, Monday to Friday 10am - 5pm

(Migraine Action Association and The Migraine Trust are independent organisations and are not associated with Merck Sharp & Dohme Limited.)

denotes registered trademark of

Merck Sharp & Dohme Corp. a subsidiary of Merck & Co., Inc. Whitehouse Station NJ USA

© Merck Sharp & Dohme Limited 2010. All rights reserved.

Merck Sharp & Dohme Limited Hertford Road Hoddesdon Hertfordshire EN11 9BU UK

PIL.MXT.10.UK.3242 (IA-008/G)


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Haemate P 500 and 1000 IU


1. Name Of The Medicinal Product

Haemate P 500 and 1000 Powder and solvent for solution for injection or infusion

2. Qualitative And Quantitative Composition

Haemate P 500 IU

Haemate P 500 is presented as a powder and solvent for solution for injection or infusion containing nominally 1200 International Units (IU) human plasma-derived von Willebrand Factor-ristocetin co-factor activity (VWF:RCo) and 500 IU human coagulation factor VIII activity (FVIII:C)per vial.

von Willebrand Factor

Haemate P 500 contains approximately 120 IU/ml (1200 IU/10ml) human plasma-derived VWF:RCo when reconstituted with 10 ml water for injections.

Factor VIII

Haemate P 500 contains approximately 50 IU/ml (500 IU/10ml) human plasma-derived coagulation Factor VIII:C when reconstituted with 10 ml water for injections.

Haemate P 1000 IU

Haemate P 1000 is presented as a powder and solvent for solution for injection or infusion containing nominally 2400 International Units (IU) human plasma-derived von Willebrand Factor-ristocetin co-factor activity (VWF:RCo) and 1000 IU human coagulation factor VIII activity (FVIII:C) per vial.

von Willebrand Factor

Haemate P 1000 contains approximately 160 IU/ml (2400 IU/15ml) human plasma-derived VWF:RCo when reconstituted with 15 ml water for injections.

Factor VIII

Haemate P 1000 contains approximately 66.6 IU/ml (1000 IU/15ml) human plasma-derived coagulation Factor VIII:C when reconstituted with 15 ml water for injections.

The specific activity of Haemate P is approximately 3-17 IU VWF:RCo/mg protein.

The factor VIII (FVIII) potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of Haemate P is approximately 2-6 IU FVIII:C/mg protein.

For a full list of excipients, see 6.1

3. Pharmaceutical Form

Powder and solvent for solution for injection or infusion

4. Clinical Particulars 4.1 Therapeutic Indications

von Willebrand Disease (VWD):

Prophylaxis and treatment of haemorrhage or surgical bleeding, when desmopressin (DDAVP) treatment alone is ineffective or contra-indicated

Haemophilia A (congenital factor VIII deficiency):

Prophylaxis and treatment of bleeding

This product may be used in the management of acquired factor VIII deficiency and for the treatment of patients with antibodies against factor VIII (see section 4.4).

4.2 Posology And Method Of Administration

Treatment of VWD and Haemophilia A should be supervised by a physician experienced in the treatment of haemostatic disorders.

Posology

von Willebrand Disease:

Generally, 1 IU/kg VWF:RCo raises the circulating level of VWF:RCo by 0.02 IU/ml (2%).

Levels of VWF:RCo greater than 0.6 IU/ml (60%) and of FVIII:C greater than 0.4 IU/ml (40%) should be achieved.

Usually, 40-80 IU/kg bodyweight VWF:RCo and 20-40 IU/kg bodyweight FVIII:C are recommended to achieve haemostasis.

An initial dose of 80 IU/kg VWF:RCo may be required, especially in patients with type 3 von Willebrand disease where maintenance of adequate levels may require higher doses than in other types of von Willebrand disease.

Prevention of haemorrhage in case of surgery or severe trauma

For prevention of excessive bleeding during or after surgery, the injection should be started 1 to 2 hours before the surgical procedure.

An appropriate dose should be re-administered every 12 - 24 hours. The dose and duration of treatment will depend on the clinical status of the patient, the type and severity of bleeding and both the VWF:RCo and FVIII:C levels.

When using a factor VIII-containing von Willebrand factor product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. After 24 - 48 hours of treatment, in order to avoid an uncontrolled rise in FVIII:C, reduced doses and/or prolongation of the dose interval should be considered.

Dosing in children is based on bodyweight and is therefore generally based on the same guidelines as for adults. The frequency of administration should always be tailored to clinical effectiveness in the individual case.

Haemophilia A:

The dosage and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on the patient's clinical condition.

The number of units of factor VIII administered is expressed in International Units, which are related to the current World Health Organisation (WHO) standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor VIII in plasma).

One IU of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma.

The calculation of the required dosage of FVIII:C is based on the empirical finding that 1 IU factor VIII:C per kg bodyweight raises the plasma factor VIII activity by about 2% of normal activity (2 IU/dl). The required dosage is determined using the following formula:

Required units = body weight (kg) x desired factor VIII:C rise (% or IU/dl) x 0.5.

The amount to be administered and the frequency of administration should always be tailored to clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the indicated plasma activity level (in % of normal or IU/dl) within the corresponding period.

The following table can be used to guide dosing in bleeding episodes and surgery:

Degree of haemorrhage / Type of surgical procedure

FVIII:C level required (% or IU/dl)

Frequency of Doses (hours) /Duration of therapy (days)

Haemorrhage

   

Early haemarthrosis, muscle bleeding or oral bleeding

20 - 40

Repeat every 12 - 24 hours (at least 1 day) until the bleeding episode, as indicated by pain, is resolved or healing is achieved.

More extensive haemarthrosis, muscle bleeding or haematoma

30 - 60

Repeat infusion every 12 - 24 hours for 3 - 4 days or more until pain and disability are resolved.

Life-threatening haemorrhages

60 - 100

Repeat infusion every 8 - 24 hours until threat is resolved.

Surgery

   

Minor

including tooth extraction

30 - 60

Every 24 hours (at least 1 day) until healing is achieved.

Major

80 - 100

(pre- and postoperative)

Repeat infusion every 8 - 24 hours until adequate wound healing, then treat for at least another 7 days to maintain a FVIII:C activity of 30 to 60% or IU/dl.

During the course of treatment, appropriate determination of FVIII:C levels is advised, to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma FVIII:C activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 - 40 IU factor VIII:C per kg bodyweight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

Patients should be monitored for the development of factor VIII inhibitors. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. . In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with haemophilia. See section 4.4.

There are no data from clinical studies regarding the dosage of Haemate P in children with haemophilia A.

Method of administration

If necessary, the preparation should be warmed to room or body temperature, then reconstituted as described in section 6.6. Then the product should be administered slowly via the intravenous route at a rate comfortable for the patient. If it is not administered immediately, storage should not exceed 8 hours at room temperature. Once the product has been transferred into a syringe, it should be used immediately.

Where a large volume is required, infusion is an alternative option. The reconstituted preparation should be transferred to an approved infusion system.

The injection or infusion rate should not exceed 4 ml per minute. The patient should be observed for any immediate reaction. Should any reaction occur which might be related to administration of Haemate P, the rate of infusion should be decreased or administration stopped, as appropriate. See section 4.4.

4.3 Contraindications

Hypersensitivity to any of the constituents of Haemate P.

4.4 Special Warnings And Precautions For Use

As with any intravenous infusion of a plasma-derived protein, allergic type hypersensitivity reactions are possible. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, the patient should be advised to discontinue use of the product immediately and contact their physician.

In case of shock, the current medical standards for shock treatment should be implemented.

Haemate P contains up to 70 mg sodium per 1000 IU. This should be taken into consideration for patients on a sodium-controlled diet.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV and for the non-enveloped virus HAV. The measures taken may be of limited value against other non-enveloped viruses such as parvovirus B19. Parvovirus B19 infection may be serious for pregnant women (foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g. haemolytic anaemia).

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived products.

It is strongly recommended that every time that Haemate P is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

von Willebrand Disease:

There is a risk of occurrence of thrombotic events, particularly in patients with known clinical or laboratory risk factors. Therefore, patients at risk must be monitored for early signs of thrombosis. Prophylaxis against venous thromboembolism should be instituted, according to the current recommendations.

When using a factor VIII-containing VWF product, the treating physician should be aware that continued treatment may cause an excessive rise in FVIII:C. In patients receiving FVIII-containing VWF products, plasma levels of FVIII:C should be monitored to avoid sustained excessive FVIII:C plasma levels which may increase the risk of thrombotic events, and anti-thrombotic measures should be considered.

Patients with von Willebrand disease, especially type 3 patients, may develop neutralising antibodies (inhibitors) to VWF. If the expected VWF:RCo activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an appropriate assay should be performed to determine if a VWF inhibitor is present. In patients with high levels of inhibitor, VWF therapy may not be effective and other therapeutic options should be considered.

Haemophilia A:

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days. Patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitory antibodies by appropriate clinical observations and laboratory tests. In patients with high levels of inhibitor, therapy may not be effective and other therapeutic options should be considered. See section 4.8.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions of human coagulation factor VIII or von Willebrand factor products with other medicinal products are known.

4.6 Pregnancy And Lactation

Animal reproduction studies have not been conducted with Haemate P.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available.

The situation is different in von Willebrand disease because of its autosomal heredity. Women are affected more than men because of additional bleeding risks such as menstruation, pregnancy, labour, childbirth and gynaecological complications. Based on post-marketing experience, substitution of VWF in the prevention and treatment of acute bleeding is not contra-indicated. There are no clinical studies available on substitution therapy in pregnant or lactating women.

Therefore, Haemate P should be administered to pregnant and lactating women only if clearly indicated and the benefit outweighs the risk.

4.7 Effects On Ability To Drive And Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable Effects

The following adverse reactions are based on experience from clinical trials and on post-marketing experience. The following standard categories of frequency are used:

Very common

Common

Uncommon

Rare

Very rare

<1/10,000

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed very rarely, and may in some cases progress to severe anaphylaxis (including shock).

When very large or frequently repeated doses are needed, e.g. when inhibitors are present or when pre- and post-surgical care is involved, all patients should be monitored for signs of hypervolaemia. In addition, those patients with blood groups A, B and AB should be monitored for signs of intravascular haemolysis and/or decreasing haematocrit values.

On rare occasions, fever has been observed.

Inhibitor development

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response.

In all such cases, it is recommended that a specialised haemophilia centre be contacted.

The experience from clinical trials with Haemate P in previously untreated patients (PUPs) is very limited. Therefore, no valid figures on incidence of clinically relevant specific inhibitors can be provided.

Patients with von Willebrand disease, especially type 3 patients, may very rarely develop neutralising antibodies (inhibitors) to VWF. If such inhibitors occur, the condition will manifest itself as an inadequate clinical response. Such antibodies are precipitating and may occur concomitantly with anaphylactic reactions. Therefore, patients experiencing anaphylactic reaction should be evaluated for the presence of an inhibitor.

In all such cases, it is recommended that a specialised haemophilia centre be contacted.

Vascular disorders

In von Willebrand disease there is a risk of thrombotic events, particularly in patients with known risk factors.

In patients receiving VWF products, sustained excessive FVIII:C plasma levels may increase the risk of thrombotic events, see section 4.4.

For safety with respect to transmissible agents, see section 4.4.

4.9 Overdose

No symptoms of overdose with human von Willebrand factor and/or coagulation factor VIII have been reported. Thromboembolic events may occur in case of major overdose.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Antihaemorrhagics: blood coagulation factors, von Willebrand factor and coagulation factor VIII in combination.

ATC code: B02BD06.

von Willebrand Factor:

Haemate P behaves in the same way as endogenous von Willebrand factor.

In addition to its role as a factor VIII protecting protein, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays the main role in platelet aggregation.

Administration of von Willebrand factor allows correction of the haemostatic abnormalities exhibited by patients who suffer from VWF deficiency (VWD) at two levels:

- VWF re-establishes platelet adhesion to the vascular sub-endothelium at the site of vascular damage (as it binds to both the vascular sub-endothelium and to the platelet membrane), providing primary haemostasis as shown by the shortening of the bleeding time. This effect occurs immediately and is known to depend to a large extent on the level of polymerisation of the protein, i.e. content of high molecular weight VWF-multimers.

- VWF produces delayed correction of the associated factor VIII deficiency. Administered intravenously, VWF binds to endogenous factor VIII (which is produced normally by the patient), and by stabilising this factor, avoids its rapid degradation.

Because of this, administration of pure VWF (VWF product with a low FVIII level) restores the FVIII:C level to normal as a secondary effect after the first infusion with a slight delay.

Administration of a FVIII:C-containing VWF preparation restores the FVIII:C level to normal immediately after the first infusion.

Factor VIII:

Haemate P behaves in the same way as endogenous factor VIII.

The factor VIII/von Willebrand factor complex consists of two molecules (FVIII and VWF) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to VWF in the patient's circulation.

- Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.

Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendency.

5.2 Pharmacokinetic Properties

von Willebrand Factor:

The pharmacokinetics of Haemate P has been evaluated in 28 VWD patients (type 1, n=10; type 2A, n=10; type 2M, n=1; type3, n=7) in the non-bleeding state.

The median terminal half-life of VWF:RCo (two compartment model) was 9.9 hours (range: 2.8 to 51.1). The median initial half-life was 1.47 hours (range: 0.28 to 13.86). The median in vivo recovery for VWF:RCo activity was 1.9 IU/dl per IU/kg (range: 0.6 to 4.5). The median area under the curve (AUC) was 1664 IU/dl x hours (range: 142 to 3846), the median residence time (MRT) was 13.7 hours (range: 3.0 to 44.6) and the median clearance was 4.81 ml/kg/h (range: 2.08 to 53.0).

Peak plasma levels of VWF usually occur at around 50 minutes after injection.

Factor VIII:

After intravenous injection, there is a rapid increase in plasma factor VIII (FVIII:C) activity, followed by a rapid decrease in activity and a subsequent slower rate of decrease in activity. Studies in patients with Haemophilia A have demonstrated a median half-life of 12.6 hours (range: 5.0 to 27.7). An overall median FVIII in vivo recovery of 1.73 IU/dl per IU/kg (range: 0.5 to 4.13) was obtained. In one study, the median residence time (MRT) was found to be 19.0 hours (range: 14.8 to 40.0), the median area under the curve (AUC) was 36.1 % x hours/IU/kg (range: 14.8 to 72.4) and the median clearance was 2.8 ml/kg/h (range: 1.4 to 6.7).

Peak plasma FVIII levels occur between 1 and 1.5 hours after injection.

5.3 Preclinical Safety Data

Haemate P contains the active ingredients, factor VIII and von Willebrand factor, both of which are derived from human plasma and act like the endogenous constituents of plasma.

Single dose toxicity testing revealed no adverse findings in different species even at dose levels several times higher than the recommended human dose. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein. To date Haemate P has not been reported to be associated with embryo-foetal toxicity, oncogenic or mutagenic potential.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Human albumin

Glycine

Sodium chloride

Sodium citrate

Sodium hydroxide or hydrochloric acid (in small amounts for pH adjustment)

Supplied diluent: Water for injections 10 ml (Haemate P 500), 15ml (Haemate P 1000)

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products, diluents and solvents, except those mentioned in section 6.1.

Only the provided injection/infusion sets should be used because treatment failure can occur as a consequence of human factor VIII adsorption to the internal surfaces of some infusion equipment.

6.3 Shelf Life

3 years.

Following reconstitution, physico-chemical stability has been demonstrated for 48 hours at room temperature (max +25°C). From a microbiological point of view and since Haemate P contains no preservatives, the reconstituted product should be used immediately. If it is not administered immediately, storage should not exceed 8 hours at room temperature.

Once the product has been transferred into a syringe, it should be used immediately.

6.4 Special Precautions For Storage

Do not store above 25 °C. Do not freeze.

Keep the vials in the outer carton, in order to protect from light.

6.5 Nature And Contents Of Container

6.5.1 Immediate containers:

Substance vial:

Injection vial of colourless, moulded glass type II (Ph. Eur.), sealed with rubber infusion stopper (latex-free), plastic disc and aluminium cap.

1 vial (hermetically sealed under vacuum) with dried substance

Solvent (diluent) vial (Water for Injections):

1 injection vial of tubular glass with inner surface treatment, colourless glass type I (Ph. Eur.), sealed with rubber infusion stopper (latex-free), plastic disc and aluminium cap.

1 vial with 10 or 15 ml water for injections

6.5.2 Administration set: (in separate box)

1 filter transfer device 20/20

1 disposable 10 or 15 ml syringe

1 venipuncture set

2 alcohol swabs

1 plaster

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

General instructions

• The solution should be clear or slightly opalescent. After filtering/withdrawal (see below), the reconstituted product should be inspected visually for particulate matter prior to administration. Even if the directions for use for the reconstitution procedure are precisely followed, it is not uncommon for a few flakes or particles to remain.

Note: the filter included in the Mix2Vial transfer device will remove any particles.

Filtration does not influence dosage calculations. Do not use visibly cloudy solutions or solutions containing flakes or particles after filtration.

• Reconstitution and withdrawal must be carried out under aseptic conditions.

Reconstitution:

Bring the solvent to room or body temperature. Remove the product and diluent vial flip caps, wipe both stoppers with an alcohol swab and allow to dry before opening the Mix2Vial package.

1. Open the Mix2Vial package by peeling away the lid. Do not remove the Mix2Vial from the blister package.

2. Place the diluent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adaptor end straight down through the diluent vial stopper.

3. Carefully remove the blister package from the Mix2Vial set by holding at the rim and pulling vertically upwards. Make sure that you only pull away the blister package and not the Mix2Vial set.

4. Place the product vial on an even and firm surface. Invert the diluent vial with the Mix2Vial set attached and push the spike of the transparent adaptor end straight down through the product vial stopper.

The diluent will automatically flow into the product vial.

5. With one hand, grasp the product-side of the Mix2Vial set and with the other hand grasp the diluent-side and unscrew the set carefully into two pieces (to avoid excessive foam build-up when dissolving the product).

Discard the diluent vial with the blue Mix2Vial adaptor attached.

6. Gently swirl the product vial with the transparent adaptor attached, until the substance is fully dissolved. Do not shake.

 

7. Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial?s Luer Lock fitting. Inject air into the product vial.

Withdrawal and application

8. While keeping the syringe plunger pressed in, turn the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly.

9. Now that the concentrate has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adaptor from the syringe.

 

Administer the solution slowly via the intravenous route, taking care that no blood enters the syringe. See section 4.2.

7. Marketing Authorisation Holder

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

8. Marketing Authorisation Number(S)

Haemate P 500: PL 15036/0009

Haemate P 1000: PL 15036/0010

9. Date Of First Authorisation/Renewal Of The Authorisation

12 April 2005

10. Date Of Revision Of The Text

15 July 2010


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Promixin, 1 million International Units (IU), Powder for Solution for Injection


1. Name Of The Medicinal Product

Promixin, 1 million International Units (IU), Powder for Solution for Infusion.

2. Qualitative And Quantitative Composition

Each vial contains 1 million International Units (IU) which is approximately equivalent to 80 mg of colistimethate sodium.

3. Pharmaceutical Form

Powder for solution for infusion

The powder is white to off white

4. Clinical Particulars 4.1 Therapeutic Indications

Promixin is indicated for treatment of the following infections caused by susceptible aerobic Gram-negative bacteria (see section 5.1):

- Hospital acquired pneumonia (HAP)

- Complicated urinary tract infections

It is recommended that Promixin should be selected when antibacterial agents that are commonly used to treat these infections are not considered to be appropriate for the individual patient and/or the causative pathogen(s) (see sections 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

It is recommended that Promixin should be administered under the supervision of physicians with appropriate experience in its use.

Method of Administration

Administration is by intravenous infusion. Each dose of Promixin can be diluted in 50 mL and administered by intravenous infusion over 30 minutes. Patients fitted with a totally implantable venous access device (TIVAD) may tolerate an injection of up to 2 million IU in 10 mL given over a minimum of 5 minutes.

Solutions should be used immediately after reconstitution. For instructions on dilution of the product before administration see section 6.6.

Posology

The dose regimen of Promixin that is selected should take into account factors such as the susceptibility of the pathogen(s), the severity and type of infection, and the ideal body weight and renal function of the patient. The duration of treatment is usually at least 5 days.

Standard dose recommendations are as follows:

Up to 60 Kg: 50,000 IU/Kg (4 mg/Kg) bodyweight, to a maximum of 75,000 IU/Kg (6 mg/Kg), in 24 hours. The total daily dose should be administered as three equal doses at 8 hourly intervals.

Over 60 Kg: 1-2 million IU every 8 hours. The maximum standard dose is 6 million IU (480 mg) in 24 hours.

Limited pharmacokinetic data from critically ill patients suggest that use of a loading dose and higher than standard doses may be appropriate (see Section 5.2). For severe infections and in critically ill patients doses up to 9 million IU per day in divided doses, have been reported in the literature. Clinical efficacy and safety data with these regimens are very limited and caution is advised (see sections 4.4 and 5.2).

Paediatric population

Dose recommendations are the same in adults and all paediatric sub groups.

Renal impairment

The suggested dose recommendations in Table 1 for patients with renal impairment are based on the standard total daily dose of 3-6 million IU/day. For patients with renal impairment in whom higher doses (e.g. up to 9 million IU/day) would be considered if their renal function was normal, corresponding proportional adjustments should be considered when calculating the dose. Caution is advised when administering Promixin to any patient with renal impairment due to the limited information available on safety and appropriate dose regimens (see section 4.4).

Table 1: Suggested modification of dosage of Promixin for adults with impaired renal function

 

Degree of Renal Impairment

     

Normal

Mild

Moderate

Severe

 

Creatinine Clearance

(% of normal)

76 to 100

40 to 75

25 to 40

Less than 25

Dose

       

Unit dose

(Million IU)

1.3 to 2

1 to 1.5

1

1 to 1.5

Frequency

(Times per day)

3

2

1 or 2

Every 36 hours

Total Daily Dose

(Million IU)

4 to 6

2 to 3

1 to 2

0.6 to 1

Hepatic impairment

It is not known whether the dose of Promixin requires adjustment in patients with hepatic impairment and therefore caution is advised.

4.3 Contraindications

Hypersensitivity to the active substance colistimethate sodium or other polymyxins.

4.4 Special Warnings And Precautions For Use

Use with caution in patients with renal impairment as colistimethate sodium is renally excreted.

Nephrotoxicity or neurotoxicity may occur especially if the recommended dose is exceeded (see also Section 4.5). There are limited safety data when colistimethate sodium is used in doses exceeding 6 million IU/day.

Monitoring of renal function should be performed before initiating treatment with Promixin. Monitoring of serum creatinine must continue at regular intervals (at least daily) during therapy. Particular caution should be exercised when administering doses greater than 6 million IU/day. The dose of Promixin may have to be reduced if serum creatinine concentrations rise or exceed the upper limit of normal.

There is evidence that it is the total cumulative dose (not the daily dose) of colistimethate sodium that may be associated with risk of nephrotoxicity.

Do not use concomitantly with other medications with nephrotoxic or neurotoxic effects except with the greatest caution.

Colistimethate sodium is known to reduce the amount of acetylcholine released from the pre-synaptic neuromuscular junction and therefore should not be used in patients with myasthenia gravis, unless in life-threatening situations.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of colistimethate sodium. Discontinuation of therapy with colistimethate sodium and the administration of specific treatment for Clostridium difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Use with extreme caution in patients with porphyria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the effects of colistimethate sodium on the release of acetylcholine, non-depolarising muscle relaxants should be used with extreme caution in patients receiving Promixin as their effects could be prolonged.

Concomitant use of colistimethate sodium with other medications that are nephrotoxic or neurotoxic (eg. cephalothin sodium, aminoglycosides, non-depolarising muscle relaxants) should only be undertaken with the greatest caution.

The potential of colistimethate sodium to affect the pharmacokinetics of other medicinal products has not been evaluated. Caution is recommended if colistimethate sodium is combined with medicinal products with a narrow therapeutic index.

4.6 Pregnancy And Lactation

Fertility

There are no data on the effects of colistimethate sodium on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

Pregnancy

Safety in human pregnancy has not been established. Animal studies are insufficient with respect to effects on reproduction. There is evidence that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity if administered during pregnancy. Hence, Promixin should only be given during pregnancy if the benefits outweigh any potential risk.

Lactation

Colistimethate sodium is excreted in breast milk; breast feeding is not recommended during therapy.

4.7 Effects On Ability To Drive And Use Machines

Neurotoxicity, characterised by dizziness, confusion or visual disturbances have been reported following parenteral administration of colistimethate sodium. If these effects occur patients should be warned against driving or operating machinery.

4.8 Undesirable Effects

The most commonly reported adverse reaction is renal function impairment, and more rarely renal failure, usually following use of higher than recommended doses in patients with normal renal function, or failure to reduce the dosage in patients with renal impairment or when used concomitantly with other nephrotoxic antibiotics. The effect is usually reversible on discontinuation of therapy, but rarely intervention (renal replacement therapy) may be required.

High serum concentrations of colistimethate sodium, which may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, have been reported to lead to neurotoxic effects such as facial paraesthesia, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnoea. Concomitant use with either non-depolarising muscle relaxants or antibiotics with similar neurotoxic effects can also lead to neurotoxicity. Dose reduction of colistimethate sodium may relieve symptoms.

Hypersensitivity reactions such as skin rash and angioedema have been known to occur. In the event such reactions occur, treatment with colistimethate sodium should be withdrawn.

Adverse reactions are tabulated below by system organ class and frequency. Frequencies are defined as Very common (

Body System

Frequency

Reported adverse reaction

Immune system disorders

Not known

Hypersensitivity reactions such as skin rash and angioedema

Nervous system disorders

Very Common

Neurotoxicity such as, facial, mouth and peri-oral paraesthesia, headache, and muscle weakness

Not known

Dizziness

Ataxia

 

Skin and subcutaneous tissue disorders

Very Common

Pruritus

Renal and urinary disorders

Very Common

Renal impairment demonstrated by increased blood creatinine and / or urea and / or decreased creatinine renal clearance

Rare

Renal failure

 

General disorders and administration site conditions

Not known

Injection site reaction

4.9 Overdose

Overdosage may cause renal insufficiency, renal failure, apnoea, muscle weakness, vertigo, slurred speech, vasomotor instability, visual disturbances, confusion and psychosis.

No antidote is available.

Management of overdose is by means of supportive treatment and measures designed to increase clearance of colistimethate sodium such as inducing an osmotic diuresis with mannitol, peritoneal dialysis or prolonged haemodialysis.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other antibacterials, Polymyxins

ATC code: J01XB01

General properties

Mode of action

The polymyxin antibiotics are surface active agents and act by binding to and changing the permeability of bacterial cell membrane causing bacterial cell death. Polymyxins are bactericidal against Gram-negative bacteria with a hydrophobic outer membrane.

PK/PD relationship

Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria.

EUCAST Breakpoints

 

Susceptible (S) Resistant (R) a

Acinetobacter

S

Enterobacteriaceae

S

Pseudomonas Spp

S

aBreakpoints apply to dosage of 2-3 million IU x 3. A loading dose (9 million IU) may be needed.

Mechanisms of resistance

Acquired resistance to Colistimethate sodium in Pseudomonas aeruginosa appears to be related to alterations in the bacterial outer membrane. In-vitro studies with Salmonella and E. coli have shown that resistance may occur due to modification of the cell wall lipopolysaccharide phosphate groups. Modification is achieved by substitution of the phosphate groups with ethanolamine or aminoarabinose. Proteus mirabilis, Burkholderia cepacia and other naturally resistant Gram-negative bacteria, show complete substitution of their lipopolysaccharide groups.

Polymyxins including colistimethate sodium differ in their mechanism of action compared with other antibiotics and there is evidence to show that Gram-negative bacteria resistant to other antibiotics may be susceptible to colistimethate sodium. There is no co- resistance between polymyxins and other groups of antibiotics.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. Expert advice should be sought when the local prevalence of resistance is such that the utility of the agent, in at least some types of infections, is questionable.

Commonly susceptible species

Acinetobacter species

Klebsiella species

Pseudomonas aeruginosa

Species for which acquired resistance may be a problem

Stenotrophomonas maltophilia

Achromobacter xylosoxidans

Inherently resistant organisms

Burkholderia cepacia and related species

Proteus spp

Providencia spp

Serratia spp

5.2 Pharmacokinetic Properties

Absorption

Absorption of colistimethate sodium from the gastrointestinal tract does not occur to any appreciable extent in the normal individual.

Distribution

The volume of distribution of colistin following administration of colistimethate sodium in healthy volunteers and in patients with cystic fibrosis has been reported to be 12.4L and 20.4L respectively. In comparison the volume of distribution for colistin following administration of colistimethate sodium has been shown to be between 90.6 L and 139.9 L in critically ill patients. The increase in the volume of distribution in critically ill patients, may lead to a delay in reaching effective plasma concentrations. Therefore the use of an initial loading dose of up to 9 million IU has been suggested, especially in critically ill patients.

In critically ill patients given colistimethate sodium 2 million IU and 3 million IU three times a day intravenously, peak colistin plasma concentrations of 2.21 and 2.93 mg/L, respectively, were observed.

Biotransformation

Colistimethate sodium undergoes conversion to polymyxin E1 and polymyxin E2 (colistin) in vivo. It has been estimated that approximately 30% of the colistimethate sodium is converted to colistin.

Elimination

Colistimethate sodium is primarily excreted unchanged in the urine where the hydrolysis to the active moiety continues. Following intravenous administration 62% of a dose is recovered in the urine within 8 hours.

Colistin is excreted by the non-renal route.

The half-life of colistin following administration of colistimethate sodium in healthy volunteers and in patients with cystic fibrosis has been reported to be 3 hours and 4.2 hours respectively. The half-life of colistin following administration of colistimethate sodium has been reported to increase when administered to critically ill patients compared to healthy volunteers and mean half life is estimated to range from approximately 5.9 hours to 7.4 hours following intravenous administration to critically ill patients.

In patients with renal impairment, colistimethate sodium excretion is reduced and a higher proportion may be converted to colistin, leading to increased plasma colistin concentrations.

5.3 Preclinical Safety Data

Animal studies are insufficient with respect to effects on reproduction.

Data on potential genotoxicity are limited and carcinogenicity data for colistimethate sodium are lacking. Colistimethate sodium has been shown to induce chromosomal aberrations in human lymphocytes, in vitro. This effect may be related to a reduction in mitotic index, which was also observed.

6. Pharmaceutical Particulars 6.1 List Of Excipients

None

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Unopened:

Two years

After reconstitution:

Chemical and physical in-use stability has been demonstrated for up to 8 hours at room temperature.

From a microbiological point of view solutions should be used immediately. If not used immediately in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

No special precautions for storage.

For storage conditions of the reconstituted/diluted product see section 6.3.

6.5 Nature And Contents Of Container

The product is supplied in clear type I glass vials sealed with a siliconised chlorobutyl type I rubber stopper and protected by a 20 mm aluminium tear-off cap incorporating a red flip-up central plastic top. The product is supplied in pack sizes of 10 vials.

6.6 Special Precautions For Disposal And Other Handling

For single use only.

Promixin must be reconstituted, under aseptic conditions, with sodium chloride solution 9 mg/mL (0.9%) to produce a clear colourless to pale yellow solution. Following reconstitution, the solution should be diluted to a suitable volume for infusion over 30 minutes with sodium chloride solution 9 mg/mL (0.9%) for infusion. The solution should be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

Solutions should be used immediately after reconstitution (see section 4.2).

Discard any unused solution. Waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Profile Pharma Limited

Chichester Business Park

City Fields Way

Tangmere

Chichester

West Sussex

PO20 2FT

United Kingdom

8. Marketing Authorisation Number(S)

PL 19419/0002

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 24th June 2003

Date of latest renewal: 13th March 2009

10. Date Of Revision Of The Text

30th August 2011


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Clindamycin Pledget


Generic Name: clindamycin phosphate
Dosage Form: pledget

Rx only
For External Use

Clindamycin Pledget Description

Clindamycin Phosphate Topical Solution USP, 1% contains clindamycin phosphate, at a concentration equivalent to 10 mg clindamycin per milliliter. Each Clindamycin Phosphate Topical Solution pledget applicator contains approximately 1 mL of topical solution.

The solution contains isopropyl alcohol 50% v/v, propylene glycol, and purified water. 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.

The structural formula is represented below:

The chemical name for clindamycin phosphate is: Methyl 7 - chloro - 6,7,8 - trideoxy - 6 - (1 - methyl - trans - 4 - propyl - L - 2 - pyrrolidinecarboxamido) - 1 - thio - L - threo - ? - D - galacto - octopyranoside 2-(dihydrogen phosphate). pH between 4.0 and 7.0.

Clindamycin Pledget - Clinical Pharmacology

Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

Cross resistance has been demonstrated between clindamycin and lincomycin.

Antagonism has been demonstrated between clindamycin and erythromycin.

Following multiple topical applications of clindamycin phosphate at a concentration equivalent to 10 mg clindamycin per mL in an isopropyl alcohol and water solution, very low levels of clindamycin are present in the serum (0–3 ng/mL) and less than 0.2% of the dose is recovered in urine as clindamycin.

Clindamycin activity has been demonstrated in comedones from acne patients. The mean concentration of antibiotic activity in extracted comedones after application of Clindamycin Phosphate Topical Solution USP, 1% for 4 weeks was 597 mcg/g of comedonal material (range 0–1490). Clindamycin in vitro inhibits all Propionibacterium acnes cultures tested (MICs 0.4 mcg/mL). Free fatty acids on the skin surface have been decreased from approximately 14% to 2% following application of clindamycin.

Indications and Usage for Clindamycin Pledget

Clindamycin Phosphate Topical Solution USP, 1% is indicated in the treatment of acne vulgaris. In view of the potential for diarrhea, bloody diarrhea and pseudomembranous colitis, the physician should consider whether other agents are more appropriate. (See CONTRAINDICATIONS , WARNINGS and ADVERSE REACTIONS.)

Contraindications

Clindamycin Phosphate Topical Solution USP, 1% is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis.

Warnings

Orally and parenterally administered clindamycin has been associated with severe colitis which may result in patient death. Use of the topical formulation of clindamycin results in absorption of the antibiotic from the skin surface. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin.

Studies indicate a toxin(s) produced by clostridia is one primary cause of antibiotic-associated colitis. The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. Endoscopic examination may reveal pseudomembranous colitis. Stool culture for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.

When significant diarrhea occurs, the drug should be discontinued. Large bowel endoscopy should be considered to establish a definitive diagnosis in cases of severe diarrhea.

Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen the condition. Vancomycin has been found to be effective in the treatment of antibiotic-associated pseudomembranous colitis produced by Clostridium difficile.The usual adult dosage is 500 mg to 2 grams of vancomycin orally per day in three to four divided doses administered for 7 to 10 days. Cholestyramine or colestipol resins bind vancomycin in vitro.If both a resin and vancomycin are to be administered concurrently, it may be advisable to separate the time of administration of each drug.

Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with clindamycin.

Precautions

General: Clindamycin Phosphate Topical Solution USP, 1% contains an alcohol base which will cause burning and irritation of the eye. In the event of accidental contact with sensitive surfaces (eye, abraded skin, mucous membranes), bathe with copious amounts of cool tap water. The solution has an unpleasant taste and caution should be exercised when applying medication around the mouth.

Clindamycin Phosphate should be prescribed with caution in atopic individuals.

Drug Interactions: Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore it should be used with caution in patients receiving such agents.

Pregnancy: Teratogenic Effects—Pregnancy Category B. Reproduction studies have been performed in rats and mice using subcutaneous and oral doses of clindamycin ranging from 100 to 600 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to clindamycin. There are, however, no adequate and 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.

Nursing Mothers: It is not known whether clindamycin is excreted in human milk following use of clindamycin phosphate. 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 in pediatric patients under the age of 12 has not been established.

Geriatric Use: Clinical studies for clindamycin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Adverse Reactions

In 18 clinical studies of various topical clindamycin formulations of clindamycin phosphate using placebo vehicle and/or active comparator drugs as controls, patients experienced a number of treatment emergent adverse dermatologic events [see table below].

Number of Patients Reporting Events Treatment Emergent Adverse Event Solution
n=553 (%) Gel
n=148 (%) Suspension
n=160 (%)

# not recorded

* of 126 subjects

Burning 62 (11) 15 (10) 17 (11) Itching 36 ( 7) 15 (10) 17 (11) Burning/Itching 60 (11) # ( – ) # ( – ) Dryness 105(19) 34 (23) 29 (18) Erythema 86 (16) 10 ( 7) 22 (14) Oiliness/Oily Skin 8 ( 1) 26 (18) 12*(10) Peeling 61 (11) # ( – ) 11 ( 7)

Orally and parenterally administered clindamycin has been associated with severe colitis which may end fatally.

Cases of diarrhea, bloody diarrhea and colitis (including pseudomembranous colitis) have been reported as adverse reactions in patients treated with oral and parenteral formulations of clindamycin and rarely with topical clindamycin (see WARNINGS).

Abdominal pain and gastrointestinal disturbances as well as gram-negative folliculitis have also been reported in association with the use of topical formulations of clindamycin.

Overdosage

Topically applied clindamycin phosphate can be absorbed in sufficient amounts to produce systemic effects (see WARNINGS).

Clindamycin Pledget Dosage and Administration

Use a Clindamycin Phosphate Topical Solution pledget for the application of clindamycin phosphate twice daily to affected area.

More than one pledget may be used. Each pledget should be used only once and then be discarded. Remove pledget from foil just before use. Do not use if the seal is broken. Discard after single use.

How is Clindamycin Pledget Supplied

Clindamycin Phosphate Topical Solution USP, 1% containing clindamycin phosphate equivalent to 10 mg clindamycin per milliliter is available in the following sizes:

Carton of 60 single-use pledget applicators NDC 0168-0201-01

Store at 20° to 25°C (68°to 77°F)[see USP Controlled Room Temperature].

Protect from freezing.

E. FOUGERA & CO.
a division of Altana Inc.
MELVILLE, NEW YORK 11747

IF5263
R10/05
#51


CLINDAMYCIN PHOSPHATE 
clindamycin phosphate  solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0168-0201 Route of Administration TOPICAL DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength Clindamycin phosphate (Clindamycin) Active 10 MILLIGRAM  In 1 MILLILITER isopropyl alcohol Inactive   propylene glycol Inactive   water Inactive   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0168-0201-01 60 PACKET In 1 CARTON contains a PACKET 1 1 mL (MILLILITER) In 1 PACKET This package is contained within the CARTON (0168-0201-01)
Revised: 08/2007E. FOUGERA & CO. More Clindamycin Pledget resources Clindamycin Pledget Use in Pregnancy & Breastfeeding Clindamycin Pledget Drug Interactions Clindamycin Pledget Support Group 20 Reviews for Clindamycin Pledget - Add your own review/rating Compare Clindamycin Pledget with other medications Acne Bacterial Vaginitis Perioral Dermatitis
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Sodium Sulfacetamide Sulfur Cleansing Pads


Generic Name: sulfacetamide sodium and sulfur swab
Dosage Form: swab
Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads In a vehicle containing Green Tea and Aloe Rx Only

DESCRIPTION: Sodium sulfacetamide is a sulfonamide with antibacterial activity while sulfur acts as a keratolytic agent.
Chemically sodium sulfacetamide is N-[(4-aminophenyl) sulfonyl]-acetamide, monosodium salt, monohydrate.
The structural formula is:


Each pad of Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads are coated with a cleanser-based formulation. Each gram of this cleanser-based
formulation contains 100 mg of Sodium Sulfacetamide and 40 mg of Sulfur. The cleanser base consists of: purified water, sodium cocoyl isethionate
disodium oleamido MEA sulfosuccinate, green tea extract, cetyl alcohol, stearyl alcohol, glycerol stearate and PEG 100 stearate methyl paraben, propyl
paraben, butylated hydroxytoluene, aloe vera gel, sodium thiosulfate, disodium EDTA, magnesium aluminum silicate, xanthan gum, sodium methyl cocoyl
taurate, white petrolatum.

CLINICAL PHARMACOLOGY: The most widely accepted mechanism of action of sulfonamides is the Woods-Fildes theory, which is based on the fact
that sulfonamides act as competitive antagonists to para-aminobenzoic acid (PABA), an essential component for bacterial growth. While absorption
through intact skin has not been determined, sodium sulfacetamide is readily absorbed from the gastrointestinal tract when taken orally and excreted in
the urine, largely unchanged. The biological half-life has variously been reported as 7 to 12.8 hours. The exact mode of action of sulfur in the treatment of
acne is not known, but it has been reported that it inhibits the growth of Propionibacterium acnes and the formation of free fatty acids.

INDICATIONS: Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads are indicated in the topical control of acne vulgaris, acne rosacea and seborrheic dermatitis.

CONTRAINDICATIONS: Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads are contraindicated for use by patients having known hypersensitivity
to sulfonamides, sulfur or ony other component of this preparation. Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads are not to be used by
patients with kidney disease.

WARNINGS: Although rare, sensitivity to sodium sulfacetaminde may occur. Therefore, caution and careful supervision should be observed when
prescribing this drug for patients who may be prone to hypersensitivity to topical sulfonamides. Systemic toxic reactions such as agranulocytosis, acute
hemolytic anemia, purpura hemorrhagica, drug fever, jaundice and contact dermatitis indicate hypersensitivity to sulfonamides. Particular caution should
be employed if areas of denuded or abraded skin are involved.
FOR EXTERNAL USE ONLY. Keep away from eyes. Keep out of reach of children. Keep container tightly closed.

PRECAUTIONS: General - If irritaition develops, use of the product should be discontinued and appropriate therapy instituted. Patients should be
carefully observed for possible local irritation or sensitization during long-term therapy. The object of this therapy is to achieve desqamation withour
irritation, but sodium sulfacetamide and sulfur can cause reddening and scaling of the epidermis. These side effects are not unusual in the treatment of
acne vulfaris, but patients should be cautioned about the possibility.
Information for patients - Avoid contact with eyes, eyelids, lips and mucous membranes. If accidental contact occurs, rinse with water. If excessive
irritation develops, discontinue use and consult your physician.

PREGNANCY: Pregnancy Category C. Animal reproduction studies have not been conducted with Sodium Sulfacetamide 10% - Sulfur 4% Cleansing
Pads. It is not known whether Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads can cause fetal harm when administered to a pregnant woman or
can affect reproduction capacity. Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads should be given to a pregnant woman only if clearly needed.

NURSING MOTHERS: It is not known whether sodium sulfacetamide is excreted in the human milk following topical use of Sodium Sulfacetamide 10% -
Sulfur 4% Cleansing Pads. However, small amounts of orally administered sulfonamides have been reported to be eliminated in human milk. In view of
this and because many drugs are excreted in human milk, caution should be exercised when Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads are
administered to a nursing woman.

PEDIATRIC USE: Safety and effectiveness in children under the age of 12 have not been established.

ADVERSE REACTIONS: Although rare, sodium sulfacetamide may cause local irritation.

DOSAGE AND ADMINISTRATION: Wash affected area(s) with cleansing pad once or twice dialy, or as directed by your physician. Wet area(s) with
water. Wet pad with a little water and work into a full lather. Cleanse area(s) with pad for 10-20 seconds, avoiding eyes. Rinse thoroughly and pat dry.
Discard pad. Do not flush.

HOW SUPPLIED: Sodium Sulfacetamide 10% - Sulfur 4% Cleansing Pads are available in boxes of 60 cloths (3.7 g), (NDC 42192-113-60).
Store at controlled room temperature, 15° - 25° (59° - 77°F).
All prescription substitutions using this product shall be made subject to state and federal statutes as applicable. Please note: this is not an Orange Book
product and has not been subjected to FDA therapeutic equivalency or other equivalency testing. Each person recommending a prescription substitution
using this product shall make such recommendations based on each such person’s professional opinion and knowledge, upon evaluating the active
ingredients, incipients, inactive ingredients and chemical formulation information provided herein.

MANUFACTURED FOR: Acella Pharmaceuticals, LLC
9005 Westside Parkway
Alpharetta, GA 30009
1-800-541-4802

Sodum Sulfacetamide 10%-

Sulfur 4% Cleansing Pads


In a vehicle containing Green Tea and Aloe
Rx Only
60 cleansing pads
Net wegith 3.7g each
Acella pharmaceuticals
Directions: Wash affected areas with Sodium Sulfacetamide 10% - Sulfur 4% once or twice daily or as direted by your physician.
1. Wet affected areas with water
2. Wet Sodium Sulfacetamide 10% - Sulfur 4% cleansing pad with water and work into a full lather.
3. Cleanse face with Sodium Sulfacetamide 10% - Sulfur 4% for 10 -20 seconds, avoiding eyes
4. Rinse thoroughly and pat dry
5. Discard pad. Do not flush.
Warnings for external use only. Keep out of reach of children. Avoid contact with eyes.
Indications: for the typical control of acne vulgaris and seborrheic dermatitis. See package insert for full prescribing information.
Contraindications: Sodium Sulfacetamide 10% - Sulfur 4% cleansing pads are contraindicated for use in patients having known hypersensitivity to sulfonamides, sulfur or anyother component of the preparation. Sodium Sulfacetamide 10% - Sulfur 4% cleansing pads are not to be used by patients with kidney disease.
 
Contents: Sodium Sulfacetamide 10% - Sulfur 4%. Other Ingredients: purified water, sodium cocoyl isethionate, disodium oleamido MEA sulfosuccinate, green tea extract, cetyl alcohol, stearyl alcohol, glycerol stearate and PEG 100 stearate methyl paraben, propyl paraben, butylated hydroxytoluene, aloe vera gel, sodium thiosufate, disodium EDTA, magnesium aluminum siliate, xanthan gum, sodium methyl cocoyl l-taurate, white petrolatum
Acella Pharmaceuticals
Store at 15 degrees to 25 degrees C or 59-77 degrees F)
All prescription substitutions and/or recommendations using this product shall be made subject to state and federal statutes as applicable. NOTE. This is not an Orange Book product. No representation is made as to generic status or bioequivalency. Please see package insert for more information.
Manufactured For:
Acella Pharmaceuticals, LLC
9005 Westside Parkway
Alpharetta, GA 30009
1-800-541-4802


SODIUM SULFACETAMIDE - SULFUR CLEANSING PADS 
sodium sulfacetamide, sulfur  swab Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 42192-113 Route of Administration TOPICAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SULFACETAMIDE SODIUM (SULFACETAMIDE) SULFACETAMIDE SODIUM 10 g  in 100 g SULFUR (SULFUR) SULFUR 4 g  in 100 g Inactive Ingredients Ingredient Name Strength WATER   ALOE VERA LEAF   SODIUM THIOSULFATE   EDETATE DISODIUM   MAGNESIUM ALUMINUM SILICATE   XANTHAN GUM   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 42192-113-60 60 POUCH In 1 BOX contains a POUCH 1 3.7 g In 1 POUCH This package is contained within the BOX (42192-113-60)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 09/16/2010
Labeler - Acella Pharmaceuticals, LLC (825380939) Revised: 12/2010Acella Pharmaceuticals, LLC
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KOGENATE Bayer 250 IU Powder and solvent for solution for injection (Medimop)


1. Name Of The Medicinal Product

KOGENATE Bayer 250 IU powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

2.1 General description

Each vial contains nominally 250 IU human coagulation factor VIII (octocog alfa).

Human coagulation factor VIII is produced by recombinant DNA technology (rDNA) in baby hamster kidney cells containing the human factor VIII gene.

2.2 Qualitative and quantitative composition

One ml of KOGENATE Bayer 250 IU contains approximately 100 IU (250 IU / 2.5 ml) of human coagulation factor VIII (octocog alfa) after reconstitution.

The potency (IU) is determined using the one-stage clotting assay against the FDA Mega standard which was calibrated against WHO standard in International Units (IU).

The specific activity of KOGENATE Bayer is approximately 4000 IU/mg protein.

Solvent: water for injections.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Powder: dry white to slightly yellow powder or cake.

Solvent: water for injection, a clear, colourless solution.

The reconstituted medicinal product is a clear and colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

This preparation does not contain von Willebrand factor and is therefore not indicated in von Willebrand's disease.

4.2 Posology And Method Of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.

Posology

The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to the International Standard for factor VIII in plasma). One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma. The calculation of the required dose of factor VIII is based on the empirical finding that 1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% to 2.5% of normal activity. The required dose is determined using the following formulae:

I. Required IU = body weight (kg) ? desired factor VIII rise (% of normal) ? 0.5

 

II. Expected factor VIII rise (% of normal) =

2 ? administered IU

body weight (kg)

On demand treatment

The dose, frequency and duration of the substitution therapy must be individualised according to the patient's needs (weight, severity of disorder of the haemostatic function, the site and extent of the bleeding, the presence of inhibitors, and the factor VIII level desired).

The following table provides a guide for factor VIII minimum blood levels. In the case of the haemorrhagic events listed, the factor VIII activity should not fall below the given level (in % of normal) in the corresponding period:

Degree of haemorrhage/ Type of surgical procedure

Factor VIII level required (%) (IU/dl)

Frequency of doses (hours)/ Duration of therapy (days)

Haemorrhage

Early haemarthrosis, muscle bleed or oral bleed

 

20 - 40

 

Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.

More extensive haemarthrosis, muscle bleed or haematoma

30 - 60

Repeat infusion every 12 - 24 hours for 3 - 4 days or more until pain and disability are resolved.

Life threatening bleeds such as intracranial bleed, throat bleed, severe abdominal bleed

60 - 100

Repeat infusion every 8 to 24 hours until threat is resolved

Surgery

Minor

including tooth extraction

 

30 - 60

 

Every 24 hours, at least 1 day, until healing is achieved.

Major

80 - 100

(pre- and postoperative)

a) By bolus infusions

Repeat infusion every 8 - 24 hours until adequate wound healing occurs, then continue with therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60%

b) By continuous infusion

Raise factor VIII activity pre-surgery with an initial bolus infusion and immediately follow with continuous infusion (in IU/Kg/h) adjusting according to patient's daily clearance and desired factor VIII levels for at least 7 days.

The amount to be administered and the frequency of administration should always be adapted according to the clinical effectiveness in the individual case. Under certain circumstances larger amounts than those calculated may be required, especially in the case of the initial dose.

During the course of treatment, appropriate determination of factor VIII levels is advised in order to guide the dose to be administered and the frequency at which to repeat the infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

Continuous Infusion

It has been shown in a clinical study performed with adult haemophilia A patients who undergo a major surgery that KOGENATE Bayer can be used for continuous infusion in surgeries (pre-, during and postoperative). In this study heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions. For the calculation of the initial infusion rate, clearance can be obtained by performing a pre-surgery decay curve, or by starting from an average population value (3.0-3.5 ml/h/kg) and then adjust accordingly.

Infusion rate (in IU/kg/h) = Clearance (in ml/h/kg) ? desired factor VIII level (in IU/ml)

For continuous infusion, clinical and in vitro stability has been demonstrated using ambulatory pumps with a PVC reservoir. KOGENATE Bayer contains low level of polysorbate-80 as an excipient, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC) materials. This should be considered for a continuous infusion administration.

Prophylaxis

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of KOGENATE Bayer per kg body weight at intervals of 2 to 3 days.

In some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary.

Paediatric population

Data have been obtained from clinical studies in 61 children under 6 years of age and non-interventional studies in children of all ages.

Patients with inhibitors

Patients should be monitored for the development of factor VIII inhibitors. If the expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. If the inhibitor is present at levels less than 10 Bethesda Units (BU) per ml, administration of additional recombinant coagulation factor VIII may neutralise the inhibitor and permit continued clinically effective therapy with KOGENATE Bayer. However, in the presence of an inhibitor the doses required are variable and must be adjusted according to clinical response and monitoring of plasma factor VIII activity. In patients with inhibitor titres above 10 BU or with high anamnestic response, the use of (activated) prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) preparations has to be considered. These therapies should be directed by physicians with experience in the care of patients with haemophilia.

Method of administration

For intravenous use.

KOGENATE Bayer should be injected intravenously over several minutes. The rate of administration should be determined by the patient's comfort level (maximal rate of infusion: 2 ml/min).

Continuous infusion

KOGENATE Bayer can be infused by continuous infusion. The infusion rate should be calculated based on the clearance and the desired FVIII level.

Example: for a 75 kg patient with a clearance of 3 ml/h/kg, the initial infusion rate would be 3 IU/h/kg to achieve a FVIII level of 100%. For calculation of ml/hour, multiply infusion rate in IU/h/kg by kg bw/concentration of solution (IU/ml).

Example for calculation of infusion rate for continuous infusion after initial bolus injection

 

Desired plasma FVIII level

Infusion rate

IU/h/kg

Infusion rate for 75 kg patient

ml/h

   

Clearance: 3 ml/h/kg

   

Concentrations of rFVIII solution

         

100 IU/ml

200 IU/ml

400 IU/ml

 

100 % (1 IU/ml)

3.0

2.25

1.125

0.56

 

60 % (0.6 IU/ml)

1.8

1.35

0.68

0.34

 

40 % (0.4 IU/ml)

1.2

0.9

0.45

0.225

Higher infusion rates may be required in conditions with accelerated clearance during major bleedings or extensive tissue damage during surgical interventions.

After the initial 24 hours of continuous infusion, the clearance should be recalculated every day using the steady state equation with the measured FVIII level and the rate of infusion using the following equation:

clearance = infusion rate/actual FVIII level.

During continuous infusion, infusion bags should be changed every 24 hours.

For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the package leaflet.

4.3 Contraindications

- Known hypersensitivity to the active substance or to any of the excipients.

- Known allergic reactions to mouse or hamster protein.

4.4 Special Warnings And Precautions For Use

Hypersensitivity reactions

As with any intravenous protein product, allergic type hypersensitivity reactions are possible.

Patients should be made aware that the potential occurrence of chest tightness, dizziness, mild hypotension and nausea during infusion can constitute an early warning for hypersensitivity and anaphylactic reactions. Symptomatic treatment and therapy for hypersensitivity should be instituted as appropriate. If allergic or anaphylactic reactions occur, the injection/infusion should be stopped immediately and patient should contact their physician. In case of shock, the current medical standards for shock treatment should be observed.

Antibodies (inhibitors)

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Modified Bethesda Units (BU) per ml of plasma. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII and to genetic factors among others, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.

Cases of recurrence of inhibitors (low titre) have been observed after switching from one recombinant factor VIII product to another in previously treated patients with more than 100 exposure days who have a history of inhibitor development.

Patients treated with recombinant coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. (See also section 4.8)

Continuous infusion

In a clinical study about the use of continuous infusion in surgeries, heparin was used to prevent thrombophlebitis at the infusion site as with any other long term intravenous infusions.

Registration

In the interest of the patients, it is recommended that, whenever possible, every time that KOGENATE Bayer is administered to them, the name and the batch number of the product is registered.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially “sodium free”.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions of KOGENATE Bayer with other medicinal products are known.

4.6 Pregnancy And Lactation

Animal reproduction studies have not been conducted with KOGENATE Bayer.

Based on the rare occurrence of haemophilia A in women, experience regarding the use of KOGENATE Bayer during pregnancy and breast-feeding is not available. Therefore, KOGENATE Bayer should be used during pregnancy and breast-feeding only if clearly indicated.

There are no fertility data available.

4.7 Effects On Ability To Drive And Use Machines

KOGENATE Bayer has no influence on the ability to drive or to use machines.

4.8 Undesirable Effects

The most commonly reported adverse drug reaction occurring is the formation of neutralising antibodies (prevalent in previously untreated or minimally treated patients).

The frequencies of adverse reactions reported with KOGENATE Bayer are summarized in the table below. Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (

MedDRA Standard

System Organ Class

Common

Uncommon

Rare

Blood and the Lymphatic System Disorders

Inhibitor Formation to FVIII

(Reported in PUP and minimally treated patients in clinical trials)*

Inhibitor Formation to FVIII

(Reported in PTP in clinical trials and Post Marketing Studies)*

 

General Disorders and Administration Site Conditions

Infusion site reaction

 

Infusion related febrile reaction (pyrexia)

Immune System Disorders

Skin associated hypersensitivity reactions, (pruritus, urticaria and rash)

 

Systemic Hypersensitivity reactions (including one anaphylactic reaction, nausea, blood pressure abnormal and, dizziness)

* see section below

Description of selected adverse reactions

The formation of neutralising antibodies to factor VIII (inhibitors) is a known complication in the management of individuals with haemophilia A. In studies with recombinant factor VIII preparations, development of inhibitors is predominantly observed in previously untreated haemophiliacs. Patients should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

In clinical studies, KOGENATE Bayer has been used in the treatment of bleeding episodes in 37 previously untreated patients (PUPs) and 23 minimally treated pediatric patients (MTPs, defined as having equal to or less than 4 exposure days). Five out of 37 (14%) PUP and 4 out of 23 (17%) MTP patients treated with KOGENATE Bayer developed inhibitors: Overall, 9 out of 60 (15%) developed inhibitors, 6 out of 60 (10%) with a titre above 10 BU and 3 out of 60 (5%) with a titre below 10 BU. The median number of exposure days at the time of inhibitor detection in these patients was 9 days (range 3 - 18 days).

The median number of exposure days in the clinical studies was 114 (range: 4-478). Four of the five patients, who had not achieved 20 exposure days at the end of the study, ultimately achieved more than 20 exposure days in post-study follow-up and one of them developed a low titre inhibitor. The fifth patient was lost to follow-up.

In clinical studies with 73 previously treated patients (PTP, defined as having more than 100 exposure days), followed over four years, no de-novo inhibitors were observed.

In extensive post-registration studies with KOGENATE Bayer, involving more than 1000 patients the following was observed: Less than 0.2% PTP developed de-novo inhibitors. In a subset defined as having less than 20 exposure days at study entry, less than 11% developed de-novo inhibitors.

During studies, no patient developed clinically relevant antibody titres against the trace amounts of mouse protein and hamster protein present in the preparation. However, the possibility of allergic reactions to constituents, e.g. trace amounts of mouse and hamster protein in the preparation exists in certain predisposed patients (see sections 4.3 and 4.4).

4.9 Overdose

No case of overdose with recombinant coagulation factor VIII has been reported.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.

The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and vWF) with different physiological functions. When infused into a haemophilic patient, factor VIII binds to vWF in the patient's circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Determination of activated partial thromboplastin time (aPTT) is a conventional in vitro assay method for biological activity of factor VIII. The aPTT is prolonged in all haemophiliacs. The degree and duration of aPTT normalisation observed after administration of KOGENATE Bayer is similar to that achieved with plasma-derived factor VIII.

5.2 Pharmacokinetic Properties

The analysis of all recorded in vivo recoveries in previously treated patients demonstrated a mean rise of 2 % per IU/kg body weight for KOGENATE Bayer. This result is similar to the reported values for factor VIII derived from human plasma.

After administration of KOGENATE Bayer, peak factor VIII activity decreased by a two-phase exponential decay with a mean terminal half-life of about 15 hours. This is similar to that of plasma-derived factor VIII which has a mean terminal half-life of approx. 13 hours. Additional pharmacokinetic parameters for KOGENATE Bayer for bolus injection are: mean residence time [MRT (0-48)] of about 22 hours and clearance of about 160 ml/h. Mean baseline clearance for 14 adult patients undergoing major surgeries with continuous infusion are 188 ml/h corresponding to 3.0 ml/h/kg (range 1.6-4.6 ml/h/kg).

5.3 Preclinical Safety Data

Even doses several fold higher than the recommended clinical dose (related to body weight) failed to demonstrate any acute or subacute toxic effects for KOGENATE Bayer in laboratory animals (mouse, rat, rabbit, and dog).

Specific studies with repeated administration such as reproduction toxicity, chronic toxicity, and carcinogenicity were not performed with octocog alfa due to the immune response to heterologous proteins in all non-human mammalian species.

No studies were performed on the mutagenic potential of KOGENATE Bayer, since no mutagenic potential could be detected in vitro or in vivo for the predecessor product of KOGENATE Bayer.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Powder

Glycine

Sodium chloride

Calcium chloride

Histidine

Polysorbate 80

Sucrose

Solvent

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6..

Only the provided components (powder vial, pre-filled syringe containing solvent, vial adapter and venipuncture set) should be used for reconstitution and injection because treatment failure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.

6.3 Shelf Life

30 months.

After reconstitution, the product should be used immediately.

However, during in vitro studies, the chemical and physical in-use stability has been demonstrated for 24 hours at 30°C in PVC bags for continuous infusion.

Do not refrigerate after reconstitution.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial and the pre-filled syringe in the outer carton in order to protect from light.

The product when kept in its outer carton may be stored at ambient room temperature (up to 25°C) for a limited period of 12 months. In this case, the product expires at the end of this 12-month period; the new expiry date must be noted on the outer carton.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Each package of KOGENATE Bayer contains:

• one vial with powder (10 ml clear glass type 1 vial with latex-free grey halogenobutyl rubber blend stopper and aluminium seal)

• one pre-filled syringe with 2.5 ml solvent (clear glass cylinder type 1 with latex-free grey bromobutyl rubber blend stopper)

• syringe plunger rod

• vial adapter

• one venipuncture set

• two sterile alcohol swabs for single use

• two dry swabs

• two plasters

6.6 Special Precautions For Disposal And Other Handling

Detailed instructions for preparation and administration are contained in the package leaflet provided with KOGENATE Bayer.

KOGENATE Bayer powder should only be reconstituted with the supplied solvent (2.5 ml water for injections) in the prefilled syringe and the vial adapter. Reconstitution should be performed in accordance with good practices rules, particularly with attention to asepsis. Gently rotate the vial until all powder is dissolved. After reconstitution the solution is clear. Do not use KOGENATE Bayer if you notice visible particulate matter or turbidity.

After reconstitution, the solution is drawn back into the syringe.

Use the provided venipuncture set for intravenous injection.

For continuous infusion, the product must be prepared under aseptic conditions.

For single use only. Any unused solution must be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Bayer Pharma AG

13342 Berlin

Germany

8. Marketing Authorisation Number(S)

EU/1/00/143/007

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 04 August 2000

Date of latest renewal: 06 August 2010

10. Date Of Revision Of The Text

1 July 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.


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Zenalb20, a Human Albumin 20% Solution


1. Name Of The Medicinal Product

Zenalb®20, a 200 g/L of human albumin solution for infusion (20% Solution).

2. Qualitative And Quantitative Composition

Zenalb®20 contains 200 g/L and is a solution containing 200 g/L (20%) of total protein of which at least 95% is human albumin.

A vial of 100 mL contains 20 g of human albumin

Zenalb®20 has a mildly hyperoncotic effect.

For excipients see section 6.1.

3. Pharmaceutical Form

Solution for infusion.

A clear, slightly viscous liquid, it is almost colourless, yellow, amber or green.

4. Clinical Particulars 4.1 Therapeutic Indications

Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated, and use of a colloid is appropriate.

The choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient, based on official recommendations.

4.2 Posology And Method Of Administration

The concentration of the albumin preparation, dosage and the infusion-rate should be adjusted to the patient's individual requirements.

The choice of albumin rather than artificial colloid will depend on the clinical situation of the patient, based on official recommendations.

Posology

The dose required depends on the size of the patient, the severity of trauma or illness and on continuing fluid and protein losses. Measures of adequacy of circulating volume, and not plasma albumin levels, should be used to determine the dose required.

If human albumin is to be administered, haemodynamic performance should be monitored regularly; this may include:

- arterial blood pressure and pulse rate

- central venous pressure

- pulmonary artery wedge pressure

- urine output

- electrolyte

- haematocrit/haemoglobin

Method of administration

Human albumin can be directly administered by the intravenous route, or it can also be diluted in an isotonic solution (e.g. 5% glucose or 0.9% sodium chloride).

The infusion rate should be adjusted according to the individual circumstances and the indication.

4.3 Contraindications

Hypersensitivity to albumin preparations or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Suspicion of allergic or anaphylactic-type reactions requires immediate discontinuation of the injection. In the case of shock, the standard medical standards treatment for shock should be implemented.

Albumin should be used with caution in conditions where hypervolaemia and its consequences or haemodilution could represent a special risk for the patient. Examples of such conditions are:

- Decompensated cardiac insufficiency

- Hypertension

- Oesophageal varices

- Pulmonary oedema

- Haemorrhagic diathesis

- Severe anaemia

- Renal and post-renal anuria

The colloid-osmotic effect of human albumin 200 g/L is approximately four times that of blood plasma. Therefore, when concentrated albumin is administered, care must be taken to ensure adequate hydration of the patient. Patients should be monitored carefully to guard against circulatory overload and hyperhydration.

200 g/L human albumin solutions are relatively low in electrolytes compared to 40-50 g/L human albumin solutions. When albumin is given, the electrolyte status of the patient should be monitored (see section 4.2) and appropriate steps taken to restore or maintain the electrolyte balance.

Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients.

If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes).

Hypervolaemia may occur if the dosage and rate of infusion are not adjusted to the patient's circulatory situation. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised venous pressure and pulmonary oedema, the infusion is to be stopped immediately.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of plasma-derived human albumin solutions.

It is strongly recommended that every time that Zenalb®20 is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific interactions of human albumin with other medicinal products are known.

4.6 Pregnancy And Lactation

The safety of Zenalb®20 for use in human pregnancy has not been established in controlled clinical trials. However, clinical experience with albumin suggests that no harmful effects on the course of pregnancy, or on the foetus or the neonate are to be expected.

No animal reproduction studies have been conducted with Zenalb®20.

Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or foetus, the course of gestation and peri and postnatal development. However, human albumin is a normal constituent of human blood.

4.7 Effects On Ability To Drive And Use Machines

No effects on the ability to drive and use machines have been observed.

4.8 Undesirable Effects

Mild reactions such as flush, urticaria, fever and nausea occur rarely. These reactions normally disappear rapidly when the infusion rate is slowed down or the infusion is stopped. Very rarely, severe reactions such as shock may occur. In these cases, the infusion should be stopped and appropriate treatment should be initiated.

Post-marketing experience:

Additional side effects reported spontaneously include rigors, hypertension, hypotension, feeling cold, tachycardia, tremor, bronchospasm, dyspnoea, chest tightness, stridor and dizziness.

For safety with respect to transmissible agents, see 4.4.

4.9 Overdose

Hypervolaemia may occur if the dosage and rate of infusion are too high. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised central venous pressure and pulmonary oedema, the infusion should be stopped immediately and the patient's haemodynamic parameters carefully monitored.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: plasma substitutes and plasma protein fractions, ATC code: B05AA01

Human albumin accounts quantitatively for more than half of the total protein in the plasma and represents about 10% of the protein synthesis activity of the liver.

Physicochemical data: Zenalb®20, human albumin 200 g/L has a corresponding hyperoncotic effect.

The most important physiological functions result from its contribution to oncotic pressure of the blood and transport function. Albumin stabilises circulating blood volume and is a carrier for hormones, enzymes, medicinal products and toxins.

5.2 Pharmacokinetic Properties

Under normal conditions the total exchangeable albumin pool is 4-5 g/kg bodyweight, of which 40-45% is present intravascularly and 55-60% in the extravascular space. Increased capillary permeability will alter albumin kinetics and abnormal distribution may occur in conditions such as severe burns or septic shock.

Under normal conditions the half-life of albumin is about 19 days. The balance between synthesis and breakdown is normally achieved by feedback regulation. Elimination is predominantly intracellular and due to lysosome proteases.

In healthy people, less than 10% of infused albumin leaves the intravascular compartment during the first 2 hours following infusion. There is considerable individual variation in the effect on plasma volume. In some patients the plasma volume can remain increased for some hours. However, in critically ill patients, albumin can leak out of the vascular space in substantial amounts at an unpredictable rate.

5.3 Preclinical Safety Data

Human albumin is a normal constituent of plasma and acts like physiological albumin.

In animals, single dose toxicity testing is of little relevance and does not permit the estimation of toxic or lethal doses or of a dose-effect relationship. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models.

To date, human albumin has not been reported to be associated with embryo-foetal toxicity, oncogenic or mutagenic potential.

No signs of acute toxicity have been described in animal models.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Sodium 50-120 mmol/L

Potassium

Chloride

Citrate

Sodium n-octanoate

Zenalb® 20 contains not more than 200 µg/L of aluminium

6.2 Incompatibilities

Human albumin should not be mixed with other medicinal products (except those mentioned in 6.6), whole blood and packed red cells.

6.3 Shelf Life

50 mL and 100 mL size

Unopened

36 months

Opened

3 hours

6.4 Special Precautions For Storage

Zenalb®20 should be stored between 2°C and 25°C. DO NOT FREEZE.

The expiry date of the product is stated on the label.

Store in the original container. Keep container in the outer carton in order to protect from light.

6.5 Nature And Contents Of Container

The solution is contained in glass bottles stoppered with a rubber bung. The bung is over-sealed with a tamper evident cap.

6.6 Special Precautions For Disposal And Other Handling

The solution can be directly administered by the intravenous route or it can be diluted in an isotonic solution (e.g. 5% glucose or 0.9% sodium chloride). Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients.

If large volumes are administered, the product should be warmed to room temperature before use.

Do not use solutions which are cloudy or have deposits. This may indicate that the protein is unstable or that the solution has become contaminated.

Once the infusion container has been opened, the contents should be used immediately. Any unused product should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

This product is manufactured and marketed by

Bio Products Laboratory

Dagger Lane

Elstree

Hertfordshire

WD6 3BX

United Kingdom.

8. Marketing Authorisation Number(S)

PL 08801/0007

9. Date Of First Authorisation/Renewal Of The Authorisation

27th April 1993 / June 2000

10. Date Of Revision Of The Text

September 2008

Version Code: ABS8

POM

 

 


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Ikorel Tablets


1. Name Of The Medicinal Product

Ikorel 10mg and 20mg Tablet

2. Qualitative And Quantitative Composition

Nicorandil 10mg or 20mg

3. Pharmaceutical Form

Tablet

Off-white, round, with faceted edges, scored on one side and bearing the inscription IK10 (10mg) or IK20 (20mg).

4. Clinical Particulars 4.1 Therapeutic Indications

Ikorel tablets are indicated for the following:

• The prevention and long term treatment of chronic stable angina pectoris

• A reduction in the risk of acute coronary syndromes in patients with chronic stable angina and at least one of the following risk factors:

Previous MI

Previous CABG

CHD on angiography or a positive exercise test together with one of the following: LVH on ECG, left ventricular dysfunction, Age

4.2 Posology And Method Of Administration

Route of administration: oral.

Adults: The recommended starting dose is 10mg nicorandil twice daily, although 5mg twice daily may be employed in patients particularly susceptible to headache. Subsequently the dosage should be titrated upward depending on the clinical response. The usual therapeutic dosage is in the range 10 to 20mg nicorandil twice daily, although up to 30mg twice daily may be employed if necessary.

Elderly:

For elderly patients use of the lowest effective dose is recommended.

Children:A paediatric dosage has not been established and use of nicorandil is not recommended.

4.3 Contraindications

Ikorel is contraindicated in patients with hypersensitivity to nicorandil or any of the excipients.

Nicorandil must not be used in the case of cardiogenic shock, hypotension or left ventricular failure with low filling pressure.

Concurrent use of nicorandil and phosphodiesterase 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) is contraindicated since it can lead to a serious drop in blood pressure.

4.4 Special Warnings And Precautions For Use

Gastrointestinal ulcerations, skin and mucosal ulceration have been reported with nicorandil. These are refractory to treatment and most only respond to withdrawal of nicorandil treatment. If ulcerations develop, it is recommended to discontinue the nicorandil treatment.

Gastrointestinal perforations in context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.

Nicorandil must be used with caution in patients who may have blood volume depletion or in those who present, low systolic blood pressure (e.g below 100 mm Hg), acute pulmonary oedema or acute myocardial infarction with acute left ventricular failure and low filling pressures.

Caution is advised if nicorandil is used in combination with other medicinal products with blood pressure lowering effect (see section 4.5).

The tablets are sensitive to moisture; hence the patients should be advised to keep the tablets in their blister until intake. Besides the nicorandil tablets, each blister contains active substance-free silica gel tablets as desiccant in a separate blister segment which is marked accordingly. The patients should be advised not to take these tablets. Although any accidental intake of this desiccant is usually harmless, it may alter the scheduled intake of the active tablets.

Paediatric patients

Ikorel is not recommended in paediatric patients since its safety and efficacy have not been established in this patient group.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Gastrointestinal perforations in the context of concomitant use of nicorandil and corticosteroids have been reported. Caution is advised when concomitant use is considered.

Concurrent use of nicorandil and phosphodiesterase 5 inhibitors, e.g. sildenafil, tadalfil, vardenafil, is contraindicated, since it can lead to a serious drop in blood pressure.

Therapeutic doses of nicorandil may lower the blood pressure of hypotensive patients. If nicorandil is used concomitantly with antihypertensive agents or other medicinal products with blood-pressure-lowering effect (e.g vasodilators, tricyclic antidepressants, alcohol) the blood-pressure-lowering effect may be increased.

4.6 Pregnancy And Lactation

Pregnancy: Although animal studies have not shown any teratogenic effect of nicorandil, the medicinal product has not been studied in human pregnancy; therefore, Ikorel must only be used in pregnant women if the anticipated benefit outweighs any potential risks.

Lactation: Animal studies have shown that nicorandil is excreted in small amounts into the breast milk. It is not known whether nicorandil is excreted in human milk, therefore Ikorel is not recommended during breastfeeding.

4.7 Effects On Ability To Drive And Use Machines

Blood pressure-lowering effects of nicorandil can reduce the ability to drive or to use machines. This effect can be increased in conjunction with alcohol or other products with blood-pressure-lowering effect (e.g. vasodilators, tricyclic antidepressants). (see section 4.5).

Patients should be warned not to drive or operate machinery until it is established that their performance is unimpaired by nicorandil.

4.8 Undesirable Effects

The following definitions apply to the frequency terminology used hereafter:

Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000).

SOC

FREQUENCY

ADR

     

Nervous system disorders

Very common

Headache,particularly during the first few days of treatment.

 

Common

Dizziness

Cardiac disorders

Common

Increase in heart rate, following the administration of high doses

Vascular disorders

Common

Cutaneous vasodilation with flushing

 

Uncommon

Decrease in blood pressure.

Gastrointestinal disorders

Common

Nausea and vomiting

 

Rare

Gastrointestinal ulcerations such as aphtosis, mouth ulcers, tongue ulcers, intestinal and anal ulcers. These ulcers, if advanced, may develop into perforation, fistula, or abscess formation. (see section 4.4).

     

Hepato-biliary disorders

Very rare

Liver disorders such as hepatitis, cholestasis, or jaundice.

Skin and subcutaneous tissue disorders

Rare

Different types of rash, pruritis.

 

Very rare

Angio-oedema. Skin and muscosal ulcerations (mainly peri-anal ulcerations, genital ulcerations and parastomal ulcerations (see section 4.4).

Musculoskeletal & connective tissue disorders

Rare

Myalgia

General disorders and administration site conditions

Common

Feeling of weakness

Additional Information

In addition, the following events have been reported at a different frequency in the IONA (Impact of Nicorandil in Angina) study which was conducted in subjects at high risk of cardiovascular events only.

Skin and subcutaneous tissue disorders

Uncommon – angio-oedema

Gastrointestinal disorders

Common – rectal bleeding.

Uncommon – mouth ulcers

Very rare – abdominal pain

Musculoskeletal & connective tissue disorders

Uncommon - myalgia

4.9 Overdose

Symptoms

In case of acute overdose, the likely symptomatology may be peripheral vasodilation with a fall in blood pressure and reflex tachycardia.

Management

Monitoring cardiac function and general supportive measures are recommended. If not successful, increase in circulating plasma volume by substitution of fluid is recommended. In life-threatening situations, administration of vasopressors must be considered. There is no experience of massive overdosage in humans, although the LD50 in dogs is in the range 62.5 to 125 mg/kg and in rodents it is in the order of 1200 mg/kg.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other vasodilators used in cardiac disease, ATC code: C01DX16

Nicorandil provides a dual mode of action leading to relaxation of vascular smooth muscle. A potassium channel opening action provides arterial vasodilation, thus reducing afterload, while the nitrate component promotes venous relaxation and a reduction in preload. Nicorandil has a direct effect on coronary arteries without leading to a steal phenomenon. The overall action improves blood flow to post-stenotic regions and the oxygen balance in the myocardium.

A reduction of coronary heart disease complications has been shown in patients suffering from angina pectoris who were treated with nicorandil in the IONA study.

The study was a randomised, double blind, placebo controlled, cardiovascular endpoint study carried out in 5126 patients to determine if Nicorandil could reduce the frequency of coronary events in men and women with chronic stable angina and standard anti anginal treatment at high risk of cardiovascular events defined by either: 1) previous myocardial infarction, or 2) coronary artery bypass grafting , or 3) coronary artery disease confirmed by angiography, or a positive exercise test in the previous two years, together with one of the following: left ventricular hypertrophy on the ECG, left ventricular ejection fraction

The primary endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction, or unplanned hospital admission for cardiac chest pain, occurred in 13.1% of patients treated with nicorandil compared with 15.5% of patients receiving placebo (hazard ratio 0.83, p=0.014). The rate of acute coronary syndrome (CHD death, non fatal MI or unstable angina) was 6.1% in patients treated with nicorandil compared with 7.6% in patients receiving placebo (hazard ratio 0.79, p=0.028). All cardiovascular events were significantly less in the nicorandil than placebo group 14.7% vs 17.0% (hazard ratio 0.86 p=0.027). The validity of these finding was confirmed by re-analysing the primary endpoint using all cause rather than cardiovascular mortality (nicorandil 14.9% compared with placebo 17.3%, hazard ratio 0.85, p=0.021). The study was not expressly powered to, nor did it detect any statistically significant reduction in any individual component endpoints.

5.2 Pharmacokinetic Properties

Nicorandil is well absorbed with no significant first-pass metabolism. Maximum plasma concentrations are achieved in 30 to 60 minutes and are directly related to the dosage. Metabolism is mainly by denitration of the molecule into the nicotinamide pathway with less than 20% of an administered dose being excreted in the urine. The main phase of elimination has a half-life of about 1 hour. Nicorandil is only slightly bound to plasma proteins.

No clinically relevant modifications in the pharmacokinetic profile have been seen in the elderly or in patients with liver disease or chronic renal failure.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that included in other sections of the SPC.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Maize starch, croscarmellose sodium, stearic acid and mannitol.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

18 months.

Each blister strip should be used within 30 days of opening.

6.4 Special Precautions For Storage

Store in a dry place below 25°C.

6.5 Nature And Contents Of Container

Ikorel tablets 10mg and 20mg are presented in hard tempered aluminium foil/ (Polyamide/aluminium/PVC) blister strips of 10 tablets, in which each tablet is linked to a silica gel capsule dessicant.

The blister strips are packaged in cartons of 60 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey, GU1 4YS, UK

8. Marketing Authorisation Number(S)

Ikorel tablets 10mg: PL 04425/0327

Ikorel tablets 20mg: PL 04425/0328

9. Date Of First Authorisation/Renewal Of The Authorisation

24 February 2009

10. Date Of Revision Of The Text

22 February 2011

LEGAL STATUS

POM


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Nexiclon XR Suspension


clonidine
Dosage Form: oral suspension, extended release
FULL PRESCRIBING INFORMATION INDICATIONS & USAGE

NEXICLON XR is indicated in the treatment of hypertension. NEXICLON XR may be employed alone or concomitantly with other antihypertensive agents.

DOSAGE & ADMINISTRATION Maintenance dose: Further increments of 0.09 mg (1 mL) once daily may be made at weekly intervals if necessary until the desired response is achieved. The therapeutic doses most commonly employed have ranged from 0.17 mg to 0.52 mg once daily (2.2)

The dose of NEXICLON XR must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration in adults.

Initial Dose

Dosing with NEXICLON XR should be initiated 0.17 mg (2 mL) once daily. Elderly patients may benefit from a lower initial dose [see Use is Specific Populations (8.4)]. Initial dose is recommended to be administered at bedtime.

Maintenance Dose

Further increments of 0.09 mg (1 mL) once daily may be made at weekly intervals if necessary until the desired response is achieved. The therapeutic doses most commonly employed have ranged from 0.17 mg (2 mL to 0.52 mg (6 mL) once daily.

NEXICLON XR was studied at doses of 0.17 to 0.52 mg to 0.52 mg (2 to 6 mL) once daily. Doses higher than 0.52 mg (6 mL) per day were not evaluated and are not recommended.

Patients Currently Using Clonidine Hydrochloride Immediate Release Tablets

The recommended does of NEXICLON XR for patients who are currently taking clonidine hydrochloride immediate-release tablets is provided in the table below.

NEXICLON XR (Clonidine Extended Release)Oral Suspension Equivalent dose of Clonidine HCl Immediate-Release Tablets Initial Dose 0.17 mg (2 mL) once daily 0.1 mg twice daily Maintenance Dose Titration Increments 0.09 mg (1 mL) once daily 0.05 mg twice daily Common Doses Used for Blood Pressure Effect 0.17 mg (2 mL) once daily 0.1 mg twice daily 0.34 mg (4 mL) once daily 0.2 mg twice daily   0.52 mg (6 mL) once daily 0.3 mg twice daily   Renal Impairment

Adjust dosage according to the degree of impairment. In patients with end stage kidney disease on maintenance dialysis, start at 0.09 mg (1 mL) per day and up-titrate slowly to minimize dose related adverse events.

Monitor patients carefully, especially for bradycardia, sedation and hypotension. Only a minimal amount of clonidine is removed during routine hemodialysis.

In patients with moderate to severe kidney impairment not undergoing dialysis, initiate clonidine at the same dose as for patients without renal impairment. Up-titrate slowly and monitor for dose-related adverse events.

DOSAGE FORMS & STRENGTHS CONTRAINDICATIONS

NEXICLON XR should not be used in patients with known hypersensitivity to clonidine [see Warnings and Precautions (5.2)]

WARNINGS AND PRECAUTIONS Withdrawal

Instruct patients not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has resulted in symptoms such as nervousness, agitation, headache, and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with NEXICLON XR, reduce the dose gradually over 2 to 4 days to avoid withdrawal symptoms.

An excessive rise in blood pressure following discontinuation of NEXICLON XR can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of NEXICLON XR.

Because children commonly have gastrointestinal illnesses that lead to vomiting, they may be particularly susceptible to hypertensive episodes resulting from abrupt inability to take medication.

General Precautions

In patients who have developed localized contact sensitization to a clonidine transdermal system, substitution of oral clonidine therapy may be associated with the development of a generalized skin rash.

In patients who develop an allergic reaction to a clonidine transdermal system, substitution of oral clonidine may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Monitor carefully and uptitrate slowly in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure.

Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. The sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.

Perioperative Use

NEXICLON XR may be administered up to 28 hours prior to surgery and resumed the following day. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required.

ADVERSE REACTIONS

The following serious adverse reactions are discussed in detail elsewhere in the labeling:

Withdrawal [seeWarnings and Precautions (5.1)] Allergic reactions [see Warnings and Precautions (5.2)]   NEXICLON XR Clinical Trial Experience

There is very limited experience with NEXICLON XR in controlled trials.  Based on this limited experience, the adverse event profile appears similar with to the immediate-release clonidine formulation.

  Experience with Immediate-Release Clonidine

Most adverse reactions are mild and tend to diminish with continued therapy. The most frequent (which also appear to be dose-related) are dry mouth (approximately 40%); drowsiness (approximately 33%; dizziness (approximately 16%); constipation and sedation (approximately 10% each).

The following less frequent adverse reactions have also been reported in patients receiving immediate-release clonidine, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.

Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome.  Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol.

Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis.

Central Nervous System (CNS): Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares.

Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria.

Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting.

Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention.

Hematologic: Thrombocytopenia.

Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain.

Musculoskeletal: Leg cramps and muscle or joint pain.

Oro-otolaryngeal: Dryness of the nasal mucosa.

Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of eyes.

DRUG INTERACTIONS

No drug interaction studies have been conducted with NEXICLON XR. The following have been reported with other oral formulations of clonidine.

Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine hydrochloride is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose.

Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers, and beta-blockers. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil.

Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats [see Nonclinical Toxicology (13.2)].

Alcohol: Based on in vitro studies, high concentration of alcohol may increase the rate of release of NEXICLON XR.

USE IN SPECIFIC POPULATIONS   Pregnancy

Pregnancy Category C. Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of clonidine hydrochloride produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same time or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6 to 15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1 to 14 (lowest dose employed in the study was 500 mcg/kg).

No adequate, well-controlled studies have been conducted 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.

Nursing Mothers

Clonidine is secreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Elderly patients may benefit from a lower initial dose [see Dosage and Administration (2)].

Patients with Renal Impairment

The initial dosage should be based on the degree of impairment. Monitor patients carefully for hypotension and bradycardia, and titrate to higher doses cautiously. Only a minimal amount of clonidine is removed during routine hemodialysis.

OVERDOSAGE

Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children.

There is no specific antidote for clonidine overdosage. Clonidine overdosage may result in the rapid development of CNS depression; therefore, induction of vomiting with ipecac syrup is not recommended. Gastric lavage may be indicated following recent and/or large ingestions. Administration of activated charcoal and/or a cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine.

The largest overdose reported to date involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after 1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively.

DESCRIPTION

NEXICLON XR (clonidine) Extended-Release Oral Suspension is available for oral administration in one extended-release dose strength 0.09 mg/mL. The 0.09 mg/mL suspension is equivalent to 0.1 mg/mL of immediate-release clonidine hydrochloride.

Clonidine hydrochloride, a centrally active alpha-adrenergic agonist, is an imidazoline derivative and exists as a mesomeric compound. The chemical name is 2-(2.6-dichlorophenylamino)-2-imidazoline hydrochloride. The following is the structural formula:

[IC]

C9H9Cl2N3·HCl Mol. Wt. 266.56

Clonidine hydrochloride is an odorless, bitter, white crystalline substance soluble in water and alcohol.

The inactive ingredients are: citric acid anhydrous, flavor, glycerin, high fructose corn syrup, methylparaben, modified food starch, polyvinyl acetate, polysorbate 80, povidone, propylparaben, purified water, sodium polystyrene sulfonate, sucrose, triacetin, and xanthan gum.

CLINICAL PHARMACOLOGY Mechanism of Action

Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. The patient’s maximum blood pressure decrease occurred within 6 to 8 hours. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent.

  Pharmacodynamics

NEXICLON XR was studied in an open-label crossover, force titration, partially randomized trial in patients with mild and moderate essential hypertension who were on two or fewer antihypertensive medications.   The trial was designed to compare steady-state exposures between the NEXICLON XR and clonidine immediate-release tablets.  There were up- and down-titration phases.  There was no washout period between phases or treatments.

Studies with immediate-release clonidine hydrochloride have demonstrated a moderate reduction (15% to 20%) in cardiac output in the supine position with no change in the peripheral resistance. At a 45° tilt, there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise.

Tolerance to the antihypertensive effect may develop in some patients, necessitating a re-evaluation of therapy.

Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated.

Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use.

  Pharmacokinetics

Following single doses of NEXICLON XR Oral Suspension 0.17 mg, clonidine mean (S.D.) peak plasma concentrations of 0.49 (±0.09) ng/mL occurred at 7.8 (±1.7) hours. The plasma half-life of clonidine was 13.7 (±3.0) hours. There was no effect of food on the pharmacokinetic parameters.

[IC]

A = NEXICLON XR Oral Suspension (0.17 mg QD) Fasted

B = Clonidine IR Tablet (0.1 mg clonidine hydrochloride Q 12h) Fasted

C = NEXICLON XR Oral Suspension (0.17 mg QD) Fed

In the multi-dose study, mild to moderate hypertensive patients were randomized to ER and BID IR clonidine formulations. The following plot shows the sitting blood pressure values for each treatment group at Day 22.

[IC]

The half-life may increase up to 41 hours in patients with severe impairment of renal function. Following oral administration of clonidine about 40 to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility

Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 or 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Fertility of male or female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis).

Animal Toxicology and/or Pharmacology

In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid.

In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged.

In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

CLINICAL STUDIES

[see Clinical Pharmacology (12.3)]

HOW SUPPLIED/STORAGE AND HANDLING

NEXICLON XR (Clonidine Extended Release) Oral Suspension 0.09 mg/mL is supplied as light beige to tan viscous suspension containing 0.09 mg clonidine base per mL in bottles of 4 fl oz (118 mL). NDC 27808-029-01.

Store at 25?C (77?F); excursions permitted from 15? to 30?C (59? to 86?F). [See USP Controlled Room Temperature.]

Dispense in tight, light-resistant container.

Distributed By: NextWave Pharmaceuticals, Inc.

Cupertino, CA 95014

 

www.nextwavepharma.com

 

Manufactured By: Tris Pharma, Inc.

Monmouth Junction, NJ 08852

 

www.trispharma.com

 

LB8151

Rev 00

10/10

PATIENT COUNSELING INFORMATION Information for Patients

Caution patients against interruption of NEXICLON XR therapy without their healthcare provider’s advice.

Advise patients who engage in potentially hazardous activities, such as operating machinery or driving, of a possible sedative effect of clonidine. The sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.

Directions for using the enclosed adapter and syringe: Shake bottle well with vigorous back and forth motion for 5 to 10 seconds and then insert adapter into the neck of bottle. Insert syringe tip into the adapter and invert the bottle. Draw out amount of suspension as prescribed by doctor or physician. Dispense directly into mouth. PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NEXICLON XR® (Clonidine Extended Release) Oral Suspension

0.09 mg/mL


NEXICLON XR 
clonidine  for suspension, extended release Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 27808-029 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLONIDINE (CLONIDINE) CLONIDINE 0.09 mg  in 1 mL Inactive Ingredients Ingredient Name Strength SODIUM POLYSTYRENE SULFONATE   POVIDONE   VINYL ACETATE   TRIACETIN   WATER   ANHYDROUS CITRIC ACID   POLYSORBATE 80   HIGH FRUCTOSE CORN SYRUP   SUCROSE   STARCH, CORN   GLYCERIN   METHYLPARABEN   PROPYLPARABEN   XANTHAN GUM   Product Characteristics Color BROWN (light beige to tan) Score      Shape Size Flavor STRAWBERRY Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 27808-029-01 118 mL In 1 BOTTLE, PLASTIC None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022499 12/17/2010
Labeler - Tris Pharma, Inc. (947472119) Registrant - Tris Pharma, Inc. (947472119) Establishment Name Address ID/FEI Operations Tris Pharma, Inc. 947472119 MANUFACTURE, ANALYSIS Establishment Name Address ID/FEI Operations PCAS Finland Oy 369587311 API MANUFACTURE Establishment Name Address ID/FEI Operations Whitehouse Analytical Laboratories, LLC 138628008 ANALYSIS Establishment Name Address ID/FEI Operations Perritt Laboratories Inc. 077106284 ANALYSIS Revised: 12/2010Tris Pharma, Inc. More Nexiclon XR Suspension resources Nexiclon XR Suspension Side Effects (in more detail)Nexiclon XR Suspension Use in Pregnancy & BreastfeedingNexiclon XR Suspension Drug Interactions0 Reviews for Nexiclon XR - Add your own review/rating Compare Nexiclon XR Suspension with other medications High Blood Pressure
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albunorm™20%, 200g / l, solution for infusion


1. Name Of The Medicinal Product

Albunorm 20%, 200 g/l, solution for infusion

2. Qualitative And Quantitative Composition

Albunorm 20% is a solution containing 200 g/l of total protein of which at least 96% is human albumin.

A bottle of 50 ml contains 10 g of human albumin.

A bottle of 100 ml contains 20 g of human albumin.

Excipients:

Sodium (144-160 mmol/l)

Potassium (< 10 mmol/l)

Albunorm 20% is a hyperoncotic solution.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for infusion.

The solution is a clear, slightly viscous liquid; it is yellow, amber or green.

4. Clinical Particulars 4.1 Therapeutic Indications

Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated, and use of a colloid is appropriate.

The choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient, based on official recommendations.

4.2 Posology And Method Of Administration

The concentration of the albumin preparation, dosage and the infusion-rate should be adjusted to the patient?s individual requirements.

Posology

The dose required depends on the size of the patient, the severity of trauma or illness and on continuing fluid and protein losses. Measures of adequacy of circulating volume and not plasma albumin levels should be used to determine the dose required.

If human albumin is to be administered, haemodynamic performance should be monitored regularly; this may include:

arterial blood pressure and pulse rate

central venous pressure

pulmonary artery wedge pressure

urine output

electrolyte

haematocrit/haemoglobin

Method of administration

Human albumin can be directly administered by the intravenous route, or it can also be diluted in an isotonic solution (e.g. 5% glucose or 0.9% sodium chloride).

The infusion rate should be adjusted according to the individual circumstances and the indication.

In plasma exchange the infusion-rate should be adjusted to the rate of removal.

4.3 Contraindications

Hypersensitivity to albumin preparations or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented.

Albumin should be used with caution in conditions where hypervolaemia and its consequences or haemodilution could represent a special risk for the patient. Examples of such conditions are:

Decompensated cardiac insufficiency

Hypertension

Oesophageal varices

Pulmonary oedema

Haemorrhagic diathesis

Severe anaemia

Renal and post-renal anuria

In a post-hoc follow-up study of critically ill patients with traumatic brain injury, fluid resuscitation with albumin was associated with higher mortality rates than was resuscitation with saline. While the mechanisms underlying this observed difference in mortality are not clear, caution is advised in the use of albumin in patients with severe traumatic brain injury.

The colloid-osmotic effect of human albumin 200 or 250 g/l is approximately four times that of blood plasma. Therefore, when concentrated albumin is administered, care must be taken to assure adequate hydration of the patient. Patients should be monitored carefully to guard against circulatory overload and hyperhydration.

200-250 g/l human albumin solutions are relatively low in electrolytes compared to 40-50 g/l human albumin solutions. When albumin is given, the electrolyte status of the patient should be monitored (see section 4.2) and appropriate steps taken to restore or maintain the electrolyte balance.

Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients.

If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes).

Hypervolaemia may occur if the dosage and rate of infusion are not adjusted to the patients circulatory situation. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised venous pressure and pulmonary oedema, the infusion is to be stopped immediately.

Data on the use of Albunorm 20% in children are limited; therefore, the product should only be administered to these individuals if the benefits clearly outweigh potential risks.

This medicinal product contains 7.2 –8 mmol / 14.4 –16 mmol sodium per one bottle of 50 ml /100 ml albumin solution, this has to be taken into consideration by patients on a controlled sodium diet.

This medicine contains maximum 1mmol potassium per one bottle of 100 ml albumin solution, this has to be taken into consideration for patients with reduced kidney function or patients on a controlled potassium diet.

Standard measure to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.

It is strongly recommended that every time that Albunorm 20% is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No specific interactions of human albumin with other medicinal products are known.

4.6 Pregnancy And Lactation

The safety of Albunorm 20% for use in human pregnancy has not been established in controlled clinical trials. However, clinical experience with albumin suggests that no harmful effects on the course of pregnancy, or on the fetus and the neonate are to be expected.

No animal reproduction studies have been conducted with Albunorm 20%.

However, human albumin is a normal constituent of human blood.

4.7 Effects On Ability To Drive And Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable Effects

Mild reactions such as flush, urticaria, fever, and nausea occur rarely. These reactions normally disappear rapidly when the infusion rate is slowed down or the infusion is stopped. Very rarely, severe reactions such as shock may occur. In case of severe reactions, the infusion should be stopped and an appropriate treatment should be initiated.

The following adverse reactions have been observed for human albumin solutions during the postmarketing phase and can therefore also be expected for Albunorm 20%.

System Organ Class

Reactions

(frequency not known)*

Immune system disorders

anaphylactic shock

anaphylactic reaction

hypersensitivity

Psychiatric disorders

confusional state

Nervous system disorders

headache

Cardiac disorders

tachycardia

Vascular disorders

hypotension

hypertension

flushing

Respiratory, thoracic and mediastinal disorders

dyspnoea

Gastrointestinal disorders

nausea

Skin and subcutaneous tissue disorders

urticaria

angioneurotic oedema

rash erythematosus

hyperhidrosis

General disorders and administration site conditions

pyrexia

chills

* cannot be estimated from the available data

For safety with respect to transmissible agents, see 4.4.

4.9 Overdose

Hypervolaemia may occur if the dosage and rate of infusion are too high. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised central venous pressure and pulmonary oedema, the infusion should be stopped immediately and the patient?s haemodynamic parameters carefully monitored.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: blood substitutes and plasma protein fractions,

ATC code: B05AA01

Human albumin accounts quantitatively for more than half of the total protein in the plasma and represents about 10% of the protein synthesis activity of the liver.

Physico-chemical data:

Human albumin 200 or 250 g/l has a corresponding hyperoncotic effect.

The most important physiological function of albumin results from its contribution to oncotic pressure of the blood and transport function. Albumin stabilises circulating blood volume and is a carrier of hormones, enzymes, medicinal products and toxins.

5.2 Pharmacokinetic Properties

Under normal conditions the total exchangeable albumin pool is 4-5 g/kg body weight, of which 40-45% is present intravascularly and 55-60% in the extravascular space. Increased capillary permeability will alter albumin kinetics and abnormal distribution may occur in conditions such as severe burns or septic shock.

Under normal conditions, the average half-life of albumin is about 19 days. The balance between synthesis and breakdown is normally achieved by feedback regulation. Elimination is predominantly intracellular and due to lysosome proteases.

In healthy subjects, less than 10% of infused albumin leaves the intravascular compartment during the first 2 hours following infusion. There is considerable individual variation in the effect on plasma volume. In some patients the plasma volume can remain increased for some hours. However, in critically ill patients, albumin can leak out of the vascular space in substantial amounts at an unpredictable rate.

5.3 Preclinical Safety Data

Human albumin is a normal constituent of human plasma and acts like physiological albumin.

In animals, single-dose toxicity testing is of little relevance and does not permit the evaluation of toxic or lethal doses or of a dose-effect-relationship. Repeated-dose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models.

To date, human albumin has not been reported to be associated with embryo-fetal toxicity, oncogenic or mutagenic potential.

No signs of acute toxicity have been described in animal models.

6. Pharmaceutical Particulars 6.1 List Of Excipients

N-acetyl-DL-tryptophan

0.080 mmol/g protein

 

 

Caprylic acid

0.080 mmol/g protein

 

 

Water for injections

ad 1000 ml

 

 

Electrolytes

 

 

 

 

Sodium

144-160 mmol/l

 

 

Potassium

< 10 mmol/l

 

 

6.2 Incompatibilities

Human albumin solution must not be mixed with other medicinal products, whole blood, packed red cells and water for injections.

6.3 Shelf Life

2 years

After the vial has been opened, the content should be used immediately.

6.4 Special Precautions For Storage

Do not store above +25 °C.

Store in the original container in order to protect from light.

Do not freeze.

6.5 Nature And Contents Of Container

- 50 ml of solution in infusion bottle (type II glass) with stopper (bromobutyl rubber).

Pack size of 1 or 10.

- 100 ml of solution in infusion bottle (type II glass) with stopper (bromobutyl rubber).

Pack size of 1 or 10.

Not all pack sizes may be marketed in all countries.

6.6 Special Precautions For Disposal And Other Handling

The solution can be directly administered by the intravenous route, or it can also be diluted in an isotonic solution (e.g. 5 % glucose or 0.9 % sodium chloride).

Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients.

If large volumes are administered, the product should be warmed to room or body temperature before use.

Do not use solutions which are cloudy or have deposits. This may indicate that the protein is unstable or that the solution has become contaminated.

Once the container has been opened the content should be used immediately.

Any unused product should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Octapharma Ltd

The Zenith Building

26 Spring Gardens

Manchester

M2 1AB

United Kingdom

8. Marketing Authorisation Number(S)

PL 10673/0031

9. Date Of First Authorisation/Renewal Of The Authorisation

23/02/2009

10. Date Of Revision Of The Text

07/07/2009


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Imodium Plus Caplets (P)


1. Name Of The Medicinal Product

IMODIUM PLUS CAPLET

2. Qualitative And Quantitative Composition

Each tablet contains loperamide hydrochloride 2 mg and simeticone equivalent to 125 mg dimeticone.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Tablet, uncoated

White, capsule-shaped tablets debossed with “IMO” on one side, the other side is debossed with a line between “2and 125.

4. Clinical Particulars 4.1 Therapeutic Indications

Imodium Plus Caplets are indicated for the symptomatic treatment of acute diarrhoea in adults and adolescents over 12 years when acute diarrhoea is associated with gas-related abdominal discomfort including bloating, cramping or flatulence.

4.2 Posology And Method Of Administration

The tablets should be taken with liquid.

Adults over 18 years:

Take two caplets initially, followed by one caplet after every loose stool. Not more than 4 caplets should be taken in a day, limited to no more than 2 days.

Adolescents between 12 and 18 years:

Take one caplet initially, followed by one caplet after every loose stool. Not more than 4 caplets should be taken in a day, limited to no more than 2 days.

Use in children:

Imodium Plus must not be used in children under 12 years.

Use in the elderly:

No dosage adjustments are required for the elderly.

Use in renal impairment:

No dosage adjustment is necessary in renal impairment.

Hepatic impairment:

Although no pharmacokinetic data are available in patients with hepatic insufficiency, Imodium Plus should be used with caution in such patients because of reduced first pass metabolism (see section 4.4).

4.3 Contraindications

Imodium Plus must not be used in:

• Children less than 12 years of age

• Patients with a known hypersensitivity (allergy) to loperamide hydrochloride, simeticone or any of the excipients

• Patients with acute dysentery, which is characterised by blood in stool and high fever

• Patients with acute ulcerative colitis

• Patients with pseudomembranous colitis associated with broad spectrum antibiotics

• Patients with bacterial enterocolitis caused by invasive organisms including Salmonella, Shigella and Campylobacter

Imodium Plus should not be used when inhibition of peristalsis is to be avoided due to the possible risk of significant sequelae including ileus, megacolon and toxic megacolon. It must be discontinued promptly if constipation, ileus or abdominal distension develop.

4.4 Special Warnings And Precautions For Use

Treatment of diarrhoea with loperamide-simeticone is only symptomatic. Whenever an underlying etiology can be determined, specific treatment should be given when appropriate.

In patients with (severe) diarrhoea, fluid and electrolyte depletion may occur. It is important that attention is paid to appropriate fluid and electrolyte replacement.

If clinical improvement is not observed within 48 hours, the administration of Imodium Plus must be discontinued. Patients should be advised to consult their physician.

Patients with AIDS treated with Imodium Plus for diarrhoea should have therapy stopped at the earliest signs of abdominal distension. There have been isolated reports of obstipation with an increased risk for toxic megacolon in AIDS patients with infectious colitis from both viral and bacterial pathogens treated with loperamide hydrochloride.

Although no pharmacokinetic data are available in patients with hepatic impairment, Imodium Plus should be used with caution in such patients because of reduced first pass metabolism. This medicine must be used with caution in patients with hepatic impairment as it may result in a relative overdose leading to central nervous system (CNS) toxicity. Imodium Plus should be used under medical supervision in patients with severe hepatic dysfunction.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Non-clinical data have shown that loperamide is a P-glycoprotein substrate. Concomitant administration of loperamide (16 mg single dose) with quinidine, or ritonavir, which are both P-glycoprotein inhibitors, resulted in a 2 to 3-fold increase in loperamide plasma concentrations. The clinical relevance of this pharmacokinetic interaction with P-glycoprotein inhibitors, when loperamide is given at recommended dosages, is unknown.

The concomitant administration of loperamide (4 mg single dose) and itraconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 3 to 4-fold increase in loperamide plasma concentrations. In the same study a CYP2C8 inhibitor, gemfibrozil, increased loperamide by approximately 2-fold. The combination of itraconazole and gemfibrozil resulted in a 4-fold increase in peak plasma levels of loperamide and a 13-fold increase in total plasma exposure. These increases were not associated with measured CNS effects, as measured by psychomotor tests (i.e. subjective drowsiness and the Digit Symbol Substitution Test).

The concomitant administration of loperamide (16 mg single dose) and ketoconazole, an inhibitor of CYP3A4 and P-glycoprotein, resulted in a 5-fold increase in loperamide plasma concentrations. This increase was not associated with increased pharmacodynamic effects as measured by pupillometry.

Concomitant treatment with oral desmopressin resulted in a 3-fold increase of desmopressin plasma concentrations, presumably due to slower gastrointestinal motility.

It is expected that drugs with similar pharmacological properties may potentiate loperamide's effect and that drugs that accelerate gastrointestinal transit may decrease its effect.

Since simeticone is not absorbed from the gastrointestinal tract, no relevant interactions between simeticone and other drugs are expected.

4.6 Pregnancy And Lactation

Use in pregnancy

Safety in human pregnancy has not been established, although from animal studies there are no indications that loperamide or simeticone possesses teratogenic or embryotoxic properties. Imodium Plus should not be given during pregnancy, especially during the first trimester, unless clinically justified.

Use in lactation

Small amounts of loperamide may appear in human breast milk. Therefore Imodium Plus is not recommended during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

Tiredness, dizziness and drowsiness have been reported in patients taking loperamide. If affected, patients should not drive or operate machinery. See Section 4.8 Undesirable effects.

4.8 Undesirable Effects

The use of loperamide plus simeticone, in the treatment of the symptoms of diarrhoea, and gas-related abdominal discomfort associated with acute diarrhoeal illness, was studied in five placebo-controlled, and active-controlled, clinical trials involving 462 adults treated with loperamide plus simeticone. The most frequently reported Adverse Drug Reactions (ADRs) associated with the use of the drug in these clinical trials were nausea and dysgeusia, reported in 1.7% and 1.9% of patients, respectively, and were considered Common.

Including the above-mentioned ADRs, the following table displays ADRs that have been reported with the use of loperamide plus simeticone, or loperamide alone, from either clinical trial or post-marketing experiences. The displayed frequency categories use the following convention:

Very common (

System Organ Class

Adverse Reactions

   

Frequency

     

Common

Uncommon

Unknown

 

Immune system disorders

   

Hypersensitivity including: Anaphylactic Shock, Anaphylactoid Reaction

Nervous System Disorders

 

Somnolence

Loss of consciousness, Depressed level of consciousness, Dizziness

Gastrointestinal disorders

(See sections 4.3 and 4.4)

Nausea, Dysgeusia

Constipation

Megacolon, including Toxic Megacolon; Ileus; Abdominal Pain; Vomiting; Abdominal Distension; Dyspepsia; Flatulence

Skin and subcutaneous tissue disorders

 

Rash

Angioedema, Urticaria, Pruritus

Renal and urinary disorders

   

Urinary Retention

4.9 Overdose

Symptoms

In case of overdosage (including relative overdosage due to hepatic dysfunction), central nervous system depression (stupor, co-ordination abnormality, somnolence, miosis, muscular hypertonia, respiratory depression), dry mouth, abdominal discomfort, nausea and vomiting, constipation, urinary retention and paralytic ileus may occur. Children may be more sensitive to CNS effects than adults.

Treatment

If symptoms of overdosage occur, naloxone can be given as an antidote. Since the duration of action of loperamide is longer than that of naloxone (1 to 3 hours) repeated treatment with naloxone may be indicated. Therefore, the patient should be monitored closely for at least 48 hours in order to detect possible CNS depression.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antipropulsive antidiarrheals, ATC code: A07D A53

Loperamide binds to the opiate receptor in the gut wall, reducing propulsive peristalsis, increasing intestinal transit time and enhancing resorption of water and electrolytes. Loperamide does not change the physiological flora. Loperamide increases the tone of the anal sphincter. Imodium Plus does not act centrally.

Simeticone is an inert surface-active agent with anti-foaming properties thereby potentially relieving gas-related symptoms associated with diarrhoea.

5.2 Pharmacokinetic Properties

Absorption: Most ingested loperamide is absorbed from the gut, but as a result of significant first pass metabolism, systemic bioavailability is only approximately 0.3%. The simeticone component of loperamide-simeticone is not absorbed.

Distribution: Studies on distribution in rats show a high affinity for the gut wall with a preference for binding to receptors of the longitudinal muscle layer. The plasma protein binding of loperamide is 95%, mainly to albumin. Non-clinical data have shown that loperamide is a P-glycoprotein substrate.

Metabolism: Loperamide is almost completely extracted by the liver, where it is predominantly metabolized, conjugated and excreted via the bile. Oxidative N-demethylation is the main metabolic pathway for loperamide, and is mediated mainly through CYP3A4 and CYP2C8. Due to this very high first pass effect, plasma concentrations of unchanged drug remain extremely low.

Elimination: The half-life of loperamide in man is about 11 hours with a range of 9-14 hours. Excretion of the unchanged loperamide and the metabolites mainly occurs through the faeces.

5.3 Preclinical Safety Data

Acute and chronic studies on loperamide showed no specific toxicity. Results of in vivo and in vitro studies carried out indicated that loperamide is not genotoxic. In reproduction studies, very high doses (40mg/kg/day - 240 times the maximum human use level) loperamide impaired fertility and foetal survival in association with maternal toxicity in rats. Lower doses had no effects on maternal or foetal health and did not affect peri- and post-natal development.

Simeticone is a member of the class of linear polydimethylsilicones, which have been in wide general and medicinal use for many years and are regarded as biologically inert and not exhibiting toxic properties and has not been the subject of specific animal toxicity studies.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Calcium hydrogen phosphate anhydrous

Microcrystalline cellulose

Acesulfame potassium

Artificial vanilla flavour (includes propylene glycol, maltodextrin and benzyl alcohol)

Sodium starch glycolate (Type A)

Stearic acid.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Push through blisters comprising polychlorotrifluoroethylene/PVC film, heat seal coating and aluminium foil.

or

Bend and peel blisters comprising polychlorotrifluoroethylene/PVC film, heat seal coating, aluminium foil/PET/paper.

Blister strips of 2, 4, 5, or 6 tablets in pack sizes of 6, 8, 10, 12, 15, 16, 18 and 20 tablets packed in printed cardboard cartons.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0342

9. Date Of First Authorisation/Renewal Of The Authorisation

01/09/2007

10. Date Of Revision Of The Text

21/09/2011


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Hetastarch



6% Hetastarch
In 0.9% Sodium Chloride Injection Hetastarch Description

6% Hetastarch in 0.9% Sodium Chloride Injection (Hetastarch Injection) is a sterile, nonpyrogenic solution for intravenous administration.

The composition of each 100 mL is as follows:

Hetastarch................................................................ 6 g Sodium Chloride, USP............................................. 0.9 g Water for Injection, USP.......................................... qs

pH adjusted with Sodium Hydroxide, NF if necessary

Concentration of Electrolytes (mEq/L): Sodium 154, Chloride 154

pH: approximately 5.5 with negligible buffering capacity

Calculated Osmolarity: approximately 309 m0sM

Hetastarch is an artificial colloid derived from a waxy starch composed almost entirely of amylopectin. Hydroxyethyl ether groups are introduced into the glucose units of the starch, and the resultant material is hydrolyzed to yield a product with a molecular weight suitable for use as a plasma volume expander and erythrocyte sedimenting agent. Hetastarch is characterized by its molar substitution and also by its molecular weight. The molar substitution is approximately 0.75 which means Hetastarch has an average of approximately 75 hydroxyethyl groups for every 100 glucose units. The weight average molecular weight is approximately 600,000 with a range of 450,000 to 800,000 and with at least 80% of the polymers falling within the range of 20,000 to 2,500,000. Hydroxyethyl groups are attached by either linkage primarily at C-2 of the glucose unit and to a lesser extent at C-3 and C-6. The polymer resembles glycogen, and the polymerized D-glucose units are joined primarily by ?-1,4 linkages with occasional ?-1,6 branching linkages. The degree of branching is approximately 1:20 which means that there is an average of approximately one ?-1,6 branch for every 20 glucose monomer units.

The chemical name for Hetastarch is hydroxyethyl starch.

The structural formula is as follows:

Amylopectin derivative in which R2 and R3 are H or CH2CH2OH and R6 is H, CH2CH2OH, or a branching point in the starch polymer connected through an ?-1,6 link to additional D-glucopyranosyl units.

Hetastarch injection is a clear, pale yellow to amber solution. Exposure to prolonged adverse storage conditions may result in a change to a turbid deep brown or the formation of a crystalline precipitate. Do not use the solution if these conditions are evident.

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. The container solution unit is a closed system and is not dependent upon entry of external air during administration. The container is overwrapped to provide protection from the physical environment and to provide an additional moisture barrier when necessary.

The closure system has two ports; the one for the administration set has a tamper evident plastic protector.

Hetastarch - Clinical Pharmacology

The plasma volume expansion produced by Hetastarch injection approximates that of 5% Albumin (Human). Intravenous infusion of Hetastarch injection results in expansion of plasma volume that decreases over the succeeding 24 to 36 hours. The degree of plasma volume expansion and improvement in hemodynamic state depend upon the patient's intravascular status.

Hetastarch molecules below 50,000 molecular weight are rapidly eliminated by renal excretion. A single dose of approximately 500 mL of Hetastarch injection (approximately 30 g) results in elimination in the urine of approximately 33% of the dose within 24 hours. This is a variable process but generally results in an intravascular Hetastarch concentration of less than 10% of the total dose injected by two weeks. A study of the biliary excretion of Hetastarch in 10 healthy males accounted for less than 1% of the dose over a 14 day period. The hydroxyethyl group is not cleaved by the body but remains intact and attached to glucose units when excreted. Significant quantities of glucose are not produced as hydroxyethylation prevents complete metabolism of the smaller polymers.

The addition of Hetastarch to whole blood increases the erythrocyte sedimentation rate. Therefore Hetastarch injection is used to improve the efficiency of granulocyte collection by centrifugal means.

In randomized, controlled, comparative studies of Hetastarch injection (n=92) and Albumin (n=85) in surgical patients, no patient in either treatment group had a bleeding complication and no significant difference was found in the amount of blood loss between the treatment groups.1-4

Indications and Usage for Hetastarch

Hetastarch injection is indicated in the treatment of hypovolemia when plasma volume expansion is desired. It is not a substitute for blood or plasma.

The adjunctive use of Hetastarch injection in leukapheresis has also been shown to be safe and efficacious in improving the harvesting and increasing the yield of granulocytes by centrifugal means.

Contraindications

Hetastarch injection is contraindicated in patients with known hypersensitivity to hydroxyethyl starch or with bleeding disorders or with congestive heart failure where volume overload is a potential problem. Hetastarch injection should not be used in renal disease with oliguria or anuria not related to hypovolemia.

Patients with pre-existing coagulation or bleeding disorders should not be given Hetastarch injection.

Warnings

Life-threatening anaphylactic/anaphylactoid reactions have been rarely reported with Hetastarch injection; death has occurred, but a causal relationship has not been established. Patients who develop severe anaphylactic/anaphylactoid reactions may need continued supportive care until symptoms have resolved.

Hypersensitivity reactions can occur even after Hetastarch injection has been discontinued.

Usage in Plasma Volume Expansion

Hetastarch injection has not been adequately evaluated to establish its safety in situations other than treatment of hypovolemia in elective surgery.

Large volumes of Hetastarch injection may transiently alter the coagulation mechanism due to hemodilution and a mild direct inhibitory action on Factor VIII. Administration of volumes of Hetastarch injection that are greater than 25% of the blood volume in less than 24 hours may cause significant hemodilution reflected by lower hematocrit and plasma protein values. Administration of packed red cells, platelets, or fresh frozen plasma should be considered if clinically indicated.

Hetastarch injection is not recommended for use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been discontinued because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired. However, this risk of bleeding diminished within hours.5-6

Hematocrit may be decreased and plasma proteins diluted excessively by administration of large volumes of Hetastarch injection. Administration of packed red cells, platelets, and fresh frozen plasma should be considered if excessive dilution occurs.

Use over extended periods: Hetastarch injection has not been adequately evaluated to establish its safety in situations other than leukapheresis that require frequent use of colloidal solutions over extended periods. In some cases, Hetastarch has been associated with coagulation abnormalities in conjunction with an acquired, reversible von Willebrand's-like syndrome and/or Factor VIII deficiency when used over a period of days. Replacement therapy should be considered if a severe Factor VIII deficiency is identified. If a coagulopathy develops, it may take several days to resolve. Certain conditions may affect the safe use of Hetastarch injection on a chronic basis. For example, in patients with subarachnoid hemorrhage where Hetastarch injection is used repeatedly over a period of days for the prevention of cerebral vasospasm, significant clinical bleeding may occur. Intracranial bleeding resulting in death has been reported.7

Usage in Leukapheresis

Slight declines in platelet counts and hemoglobin levels have been observed in donors undergoing repeated leukapheresis procedures using Hetastarch injection due to the volume expanding effects of Hetastarch and to the collection of platelets and erythrocytes. Hemoglobin levels usually return to normal within 24 hours. Hemodilution by Hetastarch injection may also result in 24 hour declines of total protein, albumin, calcium, and fibrinogen levels. None of these decreases are to a degree recognized to be clinically significant risks to healthy donors.

Precautions General

If administration is by pressure infusion, all air should be withdrawn or expelled from the bag through the medication port prior to infusion.

Caution should be used when administering Hetastarch injection to patients allergic to corn because such patients can also be allergic to Hetastarch.

If hypersensitivity effect occurs, administration of the drug should be discontinued and appropriate treatment and supportive measures should be undertaken (see WARNINGS).

When using Hetastarch injection for plasma volume expansion, caution should be taken to avoid excessive hemodilution and circulatory overload especially in those patients at risk for developing congestive heart failure and pulmonary edema. Hetastarch injection is primarily excreted via the kidneys so caution should be exercised in patients who have impaired renal function. Although the risk of circulatory overload is largely dependent on the clinical circumstances, use of doses higher than 20 mL/kg/24h will increase the risk significantly. Increased risk of coagulation abnormalities and bleeding is also associated with higher doses. Patients vital signs and hemoglobin, hematocrit, platelet count, prothrombin time and partial thromboplastin time should be monitored closely.

Hetastarch injection should be used with caution in patients who have been anticoagulated with other drugs that negatively influence the coagulation system.

Regular and frequent clinical evaluation and complete blood counts (CBC) are necessary for proper monitoring of Hetastarch injection use during leukapheresis. If the frequency of leukapheresis is to exceed the guidelines for whole blood donation, you may wish to consider the following additional tests: total leukocyte and platelet counts, leukocyte differential count, hemoglobin and hematocrit, prothrombin time (PT), and partial thromboplastin time (PTT).

Indirect bilirubin levels of 8.3 mg/L (normal 0.0-7.0 mg/L) have been reported in 2 out of 20 normal subjects who received multiple infusions of Hetastarch injection. Total bilirubin was within normal limits at all times; indirect bilirubin retuned to normal by 96 hours following the final infusion. The significance, if any, of these elevations is not known; however, caution should be observed before administering Hetastarch injection to patients with a history of liver disease.

Elevated serum amylase levels may be observed temporarily following administration of Hetastarch injection, although no association with pancreatitis has been demonstrated. Serum amylase levels cannot be used to assess or to evaluate for pancreatitis for 3-5 days after administration of Hetastarch injection. Elevated serum amylase levels persist for longer periods of time in patients with renal impairment. Hetastarch has not been shown to increase serum lipase.

One report suggests that in the presence of renal glomerular damage, larger molecules of Hetastarch can leak into the urine and elevate the specific gravity. The elevation of specific gravity can obscure the diagnosis of renal failure.

Hetastarch is not eliminated by hemodialysis. The utility of other extracorporeal elimination techniques has not been evaluated.

The flexible plastic container has a natural gum rubber/latex-containing injection port. Unless medication addition occurs a diaphragm prevents the latex from coming in contact with the Hetastarch injection solution. In patients with latex hypersensitivity, caution should be exercised when adding medication through the port of the flexible plastic container.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long –term studies of animals have not been performed to evaluate the carcinogenic potential of Hetastarch.

Teratogenic Effects:

Pregnancy Category C

Hetastarch has been shown to have an embryocidal effect on New Zealand rabbits when given intravenously over the entire organogenesis period in a daily dose 1/2 times the maximum recommended therapeutic human dose (1500 mL) and on BD rats when given intraperitoneally, from the 16th to the 21st day of pregnancy, in a daily dose 2.3 times the maximum recommended therapeutic human dose. When Hetastarch was administered to New Zealand rabbits, BD rats, and Swiss mice with intravenous daily doses of 2 times, 1/3 times, and 1 time the maximum recommended therapeutic human dose respectively over several days during the period of gestation, no evidence of teratogenicity was evident. There were no adequate and well controlled studies in pregnant women. Hetastarch injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Hetastarch is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Hetastarch injection is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Hetastarch in pediatric patients have not been established. Adequate, well-controlled clinical trials to establish the safety and effectiveness of Hetastarch injection in pediatric patients have not been conducted. However, in one small double-blind study, 47 infants, children, and adolescents (ages 1 year to 15.5 years) scheduled for repair of congenital heart disease with moderate hypothermia were randomized to receive either Hetastarch injection or Albumin as a postoperative volume expander during the first 24 hours after surgery. Thirty-eight children required colloid replacement therapy, of which 20 children received Hetastarch injection. No differences were found in the coagulation parameters or in the amount of replacement fluids required in the children receiving 20 mL/kg or less of either colloid replacement therapy. In children who received greater than 20 mL/kg of Hetastarch injection, an increase in prothrombin time was demonstrated (p=0.006).8 There were no neonates included in this study.

Adverse Reactions

Reported adverse reactions associated with Hetastarch include:

General

Hypersensitivity (see WARNINGS).

Death, life-threatening anaphylactic/anaphylactoid reactions, cardiac arrest, ventricular fibrillation, severe hypotension, non-cardiac pulmonary edema, laryngeal edema, bronchospasm, angioedema, wheezing, restlessness, tachypnea, stridor, fever, chest pain, bradycardia, tachycardia, shortness of breath, chills, urticaria, pruritus, facial and periorbital edema, coughing, sneezing, flushing, erythema multiforme, and rash.

Cardiovascular

Circulatory overload, congestive heart failure, and pulmonary edema (see PRECAUTIONS).

Hematologic

Intracranial bleeding, bleeding and/or anemia due to hemodilution (see WARNINGS) and/or Factor VIII deficiency, acquired von Willebrand's-like syndrome, and coagulopathy including rare cases of disseminated intravascular coagulopathy and hemolysis.

Metabolic

Metabolic acidosis.

Other

Vomiting, peripheral edema of the lower extremities, submaxillary and parotid glandular enlargement, mild influenza-like symptoms, headaches, and muscle pains.

Hydroxyethyl starch-associated pruritus has been reported in some patients with deposits of hydroxyethyl starch in peripheral nerves.

Hetastarch Dosage and Administration Dosage for Acute Use in Plasma Volume Expansion

Hetastarch injection is administered by intravenous infusion only. Total dosage and rate of infusion depend upon the amount of blood or plasma lost and the resultant hemoconcentration.

Adults: The amount usually administered is 500 to 1000 mL. Doses of more than 1500 mL per day for the typical 70 kg patient (approximately 20 mL per kg of body weight) are usually not required although higher doses have been reported in postoperative and trauma patients where severe blood loss has occurred (see WARNINGS and PRECAUTIONS).

Pediatric patients: Adequate, well-controlled clinical trials to establish the safety and effectiveness of Hetastarch injection in pediatric patients have not been conducted (see PRECAUTIONS, Pediatric Use).

Dosage in Leukapheresis

250 to 700 mL of Hetastarch injection to which citrate anticoagulant has been added is typically administered by aseptic addition to the input line of the centrifugation apparatus at a ratio of 1:8 to 1:13 to venous whole blood. The Hetastarch injection and citrate should be thoroughly mixed to assure effective anticoagulation of blood as it flows through the leukapheresis machine.

When stored at room temperature, Hetastarch injection admixtures of 500-560 mL with citrate concentrations up to 2.5% were compatible for 24 hours. The safety and compatibility of additives other than citrate have not been established.

General Recommendations

Do not use plastic container in series connection.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.

This solution is intended for intravenous administration using sterile equipment. It is recommended that intravenous administration apparatus be replaced at least once every 24 hours.

Use only if solution is clear and container and seals are intact.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

If administration is by pressure infusion, all air should be withdrawn or expelled from the bag through the medication port prior to infusion.

The safety and compatibility of other additives have not been established.

Directions for Use (Plastic Container)

Caution: Before administering to the patient, review these directions:

Visual Checking

Do not remove the plastic infusion container from its overwrap until immediately before use. While the overwrap is intact, identify the solution as 6% Hetastarch in 0.9% Sodium Chloride Injection, the lot number, and the expiration date. Check that the solution is clear. Inspect the intact unit for signs of obvious damage. If present, the unit should not be used.

Removal of Overwrap

To open overwrap, tear at any notch located at either end of unit. After removing overwrap, check for any leakage by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.

Preparation for Administration (Use aseptic technique)

Close flow control clamp of administration set. Twist off plug from port designated "Delivery Set Port." Insert spike of infusion set into port with a twisting motion until the set is firmly seated. Suspend container from hanger. Follow manufacturer's recommended procedures for the administration set. Discontinue administration and notify physician immediately if patient exhibits signs of adverse reactions. How is Hetastarch Supplied

6% Hetastarch in 0.9% Sodium Chloride Injection is supplied sterile and nonpyrogenic in 500 mL intravenous plastic infusion containers.

NDC 0703-5079-37 12-Pack 500 mL bags

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the product be stored at room temperature (25?C); however, brief exposure up to 40?C does not adversely affect the product.

Rx only

References: Diehl J. et al., Clinical Comparison of Hetastarch and Albumin in Postoperative Cardiac Patients. The Annals of Thoracic Surgery, 1982;34(6):674-679. Gold M. et al., Comparison of Hetastarch to Albumin for Perioperative Bleeding In Patients Undergoing Abdominal Aortic Aneurysm Surgery, Annals of Surgery, 1990;211(4):482-485. Kiklin J. et al., Hydroxyethyl Starch versus Albumin for Colloid Infusion Following Cardiopulmonary Bypass in Patients Undergoing Myocardial Revascularization, The Annals of Thoracic Surgery, 1984;37(1):40-46. Moggio RA. et al., Hemodynamic Comparison of Albumin and Hydroxyethyl Starch in Postoperative Cardiac Surgery Patients, Critical Care Medicine, 1983;11(12):943-945. Knutson JE., et al., Does Intraoperative Hetastarch Administration Increase Blood Loss and Transfusion Requirements After Cardiac Surgery? Anesthesia Analg., 2000;90:801-7. Cope JT., et al., Intraoperative Hetastarch Infusion Impairs Hemostasis After Cardiac Operations. The Annals of Thoracic Surgery, 1997;63:78-83. Damon L., Intracranial Bleeding During Treatment with Hydroxyethyl Starch, New England Journal of Medicine, 1987;317(15):964-965. Brutocao D., et al., Comparison of Hetastarch with Albumin for Postoperative Volume Expansion in Children After Cardiopulmonary Bypass, Journal of Cardiothoracic and Vascular Anesthesia, 1996;10(3):348-351.

TEVA

Manufactured for Teva Parenteral Medicines Inc., Irvine, CA 92618, USA by Fresenius Kabi Norge AS, NO-1753, Halden, Norway

To report SUSPECTED ADVERSE REACTIONS contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872 xt 6351 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Revised: October 2008

01-58-08-001-B

PRINCIPAL DISPLAY PANEL 6% Hetastarch 500 mL Label Text

DELIVERED REMAINING

6% Hetastarch 500 mL

In 0.9% Sodium Chloride Injection
For intravenous use only
Rx only

Each 100 mL contains: 6 g Hetastarch and 0.9 g Sodium Chloride, USP
in Water for Injection, USP.
pH adjusted with Sodium Hydroxide, NF if necessary.
pH: approximately 5.5 with negligible buffering capacity.
Electrolytes (mEq/L): Sodium 154, Chloride 154.
Calculated Osmolarity: approximately 309 mOsM.

IF ADMINISTRATION IS BY PRESSURE INFUSION, ALL AIR SHOULD
BE WITHDRAWN OR EXPELLED FROM THE BAG THROUGH THE
MEDICATION PORT PRIOR TO INFUSION.

Sterile, nonpyrogenic. Use only if solution is clear and container and
seal are intact. Single dose container. Discard unused solution.

Recommended storage: room temperature (25°C).
Avoid excessive heat. Protect from freezing.
Usual dosage: See package insert for complete information.

Do not remove overwrap until ready for use. After removing the overwrap,
check for any leakage by squeezing container firmly. If any leaks are
found, discard solution as sterility may be impaired.

DO NOT INTRODUCE ADDITIVES OTHER
THAN CITRATE INTO THIS BAG

TEVA
Manufactured for Teva Parental Medicines Inc.,
Irvine, CA 92618, USA
by Fresenius Kabi Norge AS, NO-1753 Halden, Norway

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Medication Port
Delivery Set Port


Hetastarch 
Hetastarch  injection Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0703-5079 Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Hetastarch (Hetastarch) Hetastarch 6 g  in 100 mL Inactive Ingredients Ingredient Name Strength SODIUM CHLORIDE 0.9 g  in 100 mL WATER   SODIUM HYDROXIDE   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0703-5079-37 12  In 1 CARTON contains a BAG (0703-5079-31) 1 0703-5079-31 500 mL In 1 BAG This package is contained within the CARTON (0703-5079-37)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA BA740592 10/19/2011
Labeler - Teva Parenteral Medicines, Inc (794362533) Establishment Name Address ID/FEI Operations Fresenius Kabi Norge AS 731170932 MANUFACTURE Revised: 01/2012Teva Parenteral Medicines, Inc
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Epanutin 300mg hard capsules


1. Name Of The Medicinal Product

Epanutin 300 mg Hard Capsules

2. Qualitative And Quantitative Composition

Each capsule contains 300mg phenytoin sodium

Each capsule also contains 61.88 mg lactose monohydrate

For full list of excipients, see Section 6.1

3. Pharmaceutical Form

Capsules, hard

Epanutin Capsules 300mg: A white powder in a No 1 hard gelatin capsule with a white opaque body and green cap, radially printed 'EPANUTIN 300'.

4. Clinical Particulars 4.1 Therapeutic Indications

Control of tonic-clonic seizures (grand mal epilepsy), partial seizures (focal including temporal lobe) or a combination of these, and the prevention and treatment of seizures occurring during or following neurosurgery and/or severe head injury. Epanutin has also been employed in the treatment of trigeminal neuralgia but it should only be used as second line therapy if carbamazepine is ineffective or patients are intolerant to carbamazepine.

4.2 Posology And Method Of Administration

For oral administration only.

Dosage:

Dosage should be individualised as there may be wide interpatient variability in phenytoin serum levels with equivalent dosage. Epanutin should be introduced in small dosages with gradual increments until control is achieved or until toxic effects appear. In some cases serum level determinations may be necessary for optimal dosage adjustments - the clinically effective level is usually 10-20mg/l (40-80 micromoles/l) although some cases of tonic-clonic seizures may be controlled with lower serum levels of phenytoin. With recommended dosage a period of seven to ten days may be required to achieve steady state serum levels with Epanutin and changes in dosage should not be carried out at intervals shorter than seven to ten days. Maintenance of treatment should be the lowest dose of anticonvulsant consistent with control of seizures.

Epanutin Capsules, Suspension and Infatabs:

Epanutin Capsules contain phenytoin sodium whereas Epanutin Suspension and Epanutin Infatabs contain phenytoin. Although 100mg of phenytoin sodium is equivalent to 92mg of phenytoin on a molecular weight basis, these molecular equivalents are not necessarily biologically equivalent. Physicians should therefore exercise care in those situations where it is necessary to change the dosage form and serum level monitoring is advised.

Adults:

Initially 3 to 4mg/kg/day with subsequent dosage adjustment if necessary. For most adults a satisfactory maintenance dose will be 200 to 500mg daily in single or divided doses. Exceptionally, a daily dose outside this range may be indicated. Dosage should normally be adjusted according to serum levels where assay facilities exist.

Elderly:

Elderly (over 65 years): As with adults the dosage of Epanutin should be titrated to the patient's individual requirements using the same guidelines. As elderly patients tend to receive multiple drug therapies, the possibility of drug interactions should be borne in mind.

Infants and Children:

Initially, 5mg/kg/day in two divided doses, with subsequent dosage individualised to a maximum of 300mg daily. A recommended daily maintenance dosage is usually 4-8mg/kg.

Neonates:

The absorption of phenytoin following oral administration in neonates is unpredictable. Furthermore, the metabolism of phenytoin may be depressed. It is therefore especially important to monitor serum levels in the neonate.

4.3 Contraindications

Phenytoin is contraindicated in those patients who are hypersensitive to phenytoin, or its excipients, or other hydantoins.

4.4 Special Warnings And Precautions For Use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Phenytoin Sodium.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Abrupt withdrawal of phenytoin in epileptic patients may precipitate status epilepticus. When, in the judgement of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative anti-epileptic medication arises, this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an anti-epileptic drug not belonging to the hydantoin chemical class.

Phenytoin is highly protein bound and extensively metabolised by the liver. Reduced dosage to prevent accumulation and toxicity may therefore be required in patients with impaired liver function. Where protein binding is reduced, as in uraemia, total serum phenytoin levels will be reduced accordingly. However, the pharmacologically active free drug concentration is unlikely to be altered. Therefore, under these circumstances therapeutic control may be achieved with total phenytoin levels below the normal range of 10-20mg/l (40-80 micromoles/l). Patients with impaired liver function, elderly patients or those who are gravely ill may show early signs of toxicity.

Phenytoin is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence seizures are present together, combined drug therapy is needed.

Phenytoin may affect glucose metabolism and inhibit insulin release. Hyperglycaemia has been reported in association with toxic levels. Phenytoin is not indicated for seizures due to hypoglycaemia or other metabolic causes.

Serum levels of phenytoin sustained above the optimal range may produce confusional states referred to as "delirium", "psychosis", or "encephalopathy", or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, serum drug level determinations are recommended. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination of therapy with phenytoin is recommended.

Herbal preparations containing St John's wort (Hypericum perforatum) should not be used while taking phenytoin due to the risk of decreased plasma concentrations and reduced clinical effects of phenytoin (see Section 4.5).

Anticonvulsant Hypersensitivity Syndrome (AHS) is a rare drug induced, multiorgan syndrome which is potentially fatal and occurs in some patients taking anticonvulsant medication. It is characterized by fever, rash, lymphadenopathy, and other multiorgan pathologies, often hepatic. The mechanism is unknown. The interval between first drug exposure and symptoms is usually 2-4 weeks but has been reported in individuals receiving anticonvulsants for 3 or more months. Patients at higher risk for developing AHS include black patients, patients who have a family history of or who have experienced this syndrome in the past, and immuno-suppressed patients. The syndrome is more severe in previously sensitized individuals. If a patient is diagnosed with AHS, discontinue the phenytoin and provide appropriate supportive measures.

Serious skin reactions

Phenytoin can cause rare, serious skin adverse events such as exfoliative dermatitis, Stevens- Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should seek medical advice from their physician immediately when observing any indicative signs or symptoms. The physician should advise the patient to discontinue treatment if the rash appears. If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated. Published literature has suggested that there may be an increased, although still rare, risk of hypersensitivity reactions, including skin rash, SJS, TEN, and hepatotoxicity in black patients.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLAB* 1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking drugs associated with SJS/TEN, including phenytoin. Consideration should be given to avoiding use of drugs associated with SJS/TEN, including phenytoin, in HLA-B*1502 positive patients when alternative therapies are otherwise equally available.

HLAB* 1502 may be associated with an increased risk of developing Stevens Johnson Syndrome (SJS) in individuals of Thai and Han Chinese Origin when treated with phenytoin. If these patients are known to be positive for HLAB*1502, the use of phenytoin should only be considered if the benefits are thought to exceed risks.

In the Caucasian and Japanese population, the frequency of HLAB*1502 allele is extremely low, and thus it is not possible at present to conclude on risk association. Adequate information about risk association in other ethnicities is currently not available.

Musculoskeletal Effect

Phenytoin and other anticonvulsants that have been shown to induce the CYP450 enzyme are thought to affect bone mineral metabolism indirectly by increasing the metabolism of Vitamin D3. This may lead to Vitamin D deficiency and heightened risk of osteomalacia, bone fractures, osteoporosis, hypocalcemia, and hypophosphatemia in chronically treated epileptic patients.

In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using the medication in patients suffering from this disease.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose metabolism should not take this medicine

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Drugs which may increase phenytoin serum levels include:

Amiodarone, antifungal agents (such as, but not limited to, amphotericin B, fluconazole, ketoconazole, miconazole and itraconazole), chloramphenicol, chlordiazepoxide, diazepam, dicoumarol, diltiazem, disulfiram, fluoxetine, fluvoxamine, sertraline, H2-antagonists e.g. cimetidine,, halothane, isoniazid, methylphenidate, nifedipine, omeprazole, oestrogens, phenothiazines, phenylbutazone, salicylates, succinimides, sulphonamides, tolbutamide, trazodone and viloxazine.

2. Drugs which may decrease phenytoin serum levels include:

Folic acid, reserpine, rifampicin, sucralfate, theophylline and vigabatrin.

Serum levels of phenytoin can be reduced by concomitant use of the herbal preparations containing St John's wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes by St John's wort. Herbal preparations containing St John's wort should therefore not be combined with phenytoin. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort. If a patient is already taking St John's wort check the anticonvulsant levels and stop St John's wort. Anticonvulsant levels may increase on stopping St John's wort. The dose of anticonvulsant may need adjusting.

A pharmacokinetic interaction study between nelfinavir and phenytoin both administered orally showed that nelfinavir reduced AUC values of phenytoin (total) and free phenytoin by 29% and 28%, respectively. Therefore, phenytoin concentration should be monitored during co-administration with nelfinavir, as nelfinavir may reduce phenytoin plasma concentration.

3. Drugs which may either increase or decrease phenytoin serum levels include:

Carbamazepine, phenobarbital, valproic acid, sodium valproate, antineoplastic agents, certain antacids and ciprofloxacin. Similarly, the effect of phenytoin on carbamazepine, phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.

Acute alcohol intake may increase phenytoin serum levels while chronic alcoholism may decrease serum levels.

4. Although not a true pharmacokinetic interaction, tricyclic antidepressants and phenothiazines may precipitate seizures in susceptible patients and phenytoin dosage may need to be adjusted.

5. Drugs whose effect is impaired by phenytoin include:

Antifungal agents (e.g. azoles), antineoplastic agents, calcium channel blockers, clozapine, corticosteroids, ciclosporin, dicoumarol, digitoxin, doxycycline, furosemide, lamotrigine, methadone, neuromuscular blockers, oestrogens, oral contraceptives, paroxetine, sertraline, quinidine, rifampicin, theophylline and vitamin D.

6. Drugs whose effect is altered by phenytoin include:

Warfarin. The effect of phenytoin on warfarin is variable and prothrombin times should be determined when these agents are combined.

Serum level determinations are especially helpful when possible drug interactions are suspected.

Drug/Laboratory Test Interactions:

Phenytoin may cause a slight decrease in serum levels of total and free thyroxine, possibly as a result of enhanced peripheral metabolism. These changes do not lead to clinical hypothyroidism and do not affect the levels of circulating TSH. The latter can therefore be used for diagnosing hypothyroidism in the patient on phenytoin. Phenytoin does not interfere with uptake and suppression tests used in the diagnosis of hypothyroidism. It may, however, produce lower than normal values for dexamethasone or metapyrone tests. Phenytoin may cause raised serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase and lowered serum levels of calcium and folic acid. It is recommended that serum folate concentrations be measured at least once every 6 months, and folic acid supplements given if necessary. Phenytoin may affect blood sugar metabolism tests.

4.6 Pregnancy And Lactation

There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans. Genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or foetus.

Anticonvulsants including phenytoin may produce congenital abnormalities in the offspring of a small number of epileptic patients. The exact role of drug therapy in these abnormalities is unclear and genetic factors, in some studies, have also been shown to be important. Epanutin should only be used during pregnancy, especially early pregnancy, if in the judgement of the physician the potential benefits clearly outweigh the risk.

In addition to the reports of increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other antiepileptic drugs, there have more recently been reports of a foetal hydantoin syndrome. This consists of prenatal growth deficiency, micro-encephaly and mental deficiency in children born to mothers who have received phenytoin, barbiturates, alcohol, or trimethadione. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes.

There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

An increase in seizure frequency during pregnancy occurs in a proportion of patients, and this may be due to altered phenytoin absorption or metabolism. Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to an appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.

Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenytoin. Vitamin K1 has been shown to prevent or correct this defect and may be given to the mother before delivery and to the neonate after birth.

Infant breast-feeding is not recommended for women taking phenytoin because phenytoin appears to be secreted in low concentrations in human milk.

4.7 Effects On Ability To Drive And Use Machines

Caution is recommended in patients performing skilled tasks (e.g. driving or operating machinery) as treatment with phenytoin may cause central nervous system adverse effects such as dizziness and drowsiness (see Section 4.8).

4.8 Undesirable Effects

Immune system reactions: Anaphylactoid reaction, and anaphylaxis.

Central Nervous System:

The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased co-ordination, mental confusion, paraesthesia, somnolence, drowsiness and vertigo. Dizziness, insomnia, transient nervousness, motor twitchings, taste perversion and headaches have also been observed. There have also been rare reports of phenytoin induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs. There are occasional reports of irreversible cerebellar dysfunction associated with severe phenytoin overdosage. A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term phenytoin therapy.

Gastrointestinal:

Nausea, vomiting and constipation, toxic hepatitis, and liver damage.

Dermatological:

Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash is the most common; dermatitis is seen more rarely. Other more serious and rare forms have included bullous, exfoliative or purpuric dermatitis, lupus erythematosus, Stevens-Johnson syndrome and toxic epidermal necrolysis (see Section 4.4).

Connective Tissue:

Coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hirsutism, hypertrichosis, Peyronie's Disease and Dupuytren's contracture may occur rarely.

Haemopoietic:

Haemopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin. These have included thrombocytopenia, leucopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression, and aplastic anaemia. While macrocytosis and megaloblastic anaemia have occurred, these conditions usually respond to folic acid therapy.

There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local and generalised) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness, eg fever, rash and liver involvement. In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Frequent blood counts should be carried out during treatment with phenytoin.

Immune System:

Hypersensitivity syndrome has been reported and may in rare cases be fatal (the syndrome may include, but is not limited to, symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, polyarteritis nodosa, and immunoglobulin abnormalities may occur. Several individual case reports have suggested that there may be an increased, although still rare, incidence of hypersensitivity reactions, including skin rash and hepatotoxicity, in black patients.

Other:

Polyarthropathy, interstitial nephritis, pneumonitis.

Musculoskeletal System: Bone fractures and osteomalacia have been associated with longterm (>10 years) use of phenytoin by patients with chronic epilepsy. Osteoporosis and other disorders of bone metabolism such as hypocalcemia, hypophophatemia and decreased levels of Vitamin D metabolites have also been reported.

4.9 Overdose

The lethal dose in children is not known. The mean lethal dose for adults is estimated to be 2 to 5g. The initial symptoms are nystagmus, ataxia and dysarthria. The patient then becomes comatose, the pupils are unresponsive and hypotension occurs followed by respiratory depression and apnoea. Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur. Nystagmus on lateral gaze usually appears at 20mg/l, and ataxia at 30mg/l, dysarthria and lethargy appear when the serum concentration is greater than 40mg/l, but a concentration as high as 50mg/l has been reported without evidence of toxicity.

As much as 25 times therapeutic dose has been taken to result in serum concentration over 100mg/l (400 micromoles/l) with complete recovery.

Treatment:

Treatment is non-specific since there is no known antidote. If ingested within the previous 4 hours the stomach should be emptied. If the gag reflex is absent, the airway should be supported. Oxygen, and assisted ventilation may be necessary for central nervous system, respiratory and cardiovascular depression. Haemodialysis can be considered since phenytoin is not completely bound to plasma proteins. Total exchange transfusion has been utilised in the treatment of severe intoxication in children.

In acute overdosage the possibility of the presence of other CNS depressants, including alcohol, should be borne in mind.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Phenytoin is effective in various animal models of generalised convulsive disorders, reasonably effective in models of partial seizures but relatively ineffective in models of myoclonic seizures.

It appears to stabilise rather than raise the seizure threshold and prevents spread of seizure activity rather than abolish the primary focus of seizure discharge.

The mechanism by which phenytoin exerts its anticonvulsant action has not been fully elucidated however, possible contributory effects include:

1. Non-synaptic effects to reduce sodium conductance, enhance active sodium extrusion, block repetitive firing and reduce post-tetanic potentiation

2. Post-synaptic action to enhance gaba-mediated inhibition and reduce excitatory synaptic transmission

3. Pre-synaptic actions to reduce calcium entry and block release of neurotransmitter.

5.2 Pharmacokinetic Properties

Phenytoin is absorbed from the small intestine after oral administration. Various formulation factors may affect the bioavailability of phenytoin, however, non-linear techniques have estimated absorption to be essentially complete. After absorption it is distributed into body fluid including CSF. Its volume of distribution has been estimated to be between 0.52 and 1.19 litres/kg, and it is highly protein bound (usually 90% in adults).

The plasma half-life of phenytoin in man averages 22 hours with a range of 7 to 42 hours. Steady state therapeutic drug levels are achieved at least 7 to 10 days after initiation of therapy.

Phenytoin is hydroxylated in the liver by an enzyme system which is saturable. Small incremental doses may produce very substantial increases in serum levels when these are in the upper range of therapeutic concentrations.

The parameters controlling elimination are also subject to wide interpatient variation. The serum level achieved by a given dose is therefore also subject to wide variation.

5.3 Preclinical Safety Data

Pre-clinical safety data do not add anything of further significance to the prescriber.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Core:

Lactose monohydrate

Magnesium stearate

Silica

Shell:

Gelatin

Patent blue V (E131)

Quinoline yellow (E104)

Titanium dioxide (E171)

Sodium laurilsulfate

Printing ink:

Shellac

Black iron oxide (E172)

Propylene glycol

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 25°C. Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

PVC/PVdC blister pack containing 28 capsules

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

PL 00057/0525

9. Date Of First Authorisation/Renewal Of The Authorisation

1st February 2004

10. Date Of Revision Of The Text

11 July 2010

Ref: EP 16_0 UK


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Novolog Mix 70/30



Dosage Form: injection, suspension
FULL PRESCRIBING INFORMATION Indications and Usage for Novolog Mix 70/30

Novolog Mix 70/30 is an insulin analog indicated to improve glycemic control in patients with diabetes mellitus.

 Important Limitations of Use:

 In premix insulins, such as Novolog Mix 70/30, the proportions of rapid acting and long acting insulins are fixed and do not allow for basal versus prandial dose adjustments.

Novolog Mix 70/30 Dosage and Administration Dosing

Novolog Mix 70/30 is an insulin analog with an earlier onset and intermediate duration of action in comparison to the basal human insulin premix. The addition of protamine to the rapid-acting aspart insulin analog (NovoLog) results in insulin activity that is 30% short-acting and 70% long-acting. Novolog Mix 70/30 is typically dosed on a twice-daily basis (with each dose intended to cover 2 meals or a meal and a snack). The dosage of Novolog Mix 70/30 must be individualized. The written prescription for Novolog Mix 70/30 should include the full name, to avoid confusion with NovoLog (insulin aspart) and Novolin 70/30 (human premix).

Novolog Mix 70/30 should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles. Novolog Mix 70/30 should not be used after the printed expiration date.

Novolog Mix 70/30 should be administered by subcutaneous injection in the abdominal region,  buttocks, thigh, or upper arm. Novolog Mix 70/30 has a faster onset of action than human insulin premix 70/30 and should be dosed within 15 minutes before meal initiation for patients with type 1 diabetes. For patients with type 2 diabetes, dosing should occur within 15 minutes before or after meal initiation. Injection sites should be rotated within the same region to reduce the risk of lipodystrophy. As with all insulins, the duration of action may vary according to the dose, injection site, blood flow, temperature, and level of physical activity.

Novolog Mix 70/30 should not be administered intravenously or used in insulin infusion pumps. Dose regimens of Novolog Mix 70/30 will vary among patients and should be determined by the health care professional familiar with the patient’s recommended glucose treatment goals, metabolic needs, eating habits, and other lifestyle variables.

Resuspension

Novolog Mix 70/30 is a suspension that must be visually inspected and resuspended immediately before use. The Novolog Mix 70/30 vial should be rolled gently in your hands in a horizontal position 10 times to mix it. The rolling procedure must be repeated until the suspension appears uniformly white and cloudy. Inject immediately. Resuspension is easier when the insulin has reached room temperature.

The Novolog Mix 70/30 FlexPen should be rolled 10 times gently between your hands in a horizontal position. Thereafter, turn the Novolog Mix 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other. Do this at least 10 times. The rolling and turning procedure must be repeated until the suspension appears uniformly white and cloudy. Inject immediately. Before each subsequent injection, turn the disposable Novolog Mix 70/30 FlexPen upside down so that the glass ball moves from one end of the reservoir to the other at least 10 times and until the suspension appears uniformly white and cloudy. Inject immediately.

Dosage Forms and Strengths

Novolog Mix 70/30 is available in the following package sizes: each presentation contains 100 units of insulin aspart per mL (U-100).

10 mL vials 3 mL Novolog Mix 70/30 FlexPen Contraindications

Novolog Mix 70/30 is contraindicated

during episodes of hypoglycemia in patients with hypersensitivity to NovoLog  Mix 70/30 or one of its excipients. Warnings and Precautions Administration

The short and long-acting components of insulin mixes, including Novolog Mix 70/30, cannot be titrated independently. Because Novolog Mix 70/30 has peak pharmacodynamic activity between 1-4 hours after injection, it should be administered within 15 minutes of meal initiation [see Clinical Pharmacology (12)]. The dose of insulin required to provide adequate glycemic control for one of the meals may result in hyper- or hypoglycemia for the other meal. The pharmacodynamic profile may also be inadequate for patients who require more frequent meals.

Novolog Mix 70/30 should not be mixed with any other insulin product.

Novolog Mix 70/30 should not be used intravenously.

Novolog Mix 70/30 should not be used in insulin infusion pumps.

Glucose monitoring is recommended for all patients with diabetes. Any change of insulin dose should be made cautiously and only under medical supervision. Changing from one insulin product to another or changing the insulin strength may result in the need for a change in dosage. Changes may also be necessary during illness, emotional stress, and other physiologic stress in addition to changes in meals and exercise.

The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site used for injection and the degree of vascularization of the site. Smoking, temperature, and exercise contribute to variations in blood flow and insulin absorption. These and other factors contribute to inter- and intra-patient variability.

Needles and Novolog Mix 70/30 FlexPen must not be shared.

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulin therapy, including Novolog Mix 70/30. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with Novolog Mix 70/30.

The timing of hypoglycemia may reflect the time-action profile of the insulin formulation [see Clinical Pharmacology (12)]. Other factors, such as changes in dietary intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions (7)]. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g. patients who are fasting or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating machinery.

Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control [see Drug Interactions (7)].

Hypokalemia

All insulin products, including Novolog Mix 70/30, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g. patients using potassium-lowering medications or patients taking medications sensitive to potassium concentrations).

Renal Impairment

Clinical or pharmacology studies with Novolog Mix 70/30 in diabetic patients with various degrees of renal impairment have not been conducted. As with other insulins, the requirements for Novolog Mix 70/30 may be reduced in patients with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment

Clinical or pharmacology studies with Novolog Mix 70/30 in diabetic patients with various degrees of hepatic impairment have not been conducted. As with other insulins, the requirements for Novolog Mix 70/30 may be reduced in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Hypersensitivity and Allergic Reactions

Local Reactions- As with other insulin therapy, patients may experience reactions such as erythema, edema or pruritus at the site of Novolog Mix 70/30 injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require  discontinuation of Novolog Mix 70/30. In some instances, these reactions may be related to the insulin molecule, other components in the insulin preparation including protamine and cresol, components in skin cleansing agents, or injection techniques. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.

Systemic Reactions- Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life threatening.

Antibody Production

Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in a 3-month, open-label comparator trial as well as in a long-term extension trial. Changes in cross-reactive antibodies were more common after Novolog Mix 70/30 than with Novolin 70/30 but these changes did not correlate with change in HbA1c or increase in insulin dose. The clinical significance of these antibodies has not been established. Antibodies did not increase further after long-term exposure (>6 months) to Novolog Mix 70/30.

Adverse Reactions

Clinical Trial Experience

Clinical trials are conducted under widely varying designs, therefore, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Novolog Mix 70/30 [see Warnings and Precautions (5.2)]. Novolog Mix 70/30 should not be used during episodes of hypoglycemia [see Contraindications (4)] and [Warnings and Precautions (5)].

Insulin initiation and glucose control intensification

Intensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Long-term use of insulin, including Novolog Mix 70/30, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy.

Weight gain

Weight gain can occur with some insulin therapies, including Novolog Mix 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Peripheral Edema

Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Frequencies of adverse drug reactions

The frequencies of adverse drug reactions during a clinical trial with Novolog Mix 70/30 in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. The trial was a three-month, open-label trial in patients with Type 1 or Type 2 diabetes who were treated twice daily (before breakfast and before supper) with Novolog Mix 70/30.

Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 diabetes mellitus (Adverse events with frequency ? 5% are included.)

Novolog Mix 70/30

(N=55)

Novolin 70/30

(N=49) Preferred Term N % N % Hypoglycemia 38 69 37 76 Headache 19 35 6 12 Influenza-like symptoms 7 13 1 2 Dyspepsia 5 9 3 6 Back pain 4 7 2 4 Diarrhea 4 7 3 6 Pharyngitis 4 7 1 2 Rhinitis 3 5 6 12 Skeletal pain 3 5 2 4 Upper respiratory tract infection 3 5 1 2 Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 diabetes mellitus (Adverse events with frequency ? 5% are included.)

Novolog Mix 70/30

(N=85)

Novolin 70/30

(N=102) Preferred Term N % N % Hypoglycemia 40 47 51 50 Upper respiratory tract infection 10 12 6 6 Headache 8 9 8 8 Diarrhea 7 8 2 2 Neuropathy 7 8 2 2 Pharyngitis 5 6 4 4 Abdominal pain 4 5 0 0 Rhinitis 4 5 2 2

Postmarketing Data

Additional adverse reactions have been identified during post-approval use of Novolog Mix 70/30. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency. They include medication errors in which other insulins have been accidentally substituted for Novolog Mix 70/30 [see Patient Counseling Information (17)].

Drug Interactions

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

The following are examples of substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide), sulfonamide antibiotics. The following are examples of substances that may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), atypical antipsychotics. Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic products such as beta-blockers, clonidine, guanethidine, and reserpine. USE IN SPECIFIC POPULATIONS Pregnancy

Pregnancy Category B.

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in such patients.

An open-label, randomized study compared the safety and efficacy of NovoLog (the rapid-acting component of Novolog Mix 70/30) versus human insulin in the treatment of pregnant women with Type 1 diabetes (322 exposed pregnancies (NovoLog: 157, human insulin: 165)). Two-thirds of the enrolled patients were already pregnant when they entered the study. Since only one-third of the patients enrolled before conception, the study was not large enough to evaluate the risk of congenital malformations. Mean HbA1c of ~ 6% was observed in both groups during pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.

Animal reproduction studies have not been conducted with Novolog Mix 70/30. However, subcutaneous reproduction and teratology studies have been performed with NovoLog (the rapid-acting component of Novolog Mix 70/30) and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog did not differ from those observed with subcutaneous regular human insulin.

NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32-times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface area.

Female patients should be advised to discuss with their physician if they intend to, or if they become pregnant. There are no adequate and well-controlled studies of the use of Novolog Mix 70/30 in pregnant women.

Nursing Mothers

It is unknown whether insulin aspart is excreted in human milk as occurs with human insulin. There are no adequate and well-controlled studies of the use of Novolog Mix 70/30 or NovoLog in lactating women. Women with diabetes who are lactating may require adjustments of their insulin doses. 

Pediatric Use

Safety and effectiveness of Novolog Mix 70/30 have not been established in pediatric patients.

Geriatric Use

Clinical studies of Novolog Mix 70/30 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population.

Overdosage

Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery.

Novolog Mix 70/30 Description

Novolog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection, [rDNA origin]) is a human insulin analog suspension containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. Novolog Mix 70/30 is a blood-glucose-lowering agent with an earlier onset and an intermediate duration of action. Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker’s yeast). Insulin aspart (NovoLog) has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.

Figure 1. Structural formula of insulin aspart

Novolog Mix 70/30 is a uniform, white, sterile suspension that contains insulin aspart 100 Units/mL.

Inactive ingredients are glycerol 16.0 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 ?g/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.877 mg/mL, and protamine sulfate 0.32 mg/mL. Novolog Mix 70/30 has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

Novolog Mix 70/30 - Clinical Pharmacology Mechanism of Action

The primary activity of Novolog Mix 70/30 is the regulation of glucose metabolism. Insulins, including Novolog Mix 70/30, bind to the insulin receptors on muscle, liver and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.

Pharmacodynamics

The two euglycemic clamp studies described below [see Clinical Pharmacology (12.3)] assessed glucose utilization after dosing of healthy volunteers. Novolog Mix 70/30 has an earlier onset of action than human premix 70/30 in studies of normal volunteers and patients with diabetes. The onset of action is between 10-20 minutes for Novolog Mix 70/30 compared to 30 minutes for Novolin 70/30. The mean ± SD time to peak activity for Novolog Mix 70/30 is 2.4 hr ± 0.8 hr compared to 4.2 hr ± 0.4 hr for Novolin 70/30. The duration of action may be as long as 24 hours (see Figure 2).

Figure 2. Pharmacodynamic Activity Profile of Novolog Mix 70/30 and Novolin 70/30 in healthy subjects.

Pharmacokinetics

The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NovoLog) reduces the molecule’s tendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of NovoLog are maintained by Novolog Mix 70/30. The insulin aspart in the soluble component of Novolog Mix 70/30 is absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining 70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection.

Bioavailability and Absorption- The relative bioavailability of Novolog Mix 70/30 compared to NovoLog and Novolin 70/30 indicates that the insulins are absorbed to similar extent. In euglycemic clamp studies in healthy volunteers (n=23) after dosing with Novolog Mix 70/30 (0.2 U/kg), a mean maximum serum concentration (Cmax) of 23.4 ± 5.3 mU/L was reached after 60 minutes. The mean half-life (t1/2) of Novolog Mix 70/30 was about 8 to 9 hours. Serum insulin levels returned to baseline 15 to 18 hours after a subcutaneous dose of Novolog Mix 70/30. Similar data were seen in a separate euglycemic clamp study in healthy volunteers (n=24) after dosing with Novolog Mix 70/30 (0.3 U/kg). A Cmax of 61.3 ± 20.1 mU/L was reached after 85 minutes. Serum insulin levels returned to baseline 12 hours after a subcutaneous dose.

The Cmax and the area under the insulin concentration-time curve (AUC) after administration of Novolog Mix 70/30 was approximately 20% greater than those after administration of Novolin 70/30, (see Fig. 3 for pharmacokinetic profiles).

Figure 3. Pharmacokinetic Profiles of NovoLog  Mix 70/30 and Novolin 70/30

Distribution and Elimination- NovoLog has a low binding to plasma proteins, 0 to 9%, similar to regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.

The effect of sex, age, obesity, ethnic origin, renal and hepatic impairment, pregnancy, or smoking, on the pharmacodynamics and pharmacokinetics of Novolog Mix 70/30 has not been studied.

Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of Novolog Mix 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog, the rapid-acting component of Novolog Mix 70/30, at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors found with NovoLog was not significantly different from that found with regular human insulin. The relevance of these findings to humans is not known.

NovoLog was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.

In fertility studies in male and female rats, NovoLog at subcutaneous doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on U/body surface area) had no direct adverse effects on male and female fertility, or on general reproductive performance of animals.

Animal Toxicology and/or Pharmacology

In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-lowering effect as one unit of regular human insulin. However, the effect of Novolog Mix 70/30 is more rapid in onset compared to Novolin (human insulin) 70/30 due to its faster absorption after subcutaneous injection.

Clinical Studies Novolog Mix 70/30 versus Novolin 70/30

In a three-month, open-label trial, patients with Type 1 (n=104) or Type 2 (n=187) diabetes were treated twice daily (before breakfast and before supper) with Novolog Mix 70/30 or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral hypoglycemic agents were not allowed within 1 month prior to the study or during the study. The small changes in HbA1c were comparable across the treatment groups (see Table 3).

Table 3: Glycemic Parameters at the End of Treatment [Mean ± SD (N subjects)] Novolog Mix 70/30 Novolin 70/30 Type 1, N=104 Fasting Blood Glucose (mg/dL) 174 ± 64 (48) 142 ± 59 (44) 1.5 Hour Post Breakfast (mg/dL) 187 ± 82 (48) 200 ± 82 (42) 1.5 Hour Post Dinner (mg/dL) 162 ± 77 (47) 171 ± 66 (41) HbA1c (%) Baseline 8.4 ± 1.2 (51) 8.5 ± 1.1 (46) HbA1c (%) Week 12 8.4 ± 1.1 (51) 8.3 ± 1.0 (47) Type 2, N=187 Fasting Blood Glucose (mg/dL) 153 ± 40 (76) 152 ± 69 (93) 1.5 Hour Post Breakfast (mg/dL) 182 ± 65 (75) 200 ± 80 (92) 1.5 Hour Post Dinner (mg/dL) 168 ± 51 (75) 191 ± 65 (93) HbA1c (%) Baseline 8.1 ± 1.2 (82) 8.2 ± 1.3 (98) HbA1c (%) Week 12 7.9 ± 1.0 (81) 8.1 ± 1.1 (96)

The significance, with respect to the long-term clinical sequelae of diabetes, of the differences in postprandial hyperglycemia between treatment groups has not been established.

Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial.

Combination Therapy: Insulin and Oral Agents in Patients with Type 2 Diabetes

Trial 1:

In a 34-week, open-label trial, insulin-na?ve patients with type 2 diabetes currently treated with 2 oral antidiabetic agents were switched to treatment with metformin and pioglitazone. During an 8-week optimization period metformin and pioglitazone were increased to 2500 mg per day and 30 or 45 mg per day, respectively. After the optimization period, subjects were randomized to receive either Novolog Mix 70/30 twice daily added on to the metformin and pioglitazone regimen or continue the current optimized metformin and pioglitazone therapy. Novolog Mix 70/30 was started at a dose of 6 IU twice daily (before breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110 mg/dL. The total daily insulin dose at the end of the study was 56.9 ± 30.5 IU.

Table 4: Combination Therapy with Oral Agents and Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)] Treatment duration 24-weeks

Novolog Mix 70/30 + Metformin

+ Pioglitazone Metformin + Pioglitazone HbA1c Baseline mean ± SD (n) 8.1 ± 1.0 (102) 8.1 ± 1.0 (98) End-of-study mean ± SD (n) - LOCF 6.6 ± 1.0 (93) 7.8 ± 1.2 (87) Adjusted Mean change from baseline ± SE (n)* -1.6 ± 0.1 (93) -0.3 ± 0.1 (87) Treatment difference mean ± SE* 95% CI*

-1.3 ± 0.1

(-1.6, -1.0)

Percentage of subjects reaching HbA1c <7.0% 76% 24% Percentage of subjects reaching HbA1c ?6.5% 59% 12% Fasting Blood Glucose (mg/dL) Baseline Mean ± SD (n) 173 ± 39.8 (93) 163 ± 35.4 (88) End of Study Mean ± SD (n) - LOCF 130 ± 50.0 (90) 162 ± 40.8 (84) Adjusted Mean change from baseline ± SE (n)* -43.0 ± 5.3 (90) -3.9 ± 5.3 (84) End-of-Study Blood Glucose (Plasma) (mg/dL) 2 Hour Post Breakfast 138 ± 42.8 (86) 188 ± 57.7 (74) 2 Hour Post Lunch 150 ± 41.5 (86) 176 ± 56.5 (74) 2 Hour Post Dinner 141 ± 57.8 (86) 195 ± 60.1 (74) % of patients with severe hypoglycemia** 3 0 % of patients with minor hypoglycemia** 52 3 Weight gain at end of study (kg)** 4.6 ± 4.3 (92) 0.8 ± 3.2 (86)

 *Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.

**If metabolic control is improved by intensified insulin therapy, an increased risk of hypoglycemia and weight gain may occur.

 

Trial 2:

In a 28-week, open-label trial, insulin-na?ve patients with type 2 diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin ± thiazolidinedione therapy were randomized to receive either Novolog Mix 70/30 twice daily [before breakfast and before supper] or insulin glargine once daily1 (see Table 5). Novolog Mix 70/30 was started at an average dose of 5-6 IU (0.07 ± 0.03 IU/kg) twice daily (before breakfast and before supper), and bedtime insulin glargine was started at 10-12 IU (0.13 ± 0.03 IU/kg). Insulin doses were titrated weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of 80-110 mg/dL. The metformin dose was adjusted to 2550 mg/day. Approximately one-third of the patients in each group were also treated with pioglitazone (30 mg/day). Insulin secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients were Caucasian (53%), and the mean initial weight was 90 kg.

Table 5: Combination Therapy with Oral Agents and Two Types of Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)] Treatment duration 28-weeks NovoLog  Mix 70/30 + Metformin ± Pioglitazone Insulin Glargine + Metformin ± Pioglitazone Number of patients 117 116 HbA1c Baseline mean (%) 9.7 ± 1.5 (117) 9.8 ± 1.4 (114) End-of-study mean (± SD) 6.9 ± 1.2 (108) 7.4 ± 1.2 (114) Mean change from baseline -2.7 ± 1.6 (108) -2.4 ± 1.5 (114) Percentage of subjects reaching HbA1c <7.0% 66% 40% Total Daily Insulin Dose at end of study (U) 78 ± 40 (117) 51 ± 27 (116) % of patients with severe hypoglycemia 0 0
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ZAMADOL 24hr 150 (200 / 300 / 400)mg TABLETS


1. Name Of The Medicinal Product

ZAMADOL 24hr 150 (200/300/400) mg prolonged release tablets.

2. Qualitative And Quantitative Composition

Each tablet contains 150 (200/300/400) mg of tramadol hydrochloride

Excipient: Each prolonged-release tablet contains 0.60 (1.00/1.40/1.80) mg lactose monohydrate (see section 4.4).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged release tablet

White film coated tablets marked T 150 (200/300/400)

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of moderate to severe pain.

4.2 Posology And Method Of Administration

ZAMADOL 24hr tablets should be taken at 24-hourly intervals and must be swallowed whole and not chewed.

As with all analgesic drugs, the dose of tramadol should be adjusted according to the severity of the pain and the clinical response of the individual patient. The correct dosage for any individual patient is that which controls the pain with no or tolerable side effects for a full 24 hours. Patients transferring from immediate release tramadol preparations should have their total daily dose calculated, and start on the nearest dose in the ZAMADOL 24hr range. It is recommended that patients are slowly titrated to higher doses to minimise transient side effects. The need for continued treatment should be assessed at regular intervals as withdrawal symptoms and dependence have been reported. (See Section 4.4 Special Warnings and Precautions for Use).A total daily dose of 400 mg should not be exceeded except in special clinical circumstances.

Adults and children over 12 years: The usual initial dose is one 150 mg tablet daily. If pain relief is not achieved, the dosage should be titrated upwards until pain relief is achieved.

Elderly patients: Dosing as for adults. The elimination half-life of tramadol may be prolonged in patients over 75 years . A starting dose of 150 mg daily is recommended. Dose titration upwards should be carefully monitored.

Patients with renal or hepatic insufficiency: The elimination half-life of tramadol may be prolonged in these patient populations. A starting dose of 150 mg daily is recommended. Dose titration upwards should be carefully monitored. Tramadol is not recommended for patients with severe renal impairment and/or severe hepatic impairment.

As tramadol is only removed very slowly by haemodialysis or by haemofiltration, post-dialysis administration to maintain analgesia is not usually necessary.

Children under 12 years: ZAMADOL 24hr has not been studied in children. Safety and efficacy of ZAMADOL 24hr have not been established and the product should not be used in children.

4.3 Contraindications

Hypersensitivity to tramadol or to any of the excipients; acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. Tramadol should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal.

Tramadol must not be used for narcotic withdrawal treatment.

4.4 Special Warnings And Precautions For Use

Warnings

At therapeutic doses withdrawal symptoms have been reported at a frequency of 1 in 8,000. Reports of dependence and abuse have been less frequent. Because of this potential the clinical need for continued analgesic treatment should be reviewed regularly.

In patients with a tendency to drug abuse or dependence, treatment should be for short periods and under strict medical supervision.

Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

Precautions

Convulsions have been reported at therapeutic doses and the risk may be increased at doses exceeding the usual upper daily dose limit. Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling reasons. The risk of convulsions may increase in patients taking tramadol and concomitant medication that can lower the seizure threshold. (See Section 4.5 Interactions with other Medicaments and other forms of Interaction).

Tramadol should be used with caution in patients with head injury, increased intracranial pressure, severe impairment of hepatic and renal function and in patients prone to convulsive disorders or in shock.

Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant drugs are being administered, as the possibility of respiratory depression cannot be excluded in these situations. At therapeutic doses respiratory depression has infrequently been reported.

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of tramadol with other centrally acting drugs, including alcohol, may potentiate CNS depressant effects.

Simultaneous treatment with carbamazepine may shorten the analgesic effect as a result of a reduction in serum levels of tramadol and its active metabolite.

Co-administration with cimetidine is associated with a small prolongation of the half-life of tramadol, but this is not clinically relevant.

Tramadol can induce convulsions and increase the potential for selective serotonin re-uptake inhibitors (SSRIs), tricyclic anti-depressants (TCAs), anti-psychotics and other seizure threshold lowering drugs to cause convulsions (see Section 4.4 Special Warnings and Special Precautions for Use and 5.2 Pharmacokinetic Properties). Co-administration with SSRIs may lead to an increase of 5HT associated effects.

Co-administered ritonavir may increase serum concentration of tramadol resulting in tramadol toxicity.

Digoxin toxicity has occurred rarely during co-administration of digoxin and tramadol.

MAO inhibitors: A serotoninergic syndrome is likely to occur: diarrhoea, tachycardia, sweating, tremor, confusion, coma. In case of recent treatment with MAOIs, treatment with tramadol should not be started until 15 days after cessation of treatment with MAOIs.

Other morphine derivatives (including anti-tussives, substitution treatments), benzodiazepines, barbiturates: Increased risk of respiratory depression, that may be fatal in overdosage.

Mixed agonists/antagonists (eg buprenorphine, nalbuphine, pentazocine): The analgesic effect of tramadol which is a pure agonist may be reduced, and a withdrawal syndrome may occur.

There have been isolated reports of interaction with coumarin anticoagulants resulting in an increased INR and so care should be taken when commencing treatment with tramadol in patients on anticoagulants.

The analgesic effect of tramadol is in part mediated by inhibition of the re-uptake of norepinephrine and enhancement of the release of serotonin (5-HT). In studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirements of tramadol in patients with postoperative pain.

4.6 Pregnancy And Lactation

There are no adequate data from the use of tramadol in pregnant women. Animal studies have shown reproductive toxicity, but not teratogenic effects (see section 5.3). Tramadol crosses the placental barrier and chronic use during pregnancy can cause withdrawal symptoms in the new-born baby. Therefore, it should not be used during pregnancy.

Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in respiratory rate which are not usually clinically relevant.

During lactation very small amounts of tramadol and its metabolites (approximately 0.1% of an intravenous dose) are found in human breast milk. Therefore tramadol should not be administered during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Tramadol may cause drowsiness, blurred vision and dizziness which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.

4.8 Undesirable Effects

The following frequency categories form the basis for classification of the undesirable effects:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000) not known (cannot be estimated from the available data)

 

Very Common

Common

Uncommon

Rare

Very Rare

Immune system disorders

 

 

 

 

 

 

Hypersensitivity

Anaphylactic reaction

 

 

Psychiatric disorders

 

 

 

 

 

 

Hallucinations

Nightmare

Mood altered

Elevated mood

Dysphoria

Decreased activity

Illusion

Agitation

Anxiety

Nervousness

Insomnia

Nervous system disorders

Dizziness

 

 

Headache

Paraesthesia

Increased activity

Cognitive disorder

Sensory disturbance

Judgement impaired

Convulsion

Hyperkinesia

Tremor

Eye disorders

 

 

 

 

 

 

Blurred vision

 

 

Cardiac disorders

 

 

 

 

Palpitations

Tachycardia

Bradycardia

 

 

Vascular disorders

 

 

 

 

Orthostatic hypotension

Circulatory collapse

Hypertension

Flushing

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

Dyspnoea

Asthma

Respiratory depression

Bronchospasm

Wheezing

 

 

Gastro-intestinal disorders

Nausea

Vomiting

Dry mouth

Retching

Constipat-ion

Abdominal discomfort

Anorexia

Diarrhoea

Gastro-intestinal disorder

Hepatobiliary disorders

 

 

 

 

 

 

 

 

Hepatic enzyme increased

Skin and subcutaneous tissue disorders

 

 

Hyperhidrosis

Pruritus

Rash

Urticaria

Angioedema

 

 

Renal and urinary disorders

 

 

 

 

 

 

Micturition disorder

Dysuria

Urinary retention

 

 

Musculoskeletal and connective tissue disorders

 

 

 

 

 

 

Muscular weakness

 

 

General disorders and administration site conditions Investigations

 

 

 

 

 

 

 

 

Drug withdrawal syndrome

4.9 Overdose

Symptoms of overdosage are typical of other opioid analgesics, and include miosis, vomiting, cardiovascular collapse, sedation and coma, seizures and respiratory depression. In severe cases tramadol overdose may result in a fatal outcome.

Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam.

Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with tramadol with haemodialysis or haemofiltration alone is not suitable for detoxification.

Emptying the gastric contents is useful to remove any unabsorbed drug, particularly when a modified release formulation has been taken.

5. Pharmacological Properties

Pharmacotherapeutic group: N02A X02

5.1 Pharmacodynamic Properties

Tramadol is a centrally acting analgesic (N02A X02). It is a non selective pure agonist at mu, delta and kappa opioid receptors with a higher affinity for the mu receptor. Other mechanisms that may contribute to its analgesic effect are inhibition of neuronal re-uptake of noradrenaline and 5HT.

5.2 Pharmacokinetic Properties

Following oral administration of a single dose, tramadol is almost completely absorbed and the absolute bioavailability is approximately 70%. Tramadol is metabolised to O

Following administration of one ZAMADOL 24hr tablet 200 mg in the fasting state, a mean peak plasma concentration (Cmax) of 192 ng.ml-1 was attained. This was associated with a median tmax of 6 hours (range 4-8 hours). The availability of tramadol from the ZAMADOL 24hr tablet 200 mg was complete when compared with an immediate release tramadol solution 100 mg, after dose adjustment. In the presence of food, the availability and controlled release properties of ZAMADOL 24hr tablets were maintained, with no evidence of dose-dumping.

A single dose-proportionality study has confirmed a linear pharmacokinetic response (in relation to tramadol and O-desmethyltramadol) following administration of the 200 mg, 300 mg and 400 mg tablets. A steady state study has confirmed the dose adjusted bioequivalence of the 150 mg and 200 mg tablets administered once-daily. This study also confirmed that the ZAMADOL 24hr tablet 150 mg provided an equivalent peak concentration and extent of availability of tramadol to an immediate release capsule 50 mg administered 8-hourly. On this basis it is recommended that patients receiving immediate release tramadol should be transferred initially to the nearest daily dose of ZAMADOL 24hr tablets. It may be necessary to titrate the dose thereafter.

A further steady state study has demonstrated that immediate release tramadol tablets 50 mg, administered 6-hourly, provided plasma concentrations that were greater than would have been anticipated following administration of a single dose. This observation is consistent with a non-linear elimination of the drug substance. In contrast, the plasma concentrations from ZAMADOL 24hr tablet 200 mg administered once-daily were in line with single dose data, confirming that the controlled delivery of tramadol from ZAMADOL 24hr minimises the non-linearity associated with faster-releasing preparations. The more predictable plasma concentrations may lead to a more manageable dose titration process.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential.

Studies in rats and rabbits have revealed no teratogenic effects. However, embryotoxicity was shown in the form of delayed ossification. Fertility, reproductive performance and development of offspring were unaffected.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Tablet core

Hydrogenated vegetable oil

Talc

Magnesium stearate

Film coat

Lactose Monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 4000

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30oC.

6.5 Nature And Contents Of Container

1) PVC blisters with aluminium backing foil (containing 2, 7, 10, 14, 15, 20, 28, 30, 50,56, 60 or 100 tablets).

2) Polypropylene containers with polyethylene lids (containing 2, 7, 10, 14, 15, 20, 28, 30, 50,56, 60 or 100 tablets).

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

UK

8. Marketing Authorisation Number(S)

PL 16950/0084 (85/86/87)

9. Date Of First Authorisation/Renewal Of The Authorisation

7 November 2001/19 June 2006

10. Date Of Revision Of The Text

August 2009


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Catapres-TTS


clonidine
Dosage Form: patch, extended release
Catapres-TTS® -1
Catapres-TTS® -2
Catapres-TTS® -3

Transdermal Therapeutic System
Programmed delivery in vivo of 0.1, 0.2, or 0.3 mg clonidine per day, for one week.

Prescribing Information

Catapres-TTS Description

Catapres-TTS is a transdermal system providing continuous systemic delivery of clonidine for 7 days at an approximately constant rate. Clonidine is a centrally acting alpha-agonist hypotensive agent. It is an imidazoline derivative with the chemical name 2, 6-dichloro-N-2-imidazolidinylidenebenzenamine and has the following chemical structure:

CATAPRES

System Structure and Components

Catapres-TTS transdermal therapeutic system is a multi-layered film, 0.2 mm thick, containing clonidine as the active agent. The system areas are 3.5 cm2 (Catapres-TTS-1), 7.0 cm2 (Catapres-TTS-2) and 10.5 cm2 (Catapres-TTS-3) and the amount of drug released is directly proportional to the area (see Release Rate Concept). The composition per unit area is the same for all three doses.

Proceeding from the visible surface towards the surface attached to the skin, there are four consecutive layers: 1) a backing layer of pigmented polyester and aluminum film; 2) a drug reservoir of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide; 3) a microporous polypropylene membrane that controls the rate of delivery of clonidine from the system to the skin surface; 4) an adhesive formulation of clonidine, mineral oil, polyisobutylene, and colloidal silicon dioxide. Prior to use, a protective slit release liner of polyester that covers the adhesive layer is removed.

Cross Section of the System:

Release Rate Concept

Catapres-TTS® (clonidine) transdermal therapeutic system is programmed to release clonidine at an approximately constant rate for 7 days. The energy for drug release is derived from the concentration gradient existing between a saturated solution of drug in the system and the much lower concentration prevailing in the skin. Clonidine flows in the direction of the lower concentration at a constant rate, limited by the rate-controlling membrane, so long as a saturated solution is maintained in the drug reservoir.

Following system application to intact skin, clonidine in the adhesive layer saturates the skin site below the system. Clonidine from the drug reservoir then begins to flow through the rate-controlling membrane and the adhesive layer of the system into the systemic circulation via the capillaries beneath the skin. Therapeutic plasma clonidine levels are achieved 2 to 3 days after initial application of Catapres-TTS transdermal therapeutic system.

The 3.5, 7.0, and 10.5 cm2 systems deliver 0.1, 0.2, and 0.3 mg of clonidine per day, respectively. To ensure constant release of drug for 7 days, the total drug content of the system is higher than the total amount of drug delivered. Application of a new system to a fresh skin site at weekly intervals continuously maintains therapeutic plasma concentrations of clonidine. If the Catapres-TTS transdermal therapeutic system is removed and not replaced with a new system, therapeutic plasma clonidine levels will persist for about 8 hours and then decline slowly over several days. Over this time period, blood pressure returns gradually to pretreatment levels.

Catapres-TTS - Clinical Pharmacology

Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent.

Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% - 20%) of cardiac output in the supine position with no change in the peripheral resistance; at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance.

During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic responses to exercise.

Tolerance to the antihypertensive effect may develop in some patients, necessitating a reevaluation of therapy.

Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated.

Clonidine acutely stimulates the release of growth hormone in children as well as adults but does not produce a chronic elevation of growth hormone with long-term use.

Pharmacokinetics

The plasma half-life of clonidine is 12.7 ± 7 hours. Following oral administration, about 40-60% of the absorbed dose is recovered in the urine as unchanged drug within 24 hours. The remainder of the absorbed dose is metabolized in the liver.

Indications and Usage for Catapres-TTS

Catapres-TTS® (clonidine) transdermal therapeutic system is indicated in the treatment of hypertension. It may be employed alone or concomitantly with other antihypertensive agents.

Contraindications

Catapres-TTS transdermal therapeutic system should not be used in patients with known hypersensitivity to clonidine or to any other component of the therapeutic system.

Warnings Withdrawal

Patients should be instructed not to discontinue therapy without consulting their physician. Sudden cessation of clonidine treatment has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and confusion accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. The likelihood of such reactions to discontinuation of clonidine therapy appears to be greater after administration of higher doses or continuation of concomitant beta-blocker treatment and special caution is therefore advised in these situations. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal. When discontinuing therapy with CATAPRES, the physician should reduce the dose gradually over 2 to 4 days to avoid withdrawal symptomatology.

An excessive rise in blood pressure following discontinuation of Catapres-TTS transdermal therapeutic system therapy can be reversed by administration of oral clonidine hydrochloride or by intravenous phentolamine. If therapy is to be discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blocker should be withdrawn several days before the gradual discontinuation of Catapres-TTS transdermal therapeutic system.

Precautions General

In patients who have developed localized contact sensitization to Catapres-TTS transdermal therapeutic system continuation of Catapres-TTS transdermal therapeutic system or substitution of oral clonidine hydrochloride therapy may be associated with development of a generalized skin rash.

In patients who develop an allergic reaction to Catapres-TTS transdermal therapeutic system, substitution of oral clonidine hydrochloride may also elicit an allergic reaction (including generalized rash, urticaria, or angioedema).

Catapres-TTS transdermal therapeutic system should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease, or chronic renal failure.

In rare instances, loss of blood pressure control has been reported in patients using Catapres-TTS transdermal therapeutic system according to the instructions for use.

Perioperative Use

Catapres-TTS transdermal therapeutic system therapy should not be interrupted during the surgical period. Blood pressure should be carefully monitored during surgery and additional measures to control blood pressure should be available if required. Physicians considering starting Catapres-TTS transdermal therapeutic system therapy during the perioperative period must be aware that therapeutic plasma clonidine levels are not achieved until 2 to 3 days after initial application of Catapres-TTS® (clonidine) transdermal therapeutic system (see DOSAGE AND ADMINISTRATION).

Defibrillation or Cardioversion

The transdermal clonidine systems should be removed before attempting defibrillation or cardioversion because of the potential for altered electrical conductivity which may increase the risk of arcing, a phenomenon associated with the use of defibrillators.

MRI

Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the Catapres-TTS PATCH contains aluminum, it is recommended to remove the system before undergoing an MRI.

Information for Patients

Patients should be cautioned against interruption of Catapres-TTS transdermal therapeutic system therapy without their physician’s advice.

Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of a possible sedative effect of clonidine. They should also be informed that this sedative effect may be increased by concomitant use of alcohol, barbiturates, or other sedating drugs.

Patients who wear contact lenses should be cautioned that treatment with Catapres-TTS transdermal therapeutic system may cause dryness of eyes.

Patients should be instructed to consult their physicians promptly about the possible need to remove the patch if they observe moderate to severe localized erythema and/or vesicle formation at the site of application or generalized skin rash.

If a patient experiences isolated, mild localized skin irritation before completing 7 days of use, the system may be removed and replaced with a new system applied to a fresh skin site.

If the system should begin to loosen from the skin after application, the patient should be instructed to place the adhesive cover directly over the system to ensure adhesion during its 7-day use.

Used Catapres-TTS PATCHES contain a substantial amount of their initial drug content which may be harmful to infants and children if accidentally applied or ingested. THEREFORE, PATIENTS SHOULD BE CAUTIONED TO KEEP BOTH USED AND UNUSED Catapres-TTS PATCHES OUT OF THE REACH OF CHILDREN. After use, Catapres-TTS should be folded in half with the adhesive sides together and discarded away from children’s reach.

Instructions for use, storage and disposal of the system are provided at the end of this monograph. These instructions are also included in each box of Catapres-TTS transdermal therapeutic system.

Drug Interactions

Clonidine may potentiate the CNS-depressive effects of alcohol, barbiturates or other sedating drugs. If a patient receiving clonidine is also taking tricyclic antidepressants, the hypotensive effect of clonidine may be reduced, necessitating an increase in the clonidine dose.

Monitor heart rate in patients receiving clonidine concomitantly with agents known to affect sinus node function or AV nodal conduction e.g., digitalis, calcium channel blockers, and beta-blockers. Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concomitantly with diltiazem or verapamil.

Amitriptyline in combination with clonidine enhances the manifestation of corneal lesions in rats (see Toxicology).

Toxicology

In several studies with oral clonidine hydrochloride, a dose-dependent increase in the incidence and severity of spontaneous retinal degeneration was seen in albino rats treated for six months or longer. Tissue distribution studies in dogs and monkeys showed a concentration of clonidine in the choroid.

In view of the retinal degeneration seen in rats, eye examinations were performed during clinical trials in 908 patients before, and periodically after, the start of clonidine therapy. In 353 of these 908 patients, the eye examinations were carried out over periods of 24 months or longer. Except for some dryness of the eyes, no drug-related abnormal ophthalmological findings were recorded and, according to specialized tests such as electroretinography and macular dazzle, retinal function was unchanged.

In combination with amitriptyline, clonidine hydrochloride administration led to the development of corneal lesions in rats within 5 days.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Chronic dietary administration of clonidine was not carcinogenic to rats (132 weeks) or mice (78 weeks) dosed, respectively, at up to 46 to 70 times the maximum recommended daily human dose as mg/kg (9 or 6 times the MRDHD on a mg/m2 basis). There was no evidence of genotoxicity in the Ames test for mutagenicity or mouse micronucleus test for clastogenicity.

Fertility of male and female rats was unaffected by clonidine doses as high as 150 mcg/kg (approximately 3 times the MRDHD). In a separate experiment, fertility of female rats appeared to be affected at dose levels of 500 to 2000 mcg/kg (10 to 40 times the oral MRDHD on a mg/kg basis; 2 to 8 times the MRDHD on a mg/m2 basis).

Pregnancy

Teratogenic Effects: Pregnancy Category C.

Reproduction studies performed in rabbits at doses up to approximately 3 times the oral maximum recommended daily human dose (MRDHD) of CATAPRES® (clonidine hydrochloride) produced no evidence of a teratogenic or embryotoxic potential in rabbits. In rats, however, doses as low as 1/3 the oral MRDHD (1/15 the MRDHD on a mg/m2 basis) of clonidine were associated with increased resorptions in a study in which dams were treated continuously from 2 months prior to mating. Increased resorptions were not associated with treatment at the same or at higher dose levels (up to 3 times the oral MRDHD) when the dams were treated on gestation days 6–15. Increases in resorption were observed at much higher dose levels (40 times the oral MRDHD on a mg/kg basis; 4 to 8 times the MRDHD on a mg/m2 basis) in mice and rats treated on gestation days 1–14 (lowest dose employed in the study was 500 mcg/kg).

No adequate well-controlled studies have been conducted 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.

Nursing Mothers

As clonidine is excreted in human milk, caution should be exercised when Catapres-TTS® (clonidine) transdermal therapeutic system is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established in adequate and well-controlled trials (see WARNINGS, Withdrawal).

Adverse Reactions Clinical trial experience with Catapres-TTS

Most systemic adverse effects during Catapres-TTS® (clonidine) transdermal therapeutic system therapy have been mild and have tended to diminish with continued therapy. In a 3-month multi-clinic trial of Catapres-TTS transdermal therapeutic system in 101 hypertensive patients, the systemic adverse reactions were, dry mouth (25 patients) and drowsiness (12), fatigue (6), headache (5), lethargy and sedation (3 each), insomnia, dizziness, impotence/sexual dysfunction, dry throat (2 each) and constipation, nausea, change in taste and nervousness (1 each).

In the above mentioned 3-month controlled clinical trial, as well as other uncontrolled clinical trials, the most frequent adverse reactions were dermatological and are described below.

In the 3-month trial, 51 of the 101 patients had localized skin reactions such as erythema (26 patients) and/or pruritus, particularly after using an adhesive cover throughout the 7-day dosage interval. Allergic contact sensitization to Catapres-TTS transdermal therapeutic system was observed in 5 patients. Other skin reactions were localized vesiculation (7 patients), hyperpigmentation (5), edema (3), excoriation (3), burning (3), papules (1), throbbing (1), blanching (1), and a generalized macular rash (1).

In additional clinical experience, contact dermatitis resulting in treatment discontinuation was observed in 128 of 673 patients (about 19 in 100) after a mean duration of treatment of 37 weeks. The incidence of contact dermatitis was about 34 in 100 among white women, about 18 in 100 in white men, about 14 in 100 in black women, and approximately 8 in 100 in black men. Analysis of skin reaction data showed that the risk of having to discontinue Catapres-TTS transdermal therapeutic system treatment because of contact dermatitis was greatest between treatment weeks 6 and 26, although sensitivity may develop either earlier or later in treatment.

In a large-scale clinical acceptability and safety study by 451 physicians in a total of 3539 patients, other allergic reactions were recorded for which a causal relationship to Catapres-TTS transdermal therapeutic system was not established: maculopapular rash (10 cases); urticaria (2 cases); and angioedema of the face (2 cases), which also affected the tongue in one of the patients.

Marketing Experience with Catapres-TTS

The following adverse reactions have been identified during post-approval use of Catapres-TTS transdermal therapeutic system. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Catapres-TTS transdermal therapeutic system.

Body as a Whole: Fever; malaise; weakness; pallor; and withdrawal syndrome.

Cardiovascular: Congestive heart failure; cerebrovascular accident; electrocardiographic abnormalities (i.e., bradycardia, sick sinus syndrome disturbances and arrhythmias); chest pain; orthostatic symptoms; syncope; increases in blood pressure; sinus bradycardia and atrioventricular (AV) block with and without the use of concomitant digitalis; Raynaud’s phenomenon; tachycardia; bradycardia; and palpitations.

Central and Peripheral Nervous System/Psychiatric: Delirium; mental depression; hallucinations (including visual and auditory); localized numbness; vivid dreams or nightmares; restlessness; anxiety; agitation; irritability; other behavioral changes; and drowsiness.

Dermatological: Angioneurotic edema; localized or generalized rash; hives; urticaria; contact dermatitis; pruritus; alopecia; and localized hypo or hyper pigmentation.

Gastrointestinal: Anorexia and vomiting.

Genitourinary: Difficult micturition; loss of libido; and decreased sexual activity.

Metabolic: Gynecomastia or breast enlargement and weight gain.

Musculoskeletal: Muscle or joint pain; and leg cramps.

Ophthalmological: Blurred vision; burning of the eyes and dryness of the eyes.

Adverse Events Associated with Oral CATAPRES Therapy: Most adverse effects are mild and tend to diminish with continued therapy. The most frequent (which appear to be dose-related) are dry mouth, occurring in about 40 of 100 patients; drowsiness, about 33 in 100; dizziness, about 16 in 100; constipation and sedation, each about 10 in 100. The following less frequent adverse experiences have also been reported in patients receiving CATAPRES (clonidine hydrochloride, USP) tablets, but in many cases patients were receiving concomitant medication and a causal relationship has not been established.

Body as a Whole: Fatigue, fever, headache, pallor, weakness, and withdrawal syndrome. Also reported were a weakly positive Coombs’ test and increased sensitivity to alcohol.

Cardiovascular: Bradycardia, congestive heart failure, electrocardiographic abnormalities (i.e., sinus node arrest, junctional bradycardia, high degree AV block and arrhythmias), orthostatic symptoms, palpitations, Raynaud’s phenomenon, syncope, and tachycardia. Cases of sinus bradycardia and AV block have been reported, both with and without the use of concomitant digitalis.

Central Nervous System: Agitation, anxiety, delirium, delusional perception, hallucinations (including visual and auditory), insomnia, mental depression, nervousness, other behavioral changes, paresthesia, restlessness, sleep disorder, and vivid dreams or nightmares.

Dermatological: Alopecia, angioneurotic edema, hives, pruritus, rash, and urticaria.

Gastrointestinal: Abdominal pain, anorexia, constipation, hepatitis, malaise, mild transient abnormalities in liver function tests, nausea, parotitis, pseudo-obstruction (including colonic pseudo-obstruction), salivary gland pain, and vomiting.

Genitourinary: Decreased sexual activity, difficulty in micturition, erectile dysfunction, loss of libido, nocturia, and urinary retention.

Hematologic: Thrombocytopenia.

Metabolic: Gynecomastia, transient elevation of blood glucose or serum creatine phosphokinase, and weight gain.

Musculoskeletal: Leg cramps and muscle or joint pain.

Oro-otolaryngeal: Dryness of the nasal mucosa.

Ophthalmological: Accommodation disorder, blurred vision, burning of the eyes, decreased lacrimation, and dryness of the eyes.

Overdosage

Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reflexes, weakness, irritability and miosis. The frequency of CNS depression may be higher in children than adults. Large overdoses may result in reversible cardiac conduction defects or dysrhythmias, apnea, coma and seizures. Signs and symptoms of overdose generally occur within 30 minutes to two hours after exposure. As little as 0.1 mg of clonidine has produced signs of toxicity in children.

If symptoms of poisoning occur following dermal exposure, remove all Catapres-TTS® (clonidine) transdermal therapeutic systems. After their removal, the plasma clonidine levels will persist for about 8 hours, then decline slowly over a period of several days. Rare cases of Catapres-TTS poisoning due to accidental or deliberate mouthing or ingestion of the patch have been reported, many of them involving children.

There is no specific antidote for clonidine overdosage. Ipecac syrup-induced vomiting and gastric lavage would not be expected to remove significant amounts of clonidine following dermal exposure. If the patch is ingested, whole bowel irrigation may be considered and the administration of activated charcoal and/or cathartic may be beneficial. Supportive care may include atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension. Naloxone may be a useful adjunct for the management of clonidine-induced respiratory depression, hypotension and/or coma; blood pressure should be monitored since the administration of naloxone has occasionally resulted in paradoxical hypertension. Tolazoline administration has yielded inconsistent results and is not recommended as first-line therapy. Dialysis is not likely to significantly enhance the elimination of clonidine.

The largest overdose reported to date, involved a 28-year old male who ingested 100 mg of clonidine hydrochloride powder. This patient developed hypertension followed by hypotension, bradycardia, apnea, hallucinations, semicoma, and premature ventricular contractions. The patient fully recovered after intensive treatment. Plasma clonidine levels were 60 ng/mL after 1 hour, 190 ng/mL after 1.5 hours, 370 ng/mL after 2 hours, and 120 ng/mL after 5.5 and 6.5 hours. In mice and rats, the oral LD50 of clonidine is 206 and 465 mg/kg, respectively.

Catapres-TTS Dosage and Administration

Apply Catapres-TTS transdermal therapeutic system once every 7 days to a hairless area of intact skin on the upper outer arm or chest. Each new application of Catapres-TTS transdermal therapeutic system should be on a different skin site from the previous location. If the system loosens during 7-day wearing, the adhesive cover should be applied directly over the system to ensure good adhesion. There have been rare reports of the need for patch changes prior to 7 days to maintain blood pressure control.

To initiate therapy, Catapres-TTS transdermal therapeutic system dosage should be titrated according to individual therapeutic requirements, starting with Catapres-TTS-1. If after one or two weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another Catapres-TTS-1 or changing to a larger system. An increase in dosage above two Catapres-TTS-3 is usually not associated with additional efficacy.

When substituting Catapres-TTS transdermal therapeutic system for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of Catapres-TTS transdermal therapeutic system may not commence until 2-3 days after initial application. Therefore, gradual reduction of prior drug dosage is advised. Some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension.

Renal Impairment

Dosage must be adjusted according to the degree of impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

How is Catapres-TTS Supplied

Catapres-TTS-1, Catapres-TTS-2, and Catapres-TTS-3 are supplied as 4 pouched systems and 4 adhesive covers per carton. See chart below.

  Programmed Delivery
Clonidine in vivo           Per Day Over 1 Week  
Clonidine
Content  
Size  
Code   Catapres-TTS®-1
(clonidine)
NDC 0597-0031-34 0.1 mg 2.5 mg 3.5 cm2 BI-31   Catapres-TTS®-2
(clonidine)
NDC 0597-0032-34 0.2 mg 5.0 mg 7.0 cm2 BI-32   Catapres-TTS®-3
(clonidine)
NDC 0597-0033-34 0.3 mg 7.5 mg 10.5 cm2  BI-33   STORAGE AND HANDLING

Store below 86°F (30°C).

Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA

Licensed from:
Boehringer Ingelheim International GmbH

Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY.

©Copyright 2010 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED

Rev: May 2010
IT7000FE0510
4044415/08

PATIENT INSTRUCTIONS

Catapres-TTS®
(clonidine)
Transdermal Therapeutic System

(Read the following instructions carefully before using this medication. If you have any questions, please consult with your doctor.)

General Information

Catapres-TTS transdermal therapeutic system is a square, tan adhesive PATCH containing an active blood-pressure-lowering medication. It is designed to deliver the drug into the body through the skin smoothly and consistently for one full week. Normal exposure to water, as in showering, bathing, and swimming, should not affect the PATCH.

The optional white, round ADHESIVE COVER should be applied directly over the PATCH, should the PATCH begin to separate from the skin. The ADHESIVE COVER ensures that the PATCH sticks to the skin. The Catapres-TTS PATCH must be replaced with a new one on a fresh skin site if the one in use significantly loosens or falls off.

Skin burns have been reported at the patch site in several patients wearing an aluminized transdermal system during a magnetic resonance imaging scan (MRI). Because the Catapres-TTS® PATCH contains aluminum, it is recommended to remove the system before undergoing an MRI.

How to Apply the Catapres-TTS PATCH

1) Apply the square, tan Catapres-TTS PATCH once a week, preferably at a convenient time on the same day of the week (i.e., prior to bedtime on Tuesday of week one; prior to bedtime on Tuesday of week two, etc.).
2) Select a hairless area such as on the upper, outer arm or upper chest. The area chosen


should be free of cuts, abrasions, irritation, scars or calluses and should not be shaved before applying the Catapres-TTS® (clonidine) PATCH. Do not place the Catapres-TTS PATCH on skin folds or under tight undergarments, since premature loosening may occur.
3) Wash hands with soap and water and thoroughly dry them.
4) Clean the area chosen with soap and water. Rinse and wipe dry with a clean, dry tissue.
5) Select the pouch with the red and orange colors labeled Catapres-TTS (clonidine) and open it as illustrated in Figure 3. Remove the square, tan PATCH from the pouch.


6) Remove the clear plastic protective backing from the PATCH by gently peeling off one half of the backing at a time as shown in Figure 4. Avoid touching the sticky side of the Catapres-TTS® (clonidine) PATCH.


7) Place the Catapres-TTS PATCH on the prepared skin site (sticky side down) by applying firm pressure over the PATCH to ensure good contact with the skin, especially around the edges (Figure 5). Discard the clear plastic protective backing and wash your hands with soap and water to remove any drug from your hands.


8) After one week, remove the old PATCH and discard it (refer to Instructions for Disposal). After choosing a different skin site, repeat instructions 2 through 7 for the application of your next Catapres-TTS PATCH.

What to do if your Catapres-TTS PATCH becomes loose while wearing:

How to Apply the ADHESIVE COVER

Note: The white, round, ADHESIVE COVER does not contain any drug and should not be used alone. The COVER should be applied directly over the Catapres-TTS PATCH only if the PATCH begins to separate from the skin, thereby ensuring that it sticks to the skin for seven full days.

1) Wash hands with soap and water and thoroughly dry them. 2) Using a clean, dry tissue, make sure that the area around the square, tan Catapres TTS® (clonidine) PATCH is clean and dry. Press gently on the Catapres-TTS PATCH to ensure that the edges are in good contact with the skin. 3) Take the white, round, ADHESIVE COVER (Figure 6) from the plain white pouch and remove the paper liner backing from the COVER. 4) Carefully center the round, white ADHESIVE COVER over the square, tan Catapres-TTS PATCH and apply firm pressure, especially around the edges in contact with the skin.

Instructions for Disposal

KEEP OUT OF REACH OF CHILDREN

During or even after use, a PATCH contains active medication which may be harmful to infants and children if accidentally applied or ingested. After use, fold in half with the sticky sides together. Dispose of carefully out of reach of children.

Distributed by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT 06877 USA

Licensed from: Boehringer Ingelheim International GmbH

©Copyright 2010 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED

Rev: May 2010
IT7000FE0510
4044415/08


CATAPRES 
clonidine  patch, extended release Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0597-0031 Route of Administration TRANSDERMAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength clonidine (clonidine) clonidine 0.1 mg  in 24 h Inactive Ingredients Ingredient Name Strength mineral oil   silicon dioxide   Product Characteristics Color      Score      Shape Size Flavor Imprint Code BI;31 Contains          Packaging # NDC Package Description Multilevel Packaging 1 0597-0031-34 4 POUCH In 1 CARTON contains a POUCH 1 1 PATCH In 1 POUCH This package is contained within the CARTON (0597-0031-34) and contains a PATCH 1 24 h In 1 PATCH This package is contained within a POUCH and a CARTON (0597-0031-34)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018891 10/01/1985
CATAPRES 
clonidine  patch, extended release Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0597-0032 Route of Administration TRANSDERMAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength clonidine (clonidine) clonidine 0.2 mg  in 24 h Inactive Ingredients Ingredient Name Strength mineral oil   silicon dioxide   Product Characteristics Color      Score      Shape Size Flavor Imprint Code BI;32 Contains          Packaging # NDC Package Description Multilevel Packaging 1 0597-0032-34 4 POUCH In 1 CARTON contains a POUCH 1 1 PATCH In 1 POUCH This package is contained within the CARTON (0597-0032-34) and contains a PATCH 1 24 h In 1 PATCH This package is contained within a POUCH and a CARTON (0597-0032-34)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018891 10/01/1985
CATAPRES 
clonidine  patch, extended release Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0597-0033 Route of Administration TRANSDERMAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength clonidine (clonidine) clonidine 0.3 mg  in 24 h Inactive Ingredients Ingredient Name Strength mineral oil   silicon dioxide   Product Characteristics Color      Score      Shape Size Flavor Imprint Code BI;33 Contains          Packaging # NDC Package Description Multilevel Packaging 1 0597-0033-34 4 POUCH In 1 CARTON contains a POUCH 1 1 PATCH In 1 POUCH This package is contained within the CARTON (0597-0033-34) and contains a PATCH 1 24 h In 1 PATCH This package is contained within a POUCH and a CARTON (0597-0033-34)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA018891 10/01/1985
Labeler - Boehringer Ingelheim Pharmaceuticals Inc. (603175944) Registrant - Boehringer Ingelheim Pharmaceuticals Inc. (603175944) Establishment Name Address ID/FEI Operations Alza Corp 058613451 MANUFACTURE Establishment Name Address ID/FEI Operations Boehringer Ingelheim Pharma GmbH and Co. KG 551147440 API MANUFACTURE Revised: 05/2010Boehringer Ingelheim Pharmaceuticals Inc. More Catapres-TTS resources Catapres-TTS Side Effects (in more detail) Catapres-TTS Use in Pregnancy & Breastfeeding Drug Images Catapres-TTS Drug Interactions Catapres-TTS Support Group 4 Reviews for Catapres-TTS - Add your own review/rating Compare Catapres-TTS with other medications Alcohol Withdrawal Anxiety Benzodiazepine Withdrawal Bipolar Disorder High Blood Pressure Migraine Prevention Opiate Withdrawal Perimenopausal Symptoms Smoking Cessation
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Thioguanine Tabloid


Generic Name: Thioguanine
Class: Antineoplastic Agents
VA Class: AN300
CAS Number: 154-42-7

Introduction

Antineoplastic agent; antimetabolite, synthetic purine antagonist.103 b

Uses for Thioguanine Tabloid Acute Myeloid Leukemia (AML)

Remission induction (in combination with other antineoplastic agents) in acute myeloid (myelogenous, nonlymphocytic) leukemia (AML, ANLL).103 104 115 116

Has been used with other antineoplastic agents in regimens of consolidation therapy for AML following induction of a complete remission; optimal regimen of such therapy in prolonging remissions remains to be established but is typically administered short-term.115 b

Not recommended for maintenance or long-term continuous therapy.103 (See Hepatic Effects under Cautions.)

Thioguanine Tabloid Dosage and Administration General

Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.103 b

Individualize dosage according to clinical and hematologic response and tolerance of the patient.103

Administration Oral Administration

Calculate total daily dose to the nearest multiple of 20 mg and administer orally once daily.b

Dosage

Consult currently published protocols for dosages used in combination regimens and method and sequence of administration.103

Dosage reduction may be necessary if used concomitantly with other myelosuppressive agents.103 (See Specific Drugs under Interactions.)

When initiating thioguanine therapy, patients with inherited deficiency of thiopurine S-methyl transferase (TPMT) activity are at increased risk of life-threatening myelotoxicity; substantial dosage reduction may be required.103 (See Hematologic Effects under Cautions.)

Pediatric Patients Acute Myeloid Leukemia Induction and Consolidation Therapy Oral

If monotherapy is appropriate, initially, approximately 2 mg/kg daily.103 If there is no clinical improvement and no leukocyte or platelet count depression after 4 weeks on initial dosage, dosage may be cautiously increased to 3 mg/kg daily.103

Thioguanine should not be part of maintenance therapy.103 (See Hepatic Effects under Cautions.)

Adults Acute Myeloid Leukemia Induction and Consolidation Therapy Oral

If monotherapy is appropriate, initially, approximately 2 mg/kg daily.103 If there is no clinical improvement and no leukocyte or platelet count depression after 4 weeks on initial dosage, dosage may be cautiously increased to 3 mg/kg daily.103

Thioguanine should not be part of maintenance therapy.103 (See Hepatic Effects under Cautions.)

Special Populations Hepatic Impairment

Consider dosage reduction; however, no specific dosage recommendations at this time.103 (See Hepatic Effects under Cautions.)

Renal Impairment

Consider dosage reduction; however, no specific dosage recommendations at this time.103

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.103

Cautions for Thioguanine Tabloid Contraindications

If a diagnosis of AML has not been adequately established and there is no responsible clinician knowledgeable in assessing response to chemotherapy.103

Patients whose disease was resistant to prior therapy with the drug.103 Consider that there is complete cross-resistance between thioguanine and mercaptopurine.103

Warnings/Precautions Warnings Toxicity

Highly toxic; low therapeutic index; therapeutic response is unlikely without some evidence of toxicity.b Administer only under supervision of qualified clinicians experienced in use of cytotoxic therapy.103 b

Hepatic Effects

Risk of hepatotoxicity associated with vascular endothelial damage; usually manifested as hepatic veno-occlusive disease (e.g., hyperbilirubinemia, hepatomegaly, ascites) or portal hypertension (e.g., splenomegaly, thrombocytopenia out of proportion with neutropenia, esophageal varices).103

Possible jaundice and increases in serum aminotransferases (AST, ALT), alkaline phosphatase, and ? glutamyl transferase concentrations.103 Hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis reported.103

Discontinue immediately if evidence of hepatotoxicity (e.g., jaundice) occurs; signs and symptoms generally reversible after discontinuance of the drug.103

Hepatic function must be carefully monitored.103 Serum transaminase, alkaline phosphatase, and bilirubin concentrations should be determined weekly during initiation of therapy and monthly thereafter.103 More frequent testing in patients with preexisting liver disease and in those receiving other hepatotoxic drugs.103

Hematologic Effects

Risk of myelosuppression (manifested as anemia, leukopenia, and/or thrombocytopenia); usually dose related.103 Hematologic status must be carefully monitored.103

Discontinue temporarily at the first sign of an abnormally large or rapid decrease in leukocytes, platelets, or hemoglobin concentration or abnormal depression of bone marrow, unless induction of bone marrow hypoplasia is desired.103 b Bone marrow examination (aspiration and/or biopsy) may be helpful in distinguishing between progression of leukemia, resistance to therapy, and marrow hypoplasia induced by therapy.103 b

Perform CBC, including platelet count and leukocyte differential, at least once weekly during therapy; more frequent blood counts may be required, particularly during remission induction therapy and with concomitant therapy with other antineoplastic agents.103 b

When initiating thioguanine therapy, patients with inherited deficiency of thiopurine S-methyl transferase (TPMT) activity are at increased risk for life-threatening myelotoxicity; substantial dosage reduction may be required.103 Concomitant use with drugs that inhibit TPMT (e.g., olsalazine, mesalamine, sulfasalazine) may exacerbate such toxicity.103 Consider testing for TPMT deficiency prior to initiating therapy.103

Infectious Complications and Hemorrhagic Complications

Life-threatening infections due to granulocytopenia may occur.103 Anti-infectives or granulocyte transfusions may be needed.103

Bleeding due to thrombocytopenia may occur.103 Platelet transfusions may be needed.103

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.103

Avoid pregnancy during therapy.103 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.103

Major Toxicities GI Effects

Possible nausea, vomiting, anorexia, and stomatitis.103

General Precautions Hyperuricemia

Hyperuricemia occurs frequently because of extensive purine catabolism accompanying rapid cellular destruction.103 Hyperuricemia may be minimized or prevented by adequate hydration, alkalinization of urine, and/or administration of allopurinol.103

Immunization

Effects of thioguanine on immunocompetence are unknown.103 Avoid live virus vaccines in immunocompromised patients.103

Specific Populations Pregnancy

Category D.103 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether thioguanine is distributed into milk.103 Discontinue nursing or the drug.103

Geriatric Use

Clinical studies did not include sufficient numbers of patients ?65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.103

Common Adverse Effects

Myelosuppression, hyperuricemia, hepatotoxicity.103

Interactions for Thioguanine Tabloid Specific Drugs

Drug

Interaction

Comments

Allopurinol

Pharmacokinetic interactions not expected103

Dosage adjustments not required103

Aminosalicylates (e.g., olsalazine, mesalamine, sulfasalazine)

Potential pharmacokinetic interaction; increased risk of thioguanine myelotoxicity103 (see Hematologic Effects under Cautions)

Use concomitantly with caution103

Myelosuppressive agents

Possible additive myelosuppressive effects103

Reduced thioguanine dosage may be necessary with concomitant therapy103

Thioguanine Tabloid Pharmacokinetics Absorption Bioavailability

Absorption from GI tract is variable and incomplete; approximately 30% of an oral dose may be absorbed.103

Distribution Extent

Incorporated into the DNA and RNA of bone marrow cells.103

Does not reach therapeutic concentrations in the CSF.103

Thioguanine crosses the placenta; not known whether distributed into milk.103

Elimination Metabolism

Rapidly and extensively metabolized in the liver and other tissues, principally to the less toxic and less active methylated derivative 2-amino-6-methylthiopurine.103

Elimination Route

Excreted principally in urine as metabolites.103 b

Half-life

Biphasic; terminal half-life averages 11 hours.b

Stability Storage Oral Tablets

15–25°C.103

ActionsActions

Converted intracellularly to ribonucleotides that result in a sequential blockade of the synthesis and utilization of purine and guanine nucleotides.103 b

Thioguanine ribonucleotides incorporate into DNA and RNA; cytotoxic effects may be related primarily to substitution of ribonucleotides into DNA.103 b

Usually complete cross-resistance between thioguanine and mercaptopurine.103 b

Advice to Patients

Advise patients that the major toxicities of the drug are related to myelosuppression, hepatotoxicity, and GI toxicity.103

Importance of taking the drug only under medical supervision.103

Importance of patients informing their clinicians if fever, sore throat, jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia occur.103

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.103

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.

Thioguanine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

40 mg

Thioguanine Tabloid (scored)

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.

Tabloid 40MG Tablets (GLAXO SMITH KLINE): 25/$235.91 or 50/$466.57

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 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. Griner PF, Elbadawi A, Packman CH. Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Ann Intern Med. 1976; 85:578-82. [IDIS 65468] [PubMed 1068643]

101. Gill RA, Onstad GR, Cardamone JM et al. Hepatic veno-occlusive disease caused by 6-thioguanine. Ann Intern Med. 1982; 96:58-60. [IDIS 142618] [PubMed 7053705]

102. Krivoy N, Raz R, Carter A et al. Reversible hepatic veno-occlusive disease and 6-thioguanine. Ann Intern Med. 1982; 96:788. [IDIS 152653] [PubMed 7091946]

103. GlaxoSmithKline. Tabloid brand thioguanine 40-mg scored tablets prescribing information. Research Triangle Park, NC; 2004 Dec.

104. Childhood acute myeloid leukemia/other myeloid malignancies. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Aug 22.

105. Thiersch JB. Effect of 2-6 diaminopurine (2-6 DP): 6 chlorpurine (CIP) and thioguanine (ThG) on rat litter in utero. Proc Soc Exp Biol Med. 1957; 94:40-3. [PubMed 13400865]

107. Key NS, Kelly PMA, Emerson PM et al. Oesophageal varices associated with busulphan-thioguanine combination therapy for chronic myeloid leukaemia. Lancet. 1987; 2:1050-2. [IDIS 235711] [PubMed 2889964]

109. Shepherd PC, Fooks J, Gray R et al. Thioguanine used in maintenance therapy of chronic myeloid leukaemia causes non-cirrhotic portal hypertension. Br J Haematol. 1991; 79:185-92. [PubMed 1958475]

110. McCauley DL. Treatment of adult acute leukemia. Clin Pharm. 1992; 11:767-96. [IDIS 300402] [PubMed 1521402]

111. Arlin Z, Case DC Jr, Moore J et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia. 1990; 4:177-83. [PubMed 2179638]

112. Feldman EJ. Acute myelogenous leukemia in the older patient. Semin Oncol. 1995; 22(Suppl 1):21-4. [PubMed 7532322]

113. Pavlovsky S, Gonzalez Llaven J, Garcia Martinez MA et al. A randomized study of mitoxantrone plus cytarabine versus daunomycin plus cytarabine in the treatment of previously untreated adult patients with acute nonlymphocytic leukemia. Ann Hematol. 1994; 69:11-5. [PubMed 8061102]

114. Wahlin A, Hornsten P, Hedenus M et al. Mitoxantrone and cytarabine versus daunorubicin and cytarabine in previously untreated patients with acute myeloid leukemia. Cancer Chemother Pharmacol. 1991; 28:480-3. [PubMed 1934252]

115. Adult acute myeloid leukemia. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Jul 17.

116. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

b. AHFS drug information 2008. McEvoy GK, ed. Thioguanine. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2008:1232-3.

More Thioguanine Tabloid resources Thioguanine Tabloid Side Effects (in more detail)Thioguanine Tabloid Use in Pregnancy & BreastfeedingDrug ImagesThioguanine Tabloid Drug InteractionsThioguanine Tabloid Support Group0 Reviews for Thioguanine Tabloid - Add your own review/rating Compare Thioguanine Tabloid with other medications Acute Nonlymphocytic Leukemia
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