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Osteolytic Bone Lesions of Multiple Myeloma Medications


Drugs associated with Osteolytic Bone Lesions of Multiple Myeloma

The following drugs and medications are in some way related to, or used in the treatment of Osteolytic Bone Lesions of Multiple Myeloma. 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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Multiple Myeloma
Drug List: Aclasta Aredia Reclast Zometa
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zoledronic acid Intravenous


zoe-le-DRON-ik AS-id

Commonly used brand name(s)

In the U.S.

Reclast Zometa

Available Dosage Forms:

Solution Powder for Solution

Therapeutic Class: Calcium Regulator

Chemical Class: Bisphosphonate

Uses For zoledronic acid

Zoledronic acid injection is used to treat hypercalcemia (high levels of calcium in the blood) that may occur in patients with some types of cancer. It is also used to treat a cancer called multiple myeloma (tumors formed by the cells of the bone marrow) or certain types of bone metastases (the spread of cancer to the bone).

Zoledronic acid injection is used to treat Paget's disease of the bone in men and women. It is also used in men with osteoporosis and in women with osteoporosis who have gone through menopause. zoledronic acid is used to reduce the risk of having more fractures in patients who have had a recent hip fracture.

zoledronic acid is to be administered only by or under the supervision of your doctor.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, zoledronic acid is used in certain patients with the following medical conditions:

Bone loss, in men, from taking certain medicines for prostate cancer. Bone loss, in breast cancer patients, from hormone therapy (prevention). Before Using zoledronic acid

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For zoledronic acid, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to zoledronic acid or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Zoledronic acid injection is not indicated for use in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of zoledronic acid injection in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution in patients receiving zoledronic acid injection.

Pregnancy Pregnancy Category Explanation All Trimesters D Studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy in a life threatening situation or a serious disease, may outweigh the potential risk. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of zoledronic acid. Make sure you tell your doctor if you have any other medical problems, especially:

Anemia or Bleeding problems or Cancer, history of or Dental or tooth problems or Dental procedures or Poor oral hygiene, or Surgery (e.g., dental surgery)—May increase risk for severe jaw problems. Asthma, aspirin-sensitive or Heart disease or Kidney disease or Mineral imbalance (e.g., high or low calcium, magnesium, phosphorus, or potassium in the blood)—Use with caution. May make these conditions worse. Bowel resection or Parathyroid disease (e.g., hypoparathyroidism) or Parathyroid surgery or Stomach absorption problems or Thyroid surgery—These conditions may increase your risk of having hypocalcemia (low levels of calcium in the blood). Dehydration (not enough water or fluid in your body)—May increase risk of severe kidney problems. Hypocalcemia (low calcium in the blood) or Kidney disease, severe (e.g., kidney failure)—Should not be used in patients with these conditions. Proper Use of zoledronic acid

A nurse or other trained health professional will give you zoledronic acid. zoledronic acid is given through a needle placed in one of your veins. The medicine must be injected slowly, so your IV tube will need to stay in place for at least 15 minutes.

For hypercalcemia, zoledronic acid is usually given only once. If your doctor decides that you need additional doses, you will receive the medicine again after at least 7 days have passed. This treatment will continue until your body responds to the medicine.

For bone cancer and multiple myeloma, zoledronic acid is usually given every 3 to 4 weeks. This treatment will continue until your body responds to the medicine.

For osteoporosis, zoledronic acid is usually given once a year and will continue until your body responds to the medicine.

You may also receive other medicines to help keep your body from losing too much fluid.

Your doctor may also give you vitamins containing Vitamin D and calcium. Tell your doctor if you are unable to take these supplements.

Drink extra fluids so you will pass more urine while you are using zoledronic acid. This will keep your kidneys working well and help prevent kidney problems. However, it is very important to not drink too much liquid. Talk to your doctor about the right amount of liquids for you.

zoledronic acid comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Precautions While Using zoledronic acid

It is very important that your doctor check your progress at regular visits after you have received zoledronic acid injection. If your condition has improved, your progress must still be checked. The results of laboratory tests or the occurrence of certain symptoms will tell your doctor if your condition is coming back and if a second treatment is needed. You will need a yearly dose of zoledronic acid if you are being treated for postmenopausal osteoporosis, so check with your doctor regularly.

Using zoledronic acid while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

You should not use other medicines that also contain zoledronic acid, such as Reclast® or Zometa®. Using these medicines together may increase your chance for more serious side effects.

zoledronic acid may rarely cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth after receiving the medicine.

zoledronic acid may cause low calcium in your blood. Check with your doctor immediately if you have numbness or tingling around the mouth, or if you have muscle spasms.

Tell your doctor right away if you have agitation; blood in the urine; confusion; decreased urine output; depression; dizziness; headache; irritability; lethargy; muscle twitching; nausea; rapid weight gain; seizures; stupor; swelling of the face, ankles, or hands; or unusual tiredness or weakness. These could be symptoms of serious kidney problems.

Your doctor will need to know if you have a history of problems with your mouth or teeth (e.g., gum disease). Make sure your doctor knows if you have been treated with a bisphosphonate medicine, such as alendronate (Fosamax®), etidronate (Didronel®), pamidronate (Aredia®), risedronate (Actonel®), or tiludronate (Skelid®) in the past.

You may need to have a dental exam before you start using zoledronic acid.

It is important that you check with your doctor before having any dental procedures or surgeries done while you are receiving zoledronic acid. Tell your doctor right away if you have jaw tightness, swelling, numbing, or pain or a loose tooth. This could be symptoms of a severe problem of your jaw.

Make sure you tell your doctor about any new medical problems, especially with your teeth or jaws. Tell your doctor if you have severe muscle, bone, or joint pain after receiving zoledronic acid.

zoledronic acid may increase your risk of developing fractures of the thigh bone. This may be more common if you use it for a long time. Check with your doctor right away if you have a dull or aching pain in the thighs, groin, or hips.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription (e.g., other medicines that also contain zoledronic acid) or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

zoledronic acid Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common Agitation black, tarry stools blurred vision chest pain chills coma confusion convulsions cough depression difficult or labored breathing dizziness dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position fever irregular heartbeat irritability lack or loss of strength lethargy lower back or side pain mood or mental changes muscle pain or cramps muscle trembling or twitching nausea or vomiting numbness and tingling around the mouth, fingertips, or feet painful or difficult urination pale skin rapid weight gain seizures shaking of the hands, arms, feet, legs, or face shortness of breath skin rash, cracks in the skin at the corners of the mouth, or soreness or redness around the fingernails and toenails sore throat sores, ulcers, or white spots on the lips or mouth stupor sudden sweating swollen glands tightness in the chest trouble breathing with exercise unusual bleeding or bruising unusual tiredness or weakness wheezing Less common Feeling of constant movement of self or surroundings muscle cramps in the hands, arms, feet, legs, or face muscle spasms neck pain pounding in the ears rapid breathing sensation of spinning slow or fast heartbeat sunken eyes tingling of the hands or feet tremor Incidence not known Blurred vision or other change in vision decreased frequency or amount of urine decreased vision eye pain eye tenderness heavy jaw feeling increased blood pressure increased tearing increased thirst large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs loosening of a tooth pain, swelling, or numbness in the mouth or jaw redness of the eye sensitivity of the eye to light severe eye pain swelling of the face, hands, fingers, lower legs, or ankles troubled breathing weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common Abdominal or stomach pain anxiety, nervousness, restlessness, or irritability back pain bad, unusual, or unpleasant (after) taste bladder pain blistering, crusting, irritation, itching, or reddening of the skin bloody or cloudy urine bone pain burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings change in taste constipation cracked lips cracked, dry, or scaly skin diarrhea difficulty with swallowing discouragement dry mouth ear congestion fear or nervousness feeling sad or empty frequent urge to urinate hair loss or thinning hair headache hyperventilation joint pain or swollen joints loss of appetite loss of interest or pleasure loss of voice muscle stiffness or difficulty with moving nasal congestion or runny nose pain, swelling, or redness in the joints partial loss of feeling seeing, hearing, or feeling things that are not there sleepiness or unusual drowsiness sleeplessness, trouble sleeping, or unable to sleep swelling or inflammation of the mouth thirst trouble with concentrating unusually cold, shivering vomiting weight loss Less common Acid or sour stomach belching heartburn indigestion red streaks on the skin stomach discomfort or upset swelling, tenderness, or pain at the injection site unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness wrinkled skin Rare Burning, dry, or itching eyes discharge or excessive tearing redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid throbbing pain

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: zoledronic acid Intravenous side effects (in more detail)

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The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More zoledronic acid Intravenous resources Zoledronic acid Intravenous Side Effects (in more detail) Zoledronic acid Intravenous Use in Pregnancy & Breastfeeding Zoledronic acid Intravenous Drug Interactions Zoledronic acid Intravenous Support Group 11 Reviews for Zoledronic acid Intravenous - Add your own review/rating Compare zoledronic acid Intravenous with other medications Hypercalcemia of Malignancy Osteolytic Bone Lesions of Multiple Myeloma Osteolytic Bone Metastases of Solid Tumors Osteoporosis Paget's Disease Prevention of Osteoporosis
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Hexalen


altretamine
Dosage Form: capsule
Hexalen®
(ALTRETAMINE) CAPSULES
50 mg
RX Only WARNINGS Hexalen® capsules should only be given under the supervision of a physician experienced in the use of antineoplastic agents. Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Hexalen® capsules, and as clinically indicated (see Adverse Reactions). Because of the possibility of Hexalen® capsules-related neurotoxicity, neurologic examination should be performed regularly during Hexalen® capsules administration (see Adverse Reactions). DESCRIPTION

Hexalen® (altretamine) capsules, is a synthetic cytotoxic antineoplastic s-triazine derivative. Hexalen® capsules contain 50 mg of altretamine for oral administration. Inert ingredients include lactose, anhydrous and calcium stearate. Altretamine, known chemically as N,N,N',N',N",N"-hexamethyl-1,3,5-triazine-2,4,6-triamine, has the following structural formula:

Its empirical formula is C9H18N6 with a molecular weight of 210.28. Altretamine is a white crystalline powder, melting at 172 ± 1°C. Altretamine is practically insoluble in water but is increasingly soluble at pH 3 and below.

CLINICAL PHARMACOLOGY

The precise mechanism by which Hexalen® capsules exerts its cytotoxic effect is unknown, although a number of theoretical possibilities have been studied. Structurally, Hexalen® capsules resembles the alkylating agent triethylenemelamine, yet in vitro tests for alkylating activity of Hexalen® capsules and its metabolites have been negative. Hexalen® capsules has been demonstrated to be efficacious for certain ovarian tumors resistant to classical alkylating agents. Metabolism of altretamine is a requirement for cytotoxicity. Synthetic monohydroxymethylmelamines, and products of altretamine metabolism, in vitro and in vivo, can form covalent adducts with tissue macromolecules including DNA, but the relevance of these reactions to antitumor activity is unknown.

Hexalen® capsules is well-absorbed following oral administration in humans, but undergoes rapid and extensive demethylation in the liver, producing variation in altretamine plasma levels. The principal metabolites are pentamethylmelamine and tetramethylmelamine.

Pharmacokinetic studies were performed in a limited number of patients and should be considered preliminary. After oral administration of Hexalen® capsules to 11 patients with advanced ovarian cancer in doses of 120-300 mg/m2, peak plasma levels (as measured by gas-chromatographic assay) were reached between 0.5 and 3 hours, varying from 0.2 to 20.8 mg/l. Half-life of the ?-phase of elimination ranged from 4.7 to 10.2 hours. Altretamine and metabolites show binding to plasma proteins. The free fractions of altretamine, pentamethylmelamine and tetramethylmelamine are 6%, 25% and 50%, respectively.

Following oral administration of 14C-ring-labeled altretamine (4 mg/kg), urinary recovery of radioactivity was 61% at 24 hours and 90% at 72 hours. Human urinary metabolites were N-demethylated homologues of altretamine with <1% unmetabolized altretamine excreted at 24 hours.

After intraperitoneal administration of 14C-ring-labeled altretamine to mice, tissue distribution was rapid in all organs, reaching a maximum at 30 minutes. The excretory organs (liver and kidney) and the small intestine showed high concentrations of radioactivity, whereas relatively low concentrations were found in other organs, including the brain.

There have been no formal pharmacokinetic studies in patients with compromised hepatic and/or renal function, though Hexalen® capsules has been administered both concurrently and following nephrotoxic drugs such as cisplatin.

Hexalen® capsules has been administered in 4 divided doses, with meals and at bedtime, though there is no pharmacokinetic data on this schedule nor information from formal interaction studies about the effect of food on its bioavailability or pharmacokinetics.

In two studies in patients with persistent or recurrent ovarian cancer following first-line treatment with cisplatin and/or alkylating agent-based combinations, Hexalen® capsules was administered as a single agent for 14 or 21 days of a 28 day cycle. In the 51 patients with measurable or evaluable disease, there were 6 clinical complete responses, 1 pathologic complete response, and 2 partial responses for an overall response rate of 18%. The duration of these responses ranged from 2 months in a patient with a palpable pelvic mass to 36 months in a patient who achieved a pathologic complete response. In some patients, tumor regression was associated with improvement in symptoms and performance status.

INDICATIONS and USAGE

Hexalen® (altretamine) capsules is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.

CONTRAINDICATIONS

Hexalen® capsules is contraindicated in patients who have shown hypersensitivity to it. Hexalen® capsules should not be employed in patients with preexisting severe bone marrow depression or severe neurologic toxicity. Hexalen® capsules has been administered safely, however, to patients heavily pretreated with cisplatin and/or alkylating agents, including patients with preexisting cisplatin neuropathies. Careful monitoring of neurologic function in these patients is essential.

WARNINGS

See boxed Warnings.

Concurrent administration of Hexalen® capsules and antidepressants of the monoamine oxidase (MAO) inhibitor class may cause severe orthostatic hypotension. Four patients, all over 60 years of age, were reported to have experienced symptomatic hypotension after 4 to 7 days of concomitant therapy with Hexalen® capsules and MAO inhibitors.

Hexalen® capsules causes mild to moderate myelosuppression and neurotoxicity. Blood counts and a neurologic examination should be performed prior to the initiation of each course of therapy and the dose of Hexalen® capsules adjusted as clinically indicated (see Dosage and Administration).

Pregnancy: Category D

Hexalen® capsules has been shown to be embryotoxic and teratogenic in rats and rabbits when given at doses 2 and 10 times the human dose. Hexalen® capsules may cause fetal damage when administered to a pregnant woman. If Hexalen® capsules is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

PRECAUTIONS General

Neurologic examination should be performed regularly (see Adverse Reactions).

Laboratory Tests

Peripheral blood counts should be monitored at least monthly, prior to the initiation of each course of Hexalen® capsules, and as clinically indicated (see Adverse Reactions).

Drug Interactions

Concurrent administration of Hexalen® capsules and antidepressants of the MAO inhibitor class may cause severe orthostatic hypotension (see Warnings section). Cimetidine, an inhibitor of microsomal drug metabolism, increased altretamine's half-life and toxicity in a rat model.

Data from a randomized trial of Hexalen® capsules and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Hexalen® capsules and/or cisplatin (1).

Carcinogenesis, Mutagenesis and Impairment of Fertility

The carcinogenic potential of Hexalen® capsules has not been studied in animals, but drugs with similar mechanisms of action have been shown to be carcinogenic. Hexalen® capsules was weakly mutagenic when tested in strain TA100 of Salmonella typhimurium. Hexalen® capsules administered to female rats 14 days prior to breeding through the gestation period had no adverse effect on fertility, but decreased post-natal survival at 120 mg/m2/day and was embryocidal at 240 mg/m2/day. Administration of 120 mg/m2/day Hexalen® capsules to male rats for 60 days prior to mating resulted in testicular atrophy, reduced fertility and a possible dominant lethal mutagenic effect. Male rats treated with Hexalen® capsules at 450 mg/m2/day for 10 days had decreased spermatogenesis, atrophy of testes, seminal vesicles and ventral prostate.

Pregnancy

Pregnancy Category D: see Warnings section.

Nursing Mothers

It is not known whether altretamine is excreted in human milk. Because there is a possibility of toxicity in nursing infants secondary to Hexalen® capsules treatment of the mother, it is recommended that breast feeding be discontinued if the mother is treated with Hexalen® capsules.

Pediatric Use

The safety and effectiveness of Hexalen® capsules in children have not been established.

ADVERSE REACTIONS Gastrointestinal

With continuous high-dose daily Hexalen® capsules, nausea and vomiting of gradual onset occur frequently. Although in most instances these symptoms are controllable with anti-emetics, at times the severity requires Hexalen® capsules dose reduction or, rarely, discontinuation of Hexalen® capsules therapy. In some instances, a tolerance of these symptoms develops after several weeks of therapy. The incidence and severity of nausea and vomiting are reduced with moderate-dose administration of Hexalen® capsules. In 2 clinical studies of single-agent Hexalen® capsules utilizing a moderate, intermittent dose and schedule, only 1 patient (1%) discontinued Hexalen® capsules due to severe nausea and vomiting.

Neurotoxicity

Peripheral neuropathy and central nervous system symptoms (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo) have been reported. They are more likely to occur in patients receiving continuous high-dose daily Hexalen® (altretamine) capsules than moderate-dose Hexalen® capsules administered on an intermittent schedule. Neurologic toxicity has been reported to be reversible when therapy is discontinued. Data from a randomized trial of Hexalen® capsules and cisplatin plus or minus pyridoxine in ovarian cancer indicated that pyridoxine significantly reduced neurotoxicity; however, it adversely affected response duration suggesting that pyridoxine should not be administered with Hexalen® capsules and/or cisplatin (1).

Hematologic

Hexalen® capsules causes mild to moderate dose-related myelosuppression. Leukopenia below 3000 WBC/mm3 occurred in <15% of patients on a variety of intermittent or continuous dose regimens. Less than 1% had leukopenia below 1000 WBC/mm3. Thrombocytopenia below 50,000 platelets/mm3 was seen in <10% of patients. When given in doses of 8-12 mg/kg/day over a 21 day course, nadirs of leukocyte and platelet counts were reached by 3-4 weeks, and normal counts were regained by 6 weeks. With continuous administration at doses of 6-8 mg/kg/day, nadirs are reached in 6-8 weeks (median).

Data in the following table are based on the experience of 76 patients with ovarian cancer previously treated with a cisplatin-based combination regimen who received single-agent Hexalen® capsules. In one study, Hexalen® capsules, 260 mg/m2/day, was administered for 14 days of a 28 day cycle. In another study, Hexalen® capsules, 6-8 mg/kg/day, was administered for 21 days of a 28 day cycle.

ADVERSE EXPERIENCES IN 76 PREVIOUSLY TREATED OVARIAN CANCER PATIENTS RECEIVING SINGLE-AGENT Hexalen® CAPSULES Adverse Experiences % Patients Gastrointestinal
Nausea and Vomiting
    Mild to Moderate
    Severe
Increased Alkaline Phosphatase
33    
       32
     1
9      Neurologic
Peripheral Sensory Neuropathy
    Mild
    Moderate to Severe
Anorexia and Fatigue
Seizures
31    
       22
     9
1     
1      Hematologic
Leukopenia
    WBC 2000-2999/mm3
    WBC <2000/mm3
Thrombocytopenia
    Platelets 75,000-99,000/mm3
    Platelets <75,000/mm3
Anemia
    Mild
    Moderate to Severe
5     
     4
     1
9     
     6
     3
33    
       20
       13 Renal
Serum Creatinine 1.6-3.75 mg/dl
BUN
    25-40 mg%
    41-60 mg%
    >60 mg%
7     
9     
     5
     3
     1

Additional adverse reaction information is available from 13 single-agent altretamine studies (total of 1014 patients) conducted under the auspices of the National Cancer Institute. The treated patients had a variety of tumors and many were heavily pretreated with other chemotherapies; most of these trials utilized high, continuous daily doses of altretamine (612 mg/kg/day). In general, adverse reaction experiences were similar in the two trials described above. Additional toxicities, not reported in the above table, included hepatic toxicity, skin rash, pruritus and alopecia, each occurring in <1% of patients.

OVERDOSAGE

No case of acute overdosage in humans has been described. The oral LD50 dose in rats was 1050 mg/kg and 437 mg/kg in mice.

DOSAGE AND ADMINISTRATION

Hexalen® capsules is administered orally. Doses are calculated on the basis of body surface area.

Hexalen® capsules may be administered either for 14 or 21 consecutive days in a 28 day cycle at a dose of 260 mg/m2/day. The total daily dose should be given as 4 divided oral doses after meals and at bedtime. There is no pharmacokinetic information supporting this dosing regimen and the effect of food on Hexalen® capsules bioavailability or pharmacokinetics has not been evaluated.

Hexalen® capsules should be temporarily discontinued (for 14 days or longer) and subsequently restarted at 200 mg/m2/day for any of the following situations:
  1) Gastrointestinal intolerance unresponsive to symptomatic measures;
  2) White blood count <2000/mm3 or granulocyte count <1000/mm3;
  3) Platelet count <75,000/mm3;
  4) Progressive neurotoxicity.

If neurologic symptoms fail to stabilize on the reduced dose schedule, Hexalen® capsules should be discontinued indefinitely.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (2-9). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

Hexalen® (altretamine) capsules is available in 50 mg clear, hard gelatin capsules imprinted with the following inscription:
USB 001.

Bottles of 100 capsules
(NDC 62856-001-10)

Store up to 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

REFERENCES Wiernik PH, et al. Hexamethylmelamine and Low or Moderate Dose Cisplatin With or Without Pyridoxine for Treatment of Advanced Ovarian Carcinoma: A Study of the Eastern Cooperative Oncology Group. Cancer Invest. 1992; 10(1): 1-9. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41. U.S. Department of Health and Human Services. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Washington DC: Division of Safety, National Institutes of Health; 1983 Public Health Service publication NIH 83-2621. AMA Council on Scientific Affairs. Guidelines for Handling Parenteral Antineoplastics. JAMA. 1985; 253:1590-1591. National Study Commission on Cytotoxic Exposure. Recommendations for Handling Cytotoxic Agents. Boston, MA: Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115; 1987. Clinical Oncological Society of Australia: Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia. 1983;1:426-428. Jones RB, Frank R, Mass T. Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA Cancer J Clin. 1983;33:258-263. American Society of Hospital Pharmacists. ASHP Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm. 1990; 47:1033-1049. OSHA Work Practice Guidelines. Controlling Occupational Exposure to Hazardous Drugs. Am J Health Syst Pharm. 1996;53:1669-1685.

Hexalen® (altretamine) capsules is a registered trademark of Eisai Inc.


Manufactured by:
AAIPharma Inc.
Wilmington, NC 28405

Manufactured for:
Eisai Inc.
Woodcliff Lake, NJ 07677

For Medical Inquiries call: 1-877-873-4724

Revision Date May 2009

PRINCIPAL DISPLAY PANEL

NDC 62856-001-10

Hexalen®
altretamine
Capsules
50 mg
100 CAPSULES
Rx only

 


Hexalen 
altretamine  capsule Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 62856-001 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ALTRETAMINE (ALTRETAMINE) ALTRETAMINE 50 mg Inactive Ingredients Ingredient Name Strength LACTOSE   CALCIUM STEARATE   Product Characteristics Color white (clear) Score no score Shape CAPSULE (CAPSULE) Size 3mm Flavor Imprint Code USB;001 Contains          Packaging # NDC Package Description Multilevel Packaging 1 62856-001-10 100 CAPSULE In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019926 12/26/1990
Labeler - Eisai Inc. (831600833) Establishment Name Address ID/FEI Operations AAIPharma Services Corp. 832395235 manufacture Revised: 05/2009Eisai Inc. More Hexalen resources Hexalen Side Effects (in more detail) Hexalen Dosage Hexalen Use in Pregnancy & Breastfeeding Drug Images Hexalen Drug Interactions Hexalen Support Group 0 Reviews for Hexalen - Add your own review/rating Hexalen Concise Consumer Information (Cerner Multum) Hexalen MedFacts Consumer Leaflet (Wolters Kluwer) Hexalen Monograph (AHFS DI) Hexalen Advanced Consumer (Micromedex) - Includes Dosage Information Altretamine Professional Patient Advice (Wolters Kluwer) Compare Hexalen with other medications Ovarian Cancer
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Sacox 60



Dosage Form: FOR ANIMAL USE ONLY
Sacox 60 FRONT PANEL

Brand of salinomycin sodium
Type A Medicated Article

For use in broiler, roaster, replacement
(breeder and layer) chickens, and quail only

Active Drug Ingredient

Salinomycin equivalent to 60 grams salinomycin sodium activity per pound

For use in manufacturing medicated feeds only Other Ingredients

Calcium Carbonate, Mineral Oil, Calcium Silicate and Silicon Dioxide

Indications for Use

Broiler, roaster and replacement (breeder and layer) chickens

Use Sacox 60 to provide salinomycin sodium concentrations ranging from 40-60 g/ton (0.0044% to 0.0066%) for the prevention of coccidiosis in broiler, roaster and replacement chickens caused by Eimeria tenella, E. necatrix, E. acervulina, E. maxima, E. brunetti and E. mivati. The dosage should be adjusted to meet the severity of the coccidial challenge, which varies with environmental and management conditions.

Quail

Use Sacox 60 to provide salinomycin sodium concentrations of 50 g/ton (0.0055%) for the prevention of coccidiosis in quail caused by Eimeria dispersa and E. lettyae.

Mixing and Feeding Directions

Mixing and Feeding Directions

Mixing Directions

Thoroughly mix Sacox® 60 with non-medicated feed to provide the
level of salinomycin sodium per ton as indicated in the table below.
Salinomycin Sodium                     Amount of Sacox® 60 Type A Medicated
Activity                                        Article (60 g/lb) Per Ton of Feed
(grams per ton)                             Lbs                     Grams
40                                               0.67                     304
45                                               0.75                     341
50                                               0.83                     377
55                                               0.92                     418
60                                               1.00                     454

Feed continuously as the sole ration

Important

Must be thoroughly mixed in feeds before use. Not approved for use with pellet binders.

Caution CautionCaution

May be fatal if fed to adult turkeys or to horses

Warning

Warning

Do not feed to laying hens producing eggs for human consumption. When mixing and handling Sacox 60 premix, use protective clothing, impervious gloves, eye protection, and an approved dust respirator. Operators should wash thoroughly with soap and water after handling. If accidental eye contact occurs, immediately rinse thoroughly with water

Storage and Handling Storage and Handling

Store in a cool, dry place

ANADA #200-075, Approved by FDA

Distributed by:

Huvepharma, Inc.

Peachtree City, GA 30269

Net Wt. 50 lb. (22.68 kg)

Bag Label Image Bag Label Image


Sacox 60 
salinomycin  powder Product Information Product Type OTC TYPE A MEDICATED ARTICLE ANIMAL DRUG NDC Product Code (Source) 23243-2050 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SALINOMYCIN (SALINOMYCIN) SALINOMYCIN 60 g  in 0.45 kg Inactive Ingredients Ingredient Name Strength CALCIUM CARBONATE   CALCIUM SILICATE   MINERAL OIL   SILICON DIOXIDE   Product Characteristics Color white ((Off White to Tan)) Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 23243-2050-5 22.68 kg In 1 BAG None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANADA ANADA200075 06/29/2009
Labeler - Huvepharama, Inc. (619153559) Registrant - Huvepharma AD (552691651) Establishment Name Address ID/FEI Operations Huvepharma, Inc. 619153559 manufacture, analysis Revised: 01/2010Huvepharama, Inc.

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Matulane


procarbazine hydrochloride
Dosage Form: capsule
Matulane® (procarbazine hydrochloride) Capsules

WARNING

It is recommended that Matulane be given only by or under the supervision of a physician experienced in the use of potent antineoplastic drugs. Adequate clinical and Iaboratory facilities should be available to patients for proper monitoring of treatment.

Matulane Description

Matulane (procarbazine hydrochloride), a hydrazine derivative antineoplastic agent, is available as capsules containing the equivalent of 50 mg procarbazine as the hydrochloride. Each capsule also contains cornstarch, mannitol and talc. Gelatin capsule shells contain parabens (methyl and propyl), potassium sorbate, titanium dioxide, FD&C Yellow No. 6 and D&C Yellow No. 10.

Chemically, procarbazine hydrochloride is N-isopropyl-?-(2-methylhydrazino)-p-toluamide monohydrochloride. It is a white to pale yellow crystalline powder which is soluble but unstable in water or aqueous solutions. The molecular weight of procarbazine hydrochloride is 257.76 and the structural formula is:

Matulane - Clinical Pharmacology

The precise mode of cytotoxic action of procarbazine has not been clearly defined. There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis. Studies have suggested that procarbazine may inhibit transmethylation of methyl groups of methionine into t-RNA. The absence of functional t-RNA could cause the cessation of protein synthesis and consequently DNA and RNA synthesis. In addition, procarbazine may directly damage DNA. Hydrogen peroxide, formed during the auto-oxidation of the drug, may attack protein sulfhydryl groups contained in residual protein which is tightly bound to DNA.

Procarbazine is metabolized primarily in the liver and kidneys. The drug appears to be auto-oxidized to the azo derivative with the release of hydrogen peroxide. The azo derivative isomerizes to the hydrazone, and following hydrolysis splits into a benzylaldehyde derivative and methylhydrazine. The methylhydrazine is further degraded to CO2 and CH4 and possibly hydrazine, whereas the aldehyde is oxidized to N-isopropylterephthalamic acid, which is excreted in the urine.

Procarbazine is rapidly and completely absorbed. Following oral administration of 30 mg of 14C-labeled procarbazine, maximum peak plasma radioactive concentrations were reached within 60 minutes.

After intravenous injection, the plasma half-life of procarbazine is approximately 10 minutes. Approximately 70% of the radioactivity is excreted in the urine as N-isopropylterephthalamic acid within 24 hours following both oral and intravenous administration of 14C-labeled procarbazine.

Procarbazine crosses the blood-brain barrier and rapidly equilibrates between plasma and cerebrospinal fluid after oral administration.

Indications and Usage for Matulane

Matulane is indicated for use in combination with other anticancer drugs for the treatment of Stage III and IV Hodgkin's disease. Matulane is used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.

Contraindications

Matulane is contraindicated in patients with known hypersensitivity to the drug or inadequate marrow reserve as demonstrated by bone marrow aspiration. Due consideration of this possible state should be given to each patient who has leukopenia, thrombocytopenia or anemia.

Warnings

To minimize CNS depression and possible potentiation, barbiturates, antihistamines, narcotics, hypotensive agents or phenothiazines should be used with caution. Ethyl alcohol should not be used since there may be an Antabuse (disulfiram)-like reaction. Because Matulane exhibits some monoamine oxidase inhibitory activity, sympathomimetic drugs, tricyclic antidepressant drugs (eg, amitriptyline HCI, imipramine HCI) and other drugs and foods with known high tyramine content, such as wine, yogurt, ripe cheese and bananas, should be avoided. A further phenomenon of toxicity common to many hydrazine derivatives is hemolysis and the appearance of Heinz-Ehrlich inclusion bodies in erythrocytes.

Pregnancy Teratogenic Effects

Pregnancy Category D. Procarbazine hydrochloride can cause fetal harm when administered to a pregnant woman. While there are no adequate and well-controlled studies with procarbazine hydrochloride in pregnant women, there are case reports of malformations in the offspring of women who were exposed to procarbazine hydrochloride in combination with other antineoplastic agents during pregnancy. Matulane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Procarbazine hydrochloride is teratogenic in the rat when given at doses approximately 4 to 13 times the maximum recommended human therapeutic dose of 6 mg/kg/day.

Nonteratogenic Effects

Procarbazine hydrochloride has not been adequately studied in animals for its effects on peri- and postnatal development. However, neurogenic tumors were noted in the offspring of rats given intravenous injections of 125 mg/kg of procarbazine hydrochloride on day 22 of gestation. Compounds which inhibit DNA, RNA and protein synthesis might be expected to have adverse effects on peri- and postnatal development.

Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis

The carcinogenicity of procarbazine hydrochloride in mice, rats and monkeys has been reported in a considerable number of studies. Instances of a second nonlymphoid malignancy, including lung cancer and acute myelocytic leukemia, have been reported in patients with Hodgkin's disease treated with procarbazine in combination with other chemotherapy and/or radiation. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use. The International Agency for Research on Cancer (IARC) considers that there is “sufficient evidence” for the human carcinogenicity of procarbazine hydrochloride when it is given in intensive regimens which include other antineoplastic agents but that there is inadequate evidence of carcinogenicity in humans given procarbazine hydrochloride alone.

Mutagenesis

Procarbazine hydrochloride has been shown to be mutagenic in a variety of bacterial and mammalian test systems.

Impairment of Fertility

Azoospermia and antifertility effects associated with procarbazine hydrochloride administration in combination with other chemotherapeutic agents for treating Hodgkin's disease have been reported in human clinical studies. Since these patients received multicombination therapy, it is difficult to determine to what extent procarbazine hydrochloride alone was involved in the male germ-cell damage. The usual Segment I fertility/reproduction studies in laboratory animals have not been carried out with procarbazine hydrochloride. However, compounds which inhibit DNA, RNA and/or protein synthesis might be expected to have adverse effects on gametogenesis. Unscheduled DNA synthesis in the testis of rabbits and decreased fertility in male mice treated with procarbazine hydrochloride have been reported.

Precautions General

Undue toxicity may occur if Matulane is used in patients with impairment of renal and/or hepatic function. When appropriate, hospitalization for the initial course of treatment should be considered.

If radiation or a chemotherapeutic agent known to have marrow-depressant activity has been used, an interval of one month or longer without such therapy is recommended before starting treatment with Matulane. The length of this interval may also be determined by evidence of bone marrow recovery based on successive bone marrow studies.

Prompt cessation of therapy is recommended if any one of the following occurs:

  Central nervous system signs or symptoms such as paresthesias, neuropathies or confusion.   Leukopenia (white blood count under 4000).   Thrombocytopenia (platelets under 100,000).   Hypersensitivity reaction.   Stomatitis - The first small ulceration or persistent spot soreness around the oral cavity is a signal for cessation of therapy.   Diarrhea - Frequent bowel movements or watery stools.   Hemorrhage or bleeding tendencies.

Bone marrow depression often occurs 2 to 8 weeks after the start of treatment. If leukopenia occurs, hospitalization of the patient may be needed for appropriate treatment to prevent systemic infection.

Information for Patients

Patients should be warned not to drink alcoholic beverages while on Matulane therapy since there may be an Antabuse (disulfiram)-like reaction. They should also be cautioned to avoid foods with known high tyramine content such as wine, yogurt, ripe cheese and bananas. Over-the-counter drug preparations which contain antihistamines or sympathomimetic drugs should also be avoided. Patients taking Matulane should also be warned against the use of prescription drugs without the knowledge and consent of their physician. Patients should be advised to discontinue tobacco use.

Laboratory Tests

Baseline laboratory data should be obtained prior to initiation of therapy. The hematologic status as indicated by hemoglobin, hematocrit, white blood count (WBC), differential, reticulocytes and platelets should be monitored closely - at least every 3 or 4 days.

Hepatic and renal evaluation are indicated prior to beginning therapy. Urinalysis, transaminase, alkaline phosphatase and blood urea nitrogen tests should be repeated at least weekly.

Drug Interactions

See WARNINGS section.

No cross-resistance with other chemotherapeutic agents, radiotherapy or steroids has been demonstrated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS section.

Pregnancy

Pregnancy Category D. See WARNINGS section.

Nursing Mothers

It is not known whether Matulane is excreted in human milk. Because of the potential for tumorigenicity shown for procarbazine hydrochloride in animal studies, mothers should not nurse while receiving this drug.

Pediatric Use

Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized (see DOSAGE AND ADMINISTRATION). Very close clinical monitoring is mandatory.

Adverse Reactions

Leukopenia, anemia and thrombopenia occur frequently. Nausea and vomiting are the most commonly reported side effects.

Other adverse reactions are:

Hematologic

Pancytopenia; eosinophilia; hemolytic anemia; bleeding tendencies such as petechiae, purpura, epistaxis and hemoptysis.

Gastrointestinal

Hepatic dysfunction, jaundice, stomatitis, hematemesis, melena, diarrhea, dysphagia, anorexia, abdominal pain, constipation, dry mouth.

Neurologic

Coma, convulsions, neuropathy, ataxia, paresthesia, nystagmus, diminished reflexes, falling, foot drop, headache, dizziness, unsteadiness.

Cardiovascular

Hypotension, tachycardia, syncope.

Ophthalmic

Retinal hemorrhage, papilledema, photophobia, diplopia, inability to focus.

Respiratory

Pneumonitis, pleural effusion, cough.

Dermatologic

Herpes, dermatitis, pruritus, alopecia, hyperpigmentation, rash, urticaria, flushing.

Allergic

Generalized allergic reactions.

Genitourinary

Hematuria, urinary frequency, nocturia.

Musculoskeletal

Pain, including myalgia and arthralgia; tremors.

Psychiatric

Hallucinations, depression, apprehension, nervousness, confusion, nightmares.

Endocrine

Gynecomastia in prepubertal and early pubertal boys.

Miscellaneous

Intercurrent infections, hearing loss, pyrexia, diaphoresis, lethargy, weakness, fatigue, edema, chills, insomnia, slurred speech, hoarseness, drowsiness.

Second nonlymphoid malignancies (including lung cancer, acute myelocytic leukemia and malignant myelosclerosis) and azoospermia have been reported in patients with Hodgkin's disease treated with procarbazine in combination with other chemotherapy and/or radiation. The risks of secondary lung cancer from treatment appear to be multiplied by tobacco use.

Overdosage

The major manifestations of overdosage with Matulane would be anticipated to be nausea, vomiting, enteritis, diarrhea, hypotension, tremors, convulsions and coma. Treatment should consist of either the administration of an emetic or gastric lavage. General supportive measures such as intravenous fluids are advised. Since the major toxicity of procarbazine hydrochloride is hematologic and hepatic, patients should have frequent complete blood counts and liver function tests throughout their period of recovery and for a minimum of two weeks thereafter. Should abnormalities appear in any of these determinations, appropriate measures for correction and stabilization should be immediately undertaken.

The estimated mean lethal dose of procarbazine hydrochloride in laboratory animals varied from approximately 150 mg/kg in rabbits to 1300 mg/kg in mice.

Matulane Dosage and Administration

The following doses are for administration of the drug as a single agent. When used in combination with other anticancer drugs, the Matulane dose should be appropriately reduced, eg, in the MOPP regimen, the Matulane dose is 100 mg/m2 daily for 14 days. All dosages are based on the patient's actual weight. However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

Adults: To minimize the nausea and vomiting experienced by a high percentage of patients beginning Matulane therapy, single or divided doses of 2 to 4 mg/kg/day for the first week are recommended. Daily dosage should then be maintained at 4 to 6 mg/kg/day until maximum response is obtained or until the white blood count falls below 4000/cmm or the platelets fall below 100,000/cmm. When maximum response is obtained, the dose may be maintained at 1 to 2 mg/kg/day. Upon evidence of hematologic or other toxicity (see PRECAUTIONS section), the drug should be discontinued until there has been satisfactory recovery. After toxic side effects have subsided, therapy may then be resumed at the discretion of the physician, based on clinical evaluation and appropriate laboratory studies, at a dosage of 1 to 2 mg/kg/day.

Pediatric Patients: Very close clinical monitoring is mandatory. Undue toxicity, evidenced by tremors, coma and convulsions, has occurred in a few cases. Dosage, therefore, should be individualized. The following dosage schedule is provided as a guideline only.

Fifty (50) mg per square meter of body surface per day is recommended for the first week. Dosage should then be maintained at 100 mg per square meter of body surface per day until maximum response is obtained or until leukopenia or thrombocytopenia occurs. When maximum response is attained, the dose may be maintained at 50 mg per square meter of body surface per day. Upon evidence of hematologic or other toxicity (see PRECAUTIONS section), the drug should be discontinued until there has been satisfactory recovery, based on clinical evaluation and appropriate laboratory tests. After toxic side effects have subsided, therapy may then be resumed.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-6 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How is Matulane Supplied

Capsules, ivory, containing the equivalent of 50 mg procarbazine as the hydrochloride; in bottles of 100 (NDC 54482-053-01). Imprint on capsules: Matulane ? sigma-tau.

REFERENCES Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: U.S. Government Printing Office NIH Publication No. 83-2621. AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA. Mar 15, 1985; 253:1590-1592. National Study Commission on Cytotoxic Exposure: Recommendations for handling cytotoxic agents. Available from Louis P. Jeffrey, ScD, Director of Pharmacy Services, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02902. Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. Apr 30,1983; 1:426-428. Jones RB, Frank R, Mass T: Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA. Sept-Oct 1983; 33:258-263. ASHP technical assistance bulletin on handling cytotoxic drugs in hospitals. Am J Hosp Pharm. Jan 1985; 42:131-137. PRINCIPAL DISPLAY PANEL - BOTTLE LABEL

NDC 54482-053-01

Matulane®

(PROCARBAZINE HYDROCHLORIDE)

50 mg

Each capsule contains 50 mg procarbazine

in the form of the hydrochloride salt.

Rx only

100 Capsules

sigma-tau

Disperse in tight, light-resistant containers as

defined in USP/NF.

Store at 59° to 86°F (15° to 30°C).

LOT EXP.

M5-01/08AAl PC3986

Usual Dosage: See

package insert.

Mfd. for: sigma-tau Pharmaceuticals, Inc.,

Gaithersburg, MD 20878 Mfd. by: AAIPharma

Inc., 1726 North 23rd St., Wilmington, NC 28405

Bottle Label


Matulane 
procarbazine hydrochloride  capsule Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 54482-053 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength PROCARBAZINE HYDROCHLORIDE (PROCARBAZINE) PROCARBAZINE HYDROCHLORIDE 50 mg Inactive Ingredients Ingredient Name Strength STARCH, CORN   MANNITOL   TALC   GELATIN   METHYLPARABEN   PROPYLPARABEN   POTASSIUM SORBATE   TITANIUM DIOXIDE   FD&C YELLOW NO. 6   D&C YELLOW NO. 10   Product Characteristics Color WHITE (Ivory) Score no score Shape CAPSULE Size 12mm Flavor Imprint Code Matulane;sigma;tau Contains          Packaging # NDC Package Description Multilevel Packaging 1 54482-053-01 100 CAPSULE In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA016785 12/27/1985
Labeler - Sigma-Tau Pharmaceuticals, Inc. (068301431) Establishment Name Address ID/FEI Operations AAI Pharma 832395235 MANUFACTURE Establishment Name Address ID/FEI Operations F.I.S. Fabbrica Italiana Sintetici S.p.A. 431189117 API MANUFACTURE Revised: 07/2011Sigma-Tau Pharmaceuticals, Inc. More Matulane resources Matulane Side Effects (in more detail) Matulane Dosage Matulane Use in Pregnancy & Breastfeeding Drug Images Matulane Drug Interactions Matulane Support Group 0 Reviews for Matulane - Add your own review/rating Matulane Concise Consumer Information (Cerner Multum) Matulane MedFacts Consumer Leaflet (Wolters Kluwer) Matulane Monograph (AHFS DI) Matulane Advanced Consumer (Micromedex) - Includes Dosage Information Procarbazine Professional Patient Advice (Wolters Kluwer) Compare Matulane with other medications Anaplastic Astrocytoma Anaplastic Oligodendroglioma Glioblastoma Multiforme Hodgkin's Lymphoma
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Safe-Guard Fenbendazole



Dosage Form: FOR ANIMAL USE ONLY
intervet
safe-guard®
(fenbendazole) INDICATIONS

Beef and Dairy Cattle - 2.3 mg/lb (5 mg/kg) body weight for the removal and control of:

- Lungworm (Dictyocaulus viviparus); - Stomach worm (adults): brown stomach worm (Ostertagia ostertagi); - Stomach worms (adults and fourth stage larvae): barberpole worm (Haemonchus contortus and H. placei) and small stomach worm (Trichostrongylus axei); - Intestinal worms (adults and fourth stage larvae): hookworm (Bunostomum phlebotomum), thread-necked intestinal worm (Nematodirus helvetianus), small intestinal worm (Cooperia punctata and C. oncophora), bankrupt worm (Trichostrongylus colubriformis), and nodular worm (Oesophagostomum radiatum).

Goats - 2.3 mg/lb (5 mg/kg) body weight for the removal and control of:

- Stomach worms (adults): Haemonchus contortus and Teladorsagia circumcincta.

Store at or below 25°C (77°F).

Protect from freezing. Shake well before use.

Restricted drug (California) – use only as directed.

For Use in Animals Only.

DIRECTIONS

Determine the proper dose according to estimated body weight. Administer orally. The recommended dose of 2.3 mg/lb (5 mg/kg) of body weight is achieved when 2.3 mL of the drug are given for each 100 lbs body weight.

EXAMPLES Cattle: Body Weight Amount 100 lb 2.3 mL 200 lb 4.6 mL 300 lb 6.9 mL 400 lb 9.2 mL 500 lb 11.5 mL   1,000 lb     23.0 mL   1,500 lb     34.5 mL   Goats: Body Weight Amount   25 lb 0.6 mL   50 lb 1.2 mL   75 lb 1.7 mL 100 lb 2.3 mL 125 lb 2.9 mL

Under conditions of continued exposure to parasites, retreatment may be needed after 4 to 6 weeks.

Made in France

Distributed by: Intervet Inc., Millsboro, DE 19966
NADA # 128-620, Approved by FDA

PRINCIPAL DISPLAY PANEL - 3,785 mL label

intervet

safe-guard®
(fenbendazole)

Dewormer

for Beef & Dairy Cattle and Goats

Suspension 10% (100 mg/mL)

RESIDUE WARNINGS: Cattle must not be slaughtered within 8 days
following treatment. A withdrawal period has not been established
for this product in pre-ruminating calves. Do not use in calves
to be processed for veal. Goats must not be slaughtered for food
within 6 days following treatment. Because a withdrawal time
in milk has not been established, do not use in lactating goats.
For dairy cattle, there is no milk withdrawal period.

Consult your veterinarian for assistance in the
diagnosis, treatment and control of parasitism.

Keep this and all medication out of the
reach of children.

1 Gallon (3,785 mL)


SAFE-GUARD 
fenbendazole   suspension Product Information Product Type OTC ANIMAL DRUG NDC Product Code (Source) 57926-088 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Fenbendazole (Fenbendazole) Fenbendazole 100 mg  in 1 mL Inactive Ingredients Ingredient Name Strength methylparaben   propylparaben   silicon dioxide   carboxymethylcellulose sodium   povidone   trisodium citrate dihydrate   citric acid monohydrate   water   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 57926-088-01 3785 mL In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NADA NADA128620 09/16/2009
Labeler - Schering Corporation (001317601) Establishment Name Address ID/FEI Operations Intervet Production S.A. 771867553 ANALYSIS, MANUFACTURE Revised: 09/2009Schering Corporation

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Hydromol Intensive


1. Name Of The Medicinal Product

Hydromol Intensive

2. Qualitative And Quantitative Composition

Hydromol Intensive contains urea Ph Eur 10% w/w.

3. Pharmaceutical Form

A smooth, unperfumed, non greasy, off white cream for topical administration.

4. Clinical Particulars 4.1 Therapeutic Indications

For the treatment of ichthyosis and hyperkeratotic skin conditions associated with atopic eczema, xeroderma, iasteatosis and other chronic dry skin conditions.

4.2 Posology And Method Of Administration

Hydromol Intensive is applied topically. Wash affected areas well, rinse off all traces of soap, dry, and apply sparingly twice daily. Occlusive dressings may be used but are usually unnecessary because of the self-occlusive nature of the cream.

4.3 Contraindications

Known hypersensitivity to the product.

4.4 Special Warnings And Precautions For Use

Avoid application to moist or broken skin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Hydromol Intensive may increase the penetration through the skin barrier of other topically applied medicaments.

4.6 Pregnancy And Lactation

Animal reproduction studies have not been conducted with Hydromol Intensive. Hydromol Intensive should only be used if the anticipated benefits outweigh the risks.

4.7 Effects On Ability To Drive And Use Machines

Hydromol Intensive does not interfere with the ability to drive or use machines.

4.8 Undesirable Effects

May produce local irritations (including erythema, burning or pruritus) and oedema when applied to sensitive, moist or fissured skin.

4.9 Overdose

Topical applications of excessive amounts of Hydromol Intensive might cause skin irritation but no other effects would be expected. Ingestion of a large amount of Hydromol Intensive would be expected to result in gastrointestinal irritation (nausea and vomiting). Symptomatic and supportive care should be given. Liberal oral administration of milk or water may be helpful.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Urea has a therapeutic effect in chronic dry skin conditions through its hydrating, keratolytic and anti-pruritic properties.

5.2 Pharmacokinetic Properties

There is no information available on the pharmacokinetics of urea.

6. Pharmaceutical Particulars 6.1 List Of Excipients

The cream also contains white soft paraffin, maize starch, isopropyl myristate, syncrowax HR-C, palmitic acid, sorbitan laurate and arlatone G.

6.2 Incompatibilities

None known.

6.3 Shelf Life

Two years.

6.4 Special Precautions For Storage

Store below 30°C.

6.5 Nature And Contents Of Container

Hydromol Intensive is available in tubes of 30g and 100g.

6.6 Special Precautions For Disposal And Other Handling

A patient leaflet is provided with details of use and handling of the product.

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL 16853/0061

9. Date Of First Authorisation/Renewal Of The Authorisation

10 September 1991

10. Date Of Revision Of The Text

5th December 2008


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Geref Diagnostic


Generic Name: sermorelin (Injection route)

ser-moe-REL-in

Commonly used brand name(s)

In the U.S.

Geref Geref Diagnostic

Available Dosage Forms:

Powder for Solution

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Growth Hormone Releasing Hormone Analog

Uses For Geref Diagnostic

Sermorelin is a synthetic (man-made) version of a naturally occurring substance that causes release of growth hormone from the pituitary gland. Growth hormone is naturally produced by the pituitary gland and is necessary for growth in children. In children who fail to grow normally because their bodies are not producing enough growth hormone, this medicine may be used to increase the amount of growth hormone produced by the pituitary gland.

This medicine is available only with your doctor's prescription.

Before Using Geref Diagnostic

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pregnancy Pregnancy Category Explanation All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

Underactive thyroid—This condition can interfere with the effects of sermorelin Proper Use of sermorelin

This section provides information on the proper use of a number of products that contain sermorelin. It may not be specific to Geref Diagnostic. Please read with care.

If you are injecting this medicine yourself, use it exactly as directed by your doctor. Do not use more or less of it, and do not use it more often than your doctor ordered. The exact amount of medicine needed has been carefully worked out. Using too much will increase the risk of side effects, while using too little may not improve the condition.

Each package of sermorelin contains a patient instruction sheet. Read this sheet carefully and make sure you understand:

How to prepare the injection. Proper use of disposable syringes and needles, including safe handling and disposal. How to give the injection. How long the injection is safe to use.

It is best to use a different place on the body for each injection (for example, abdomen, hip, thigh, or upper arm). To help you remember to do this, you may want to keep a record of the date and location for each injection.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Storage

Store in the refrigerator. Do not freeze.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using Geref Diagnostic

It is very important that your doctor check your progress at regular visits.

Geref Diagnostic Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

More common Pain, redness, or swelling at the place of injection Rare Itching trouble in swallowing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Rare Dizziness flushing headache sleepiness trouble sitting still

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Geref Diagnostic resources Geref Diagnostic Use in Pregnancy & BreastfeedingGeref Diagnostic Support Group0 Reviews · Be the first to review/rate this drug Geref MedFacts Consumer Leaflet (Wolters Kluwer)
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PanOxyl 5 Aquagel 5%w / w Gel


1. Name Of The Medicinal Product

PanOxyl 5 Aquagel 5%w/w Gel

PanOxyl Aquagel 5

2. Qualitative And Quantitative Composition

Benzoyl peroxide 5% w/w. Also contains propylene glycol.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gel

4. Clinical Particulars 4.1 Therapeutic Indications

The product is indicated for use in the topical treatment of acne vulgaris.

4.2 Posology And Method Of Administration

Treatment should normally begin with PanOxyl Aquagel 2.5. Apply to the affected areas once daily. Washing prior to application enhances the efficacy of the preparation.

The reaction of the skin to benzoyl peroxide differs in individual patients. The higher concentration in PanOxyl Aquagel 5 or 10 may be required to produce a satisfactory response.

4.3 Contraindications

PanOxyl Aquagel should not be prescribed for patients with a known hypersensitivity to benzoyl peroxide.

4.4 Special Warnings And Precautions For Use

Avoid contact with the eyes, mouth and mucous membranes. Care should be taken when applying the product to the neck and other sensitive areas.

During the first few days of treatment a moderate reddening and peeling will occur. During the first few weeks of treatment a sudden increase in peeling will occur in most patients. This is not harmful and will normally subside within a day or two if treatment is discontinued. If excessive irritation, redness or peeling occurs, discontinue use.

The product may bleach dyed fabrics.

PanOxyl 5 Aquagel contains propylene glycol. Propylene glycol may cause skin irritation.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None

4.6 Pregnancy And Lactation

There are no restriction on the use of PanOxyl Aquagel in pregnancy and lactation.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

None

4.9 Overdose

Not applicable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Benzoyl peroxide has sebostatic and keratolytic activity coupled with antibacterial activity against Propionibacterium acnes, the organism implicated in acne vulgaris. Its use in the treatment of acne is well established.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

Not applicable. Benzoyl peroxide has been in widespread use for many years.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Carbomer 940

Di-isopropanolamine

Propylene glycol

Polyoxyethylene lauryl ether

Sodium lauryl sulphate

Purified water

6.2 Incompatibilities

None

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Internally lacquered aluminium tubes with screw caps. Licensed pack sizes: 40g and 50g.

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions for use or handling of PanOxyl Aquagel 5.

7. Marketing Authorisation Holder

GlaxoSmithKline UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as Stiefel

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

8. Marketing Authorisation Number(S)

PL 19494/0058

9. Date Of First Authorisation/Renewal Of The Authorisation

21st August 1984

10. Date Of Revision Of The Text

18 October 2011


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Polytar AF


1. Name Of The Medicinal Product

Polytar AF

2. Qualitative And Quantitative Composition

Tar Blend 1% w/w, Zinc Pyrithione 1% w/w in a shampoo base

Tar Blend comprises:

Pine tar, Cade oil, Coal Tar Solution, Arachis Oil extract of Coal Tar.

3. Pharmaceutical Form

Medicated Shampoo

4. Clinical Particulars 4.1 Therapeutic Indications

Polytar AF is indicated in the topical treatment of scalp disorders such as dandruff, seborrhoeic dermatitis and psoriasis.

4.2 Posology And Method Of Administration

Shake the bottle before use. Wet the hair and massage Polytar AF into the hair, scalp and surrounding skin. Leave for 2-3 minutes, then rinse thoroughly.

Polytar AF should be used two or three times weekly for at least 3 weeks or until the condition clears.

4.3 Contraindications

Polytar AF should not be used by patients with known hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Avoid contact with the eyes. Tar products may cause skin irritation, rashes and, rarely, photosensitivity. Zinc pyrithione may cause dermatitis, should this occur, Polytar AF should be discontinued.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

The safety of Polytar AF in human pregnancy and lactation has not been established.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

None.

4.9 Overdose

Not applicable.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Tar blend:

Tars suppress DNA synthesis in hyperplastic skin, this inhibits mitotic activity and protein synthesis. By decreasing proliferation and dermal infiltration, they promote a return to normal keratinisation. Tars also have vasoconstricting astringent and antipruritic properties.

Zinc Pyrithione:

Zinc Pyrithione has antibacterial and antifungal properties. It is fungicidal against the pathogenic yeasts of the pityrosporum genus which are implicated in dandruff and seborrhoeic dermatitis.

5.2 Pharmacokinetic Properties

Not Applicable.

5.3 Preclinical Safety Data

Not Applicable.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Coconut diethanolamide

Triethanolamine Lauryl Sulphate

Carbomer

Sodium Hydroxide

Hypromellose

Octoxinol

Glycerol

Imidurea

Purified Water

6.2 Incompatibilities

None

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Store below 25oC

6.5 Nature And Contents Of Container

High density polyethylene bottles of 25ml, 65ml, 150ml, 250ml, 350ml, 400ml, 1000ml

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions for use or handling of Polytar AF.

7. Marketing Authorisation Holder

GlaxoSmithKline UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as Stiefel

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

8. Marketing Authorisation Number(S)

PL 19494/0061

9. Date Of First Authorisation/Renewal Of The Authorisation

16th March 1992.

10. Date Of Revision Of The Text

20 December 2010


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Aclasta 5 mg solution for infusion


1. Name Of The Medicinal Product

Aclasta 5 mg solution for infusion

2. Qualitative And Quantitative Composition

Each bottle with 100 ml of solution contains 5 mg zoledronic acid (as monohydrate).

Each ml of the solution contains 0.05 mg zoledronic acid anhydrous, corresponding to 0.0533 mg zoledronic acid monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for infusion

Clear and colourless solution.

4. Clinical Particulars 4.1 Therapeutic Indications

Treatment of osteoporosis

• in post-menopausal women

• in men

at increased risk of fracture, including those with a recent low-trauma hip fracture.

Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy

• in post-menopausal women

• in men

at increased risk of fracture.

Treatment of Paget's disease of the bone in adults.

4.2 Posology And Method Of Administration

Posology

For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy, the recommended dose is a single intravenous infusion of 5 mg Aclasta administered once a year.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established.

The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Aclasta on an individual patient basis, particularly after 5 or more years of use.

In patients with a recent low-trauma hip fracture, it is recommended to give the Aclasta infusion two or more weeks after hip fracture repair (see section 5.1).

For the treatment of Paget's disease, Aclasta should be prescribed only by physicians with experience in the treatment of Paget's disease of the bone. The recommended dose is a single intravenous infusion of 5 mg Aclasta.

Re-treatment of Paget's disease: specific re-treatment data are not available. After a single treatment with Aclasta in Paget's disease an extended remission period is observed in responding patients. However, re-treatment with Aclasta may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, in patients who failed to achieve normalisation of serum alkaline phosphatase, or in patients with symptoms, as dictated by medical practice (see section 5.1).

Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important for the elderly and for patients receiving diuretic therapy.

Adequate calcium and vitamin D intake are recommended in association with Aclasta administration. In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Aclasta administration (see section 4.4).

In patients with a recent low-trauma hip fracture, a loading dose of 50,000 to 125,000 IU of vitamin D given orally or via the intramuscular route is recommended prior to the first Aclasta infusion.

The incidence of post-dose symptoms occurring within the first three days after administration of Aclasta can be reduced with the administration of paracetamol or ibuprofen shortly following Aclasta administration.

Patients with renal impairment

Aclasta is contraindicated in patients with creatinine clearance < 35 ml/min (see sections 4.3 and 4.4).

No dose adjustment is necessary in patients with creatinine clearance

Patients with hepatic impairment

No dose adjustment is required (see section 5.2).

Elderly patients (

No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.

Paediatric population

The safety and efficacy of Aclasta in children and adolescents below 18 years of age have not been established.

Method of administration

Intravenous use.

Aclasta (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line and given at a constant infusion rate. The infusion time must not be less than 15 minutes. For information on the infusion of Aclasta, see section 6.6.

4.3 Contraindications

- Hypersensitivity to the active substance, to any bisphosphonates or to any of the excipients.

- Patients with hypocalcaemia (see section 4.4).

- Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4).

- Pregnancy and breast-feeding (see section 4.6).

4.4 Special Warnings And Precautions For Use

The use of Aclasta in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.

Renal impairment has been observed following the administration of Aclasta (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring after Aclasta administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.

The following precautions should be taken into account to minimise the risk of renal adverse reactions:

• Creatinine clearance should be measured before each Aclasta dose.

• Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.

• Monitoring of serum creatinine should be considered in at-risk patients.

• Aclasta should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5).

• Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of Aclasta.

• A single dose of Aclasta should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2).

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Aclasta (see section 4.3). Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.

Elevated bone turnover is a characteristic of Paget's disease of the bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of Aclasta (see section 4.8).

Adequate calcium and vitamin D intake are recommended in association with Aclasta administration. In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Aclasta administration (see section 4.2). Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring during the period of risk. Measurement of serum calcium before infusion of Aclasta is recommended for patients with Paget?s disease.

Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Aclasta (see section 4.8).

Aclasta contains the same active substance found in Zometa (zoledronic acid), used for oncology indications, and a patient being treated with Zometa should not be treated with Aclasta.

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw has been reported predominantly in patients with cancer receiving treatment regimens including bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies with other medicinal products have been performed. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see section 5.2). Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions resulting from displacement of highly protein-bound drugs are therefore unlikely.

Zoledronic acid is eliminated by renal excretion. Caution is indicated when Aclasta is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration) (see section 4.4).

In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data on the use of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive toxicological effects including malformations (see section 5.3). The potential risk for humans is unknown.

Breast-feeding

It is not known whether zoledronic acid is excreted into human breast milk. Aclasta is contraindicated during pregnancy and in breast-feeding women (see section 4.3).

Women of childbearing potential

Aclasta is not recommended in women of childbearing potential.

Fertility

Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered related to the compound's inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded determining a definitive effect of Aclasta on fertility in humans.

4.7 Effects On Ability To Drive And Use Machines

Adverse reactions, such as dizziness, may affect the ability to drive or use machines, though no studies on this effect with Aclasta have been performed.

4.8 Undesirable Effects

The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first infusion was: fever (17.1%), myalgia (7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache (5.1%). The incidence of these reactions decreased markedly with subsequent annual doses of Aclasta. The majority of these reactions occur within the first three days following Aclasta administration. The majority of these reactions were mild to moderate and resolved within three days of the event onset. The percentage of patients who experienced adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against adverse reactions was used as described below.

The incidence of adverse reactions occurring within the first three days after administration of Aclasta can be reduced with the administration of paracetamol or ibuprofen shortly following Aclasta administration as needed (see section 4.2).

In the HORIZON - Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving Aclasta and placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving Aclasta (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable between Aclasta (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled incidences were 1.3% for Aclasta and 0.8% for placebo.

Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (

Table 1

Infections and infestations

Uncommon

Influenza, nasopharyngitis

Blood and lymphatic system disorders

Uncommon

Anaemia

Immune system disorders

Not known**

Hypersensitivity reactions including rare cases of bronchoconstriction, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock

Metabolism and nutrition disorders

Common

Hypocalcaemia*

 

Uncommon

Anorexia, decreased appetite

Psychatric disorders

Uncommon

Insomnia

Nervous system disorders

Common

Headache, dizziness

 

Uncommon

Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia

Eye disorders

Common

Ocular hyperaemia

 

Uncommon

Conjunctivitis, eye pain

 

Rare

Uveitis, episcleritis, iritis

 

Not known**

Scleritis and orbital inflammation

Ear and labyrinth disorders

Uncommon

Vertigo

Cardiac disorders

Common

Atrial fibrillation

 

Uncommon

Palpitations

Vascular disorders

Uncommon

Hypertension, flushing

 

Not known**

Hypotension (some of the patients had underlying risk factors)

Respiratory, thoracic and mediastinal disorders

Uncommon

Cough, dyspnoea

Gastrointestinal disorders

Common

Nausea, vomiting, diarrhoea

 

Uncommon

Dyspepsia, abdominal pain upper, abdominal pain, gastroesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis#

Skin and subcutaneous tissue disorders

Uncommon

Rash, hyperhydrosis, pruritus, erythema

Musculoskeletal and connective tissue disorders

Common

Myalgia, arthralgia, bone pain, back pain, pain in extremity

 

Uncommon

Neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, shoulder pain, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness

 

Rare

Atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction)

 

Not known**

Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects)

Renal and urinary disorders

Uncommon

Blood creatinine increased, pollakiuria, proteinuria

 

Not known**

Renal impairment. Rare cases of renal failure requiring dialysis and rare cases with a fatal outcome have been reported in patients with pre-existing renal dysfunction or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period (see sections 4.4 and 4.8 Class effects)

General disorders and administration site conditions

Very common

Fever

Common

Flu-like symptoms, chills, fatigue, asthenia, pain, malaise, infusion site reaction

 

 

Uncommon

Peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain

 

Not known**

Dehydration secondary to post-dose symptoms such as fever, vomiting and diarrhoea

Investigations

Common

C-reactive protein increased

 

Uncommon

Blood calcium decreased

# Observed in patients taking concomitant glucocorticosteroids.

* Common in Paget's disease only.

** Based on post-marketing reports. Frequency cannot be estimated from available data.

† Identified in post-marketing experience.

   

Class effects:

Renal impairment

Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or additional risk factors (e.g advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of them receiving a 4 mg dose every 3–4 weeks, but it has been observed in patients after a single administration.

In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Aclasta and placebo treatment groups over three years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of Aclasta-treated patients versus 0.8% of placebo-treated patients.

Hypocalcaemia

In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/l) following Aclasta administration. No symptomatic cases of hypocalcaemia were observed.

In the Paget's disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in all of whom it resolved.

Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range (less than 2.10 mmol/l) occurred in 2.3% of Aclasta-treated patients in a large clinical trial compared to 21% of Aclasta-treated patients in the Paget's disease trials. The frequency of hypocalcaemia was much lower following subsequent infusions.

All patients received adequate supplementation with vitamin D and calcium in the post-menopausal osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget's disease trials (see also section 4.2). In the trial for the prevention of clinical fractures following a recent hip fracture, vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin D prior to Aclasta administration (see section 4.2).

Local reactions

In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were reported (0.7%) following the administration of zoledronic acid.

Osteonecrosis of the jaw

Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported, predominantly in cancer patients treated with bisphosphonates, including zoledronic acid. Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with Aclasta and one patient treated with placebo. Both cases resolved.

4.9 Overdose

Clinical experience with acute overdose is limited. Patients who have received doses higher than those recommended should be carefully monitored. In the event of overdose leading to clinically significant hypocalcaemia, reversal may be achieved with supplemental oral calcium and/or an intravenous infusion of calcium gluconate.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08

Mechanism of action

Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.

Pharmacodynamic effects

The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone.

The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.

Aclasta treatment rapidly reduced the rate of bone turnover from elevated post-menopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.

Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT)

The efficacy and safety of Aclasta 5 mg once a year for 3 consecutive years were demonstrated in post-menopausal women (7,736 women aged 65-89 years) with either: a femoral neck bone mineral density (BMD) with a T-score

Effect on morphometric vertebral fractures

Aclasta significantly decreased the incidence of one or more new vertebral fractures over three years and as early as the one year timepoint (see Table 2).

Table 2 Summary of vertebral fracture efficacy at 12, 24 and 36 months

Outcome

Aclasta (%)

Placebo (%)

Absolute reduction in fracture incidence % (CI)

Relative reduction in fracture incidence % (CI)

At least one new vertebral fracture (0-1 year)

1.5

3.7

2.2 (1.4, 3.1)

60 (43, 72)**

At least one new vertebral fracture (0-2 year)

2.2

7.7

5.5 (4.4, 6.6)

71 (62, 78)**

At least one new vertebral fracture (0-3 year)

3.3

10.9

7.6 (6.3, 9.0)

70 (62, 76)**

** p <0.0001

       

Aclasta-treated patients aged 75 years and older exhibited a 60% reduction in the risk of vertebral fractures compared to placebo patients (p<0.0001).

Effect on hip fractures

Aclasta demonstrated a consistent effect over 3 years, resulting in a 41% reduction in the risk of hip fractures (95% CI, 17% to 58%). The hip fracture event rate was 1.44% for Aclasta-treated patients compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-na?ve patients and 42% in patients allowed to take concomitant osteoporosis therapy.

Effect on all clinical fractures

All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 3.

Table 3 Between treatment comparisons of the incidence of key clinical fracture variables over 3 years

Outcome

Aclasta

(N=3,875)

event rate (%)

Placebo

(N=3,861)

event rate (%)

Absolute reduction in fracture event rate % (CI)

Relative risk reduction in fracture incidence % (CI)

Any clinical fracture (1)

8.4

12.8

4.4 (3.0, 5.8)

33 (23, 42)**

Clinical vertebral fracture (2)

0.5

2.6

2.1 (1.5, 2.7)

77 (63, 86)**

Non-vertebral fracture (1)

8.0

10.7

2.7 (1.4, 4.0)

25 (13, 36)*

*p-value <0.001, **p-value <0.0001

(1) Excluding finger, toe and facial fractures

(2) Including clinical thoracic and clinical lumbar vertebral fractures

       

Effect on bone mineral density (BMD)

Aclasta significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatment with placebo at all timepoints (6, 12, 24 and 36 months). Treatment with Aclasta resulted in a 6.7% increase in BMD at the lumbar spine, 6.0% at the total hip, 5.1% at the femoral neck, and 3.2% at the distal radius over 3 years as compared to placebo.

Bone histology

Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in 152 post-menopausal patients with osteoporosis treated with Aclasta (N=82) or placebo (N=70). Histomorphometric analysis showed a 63% reduction in bone turnover. In patients treated with Aclasta, no osteomalacia, marrow fibrosis or woven bone formation was detected. Tetracycline label was detectable in all but one of 82 biopsies obtained from patients on Aclasta. Microcomputed tomography (?CT) analysis demonstrated increased trabecular bone volume and preservation of trabecular bone architecture in patients treated with Aclasta compared to placebo.

Bone turnover markers

Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and serum beta-C-telopeptides (b-CTx) were evaluated in subsets ranging from 517 to 1,246 patients at periodic intervals throughout the study. Treatment with a 5 mg annual dose of Aclasta significantly reduced BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baseline levels at 36 months. P1NP was significantly reduced by 61% below baseline levels at 12 months and was sustained at 52% below baseline levels at 36 months. B-CTx was significantly reduced by 61% below baseline levels at 12 months and was sustained at 55% below baseline levels at 36 months. During this entire time period bone turnover markers were within the pre-menopausal range at the end of each year. Repeat dosing did not lead to further reduction of bone turnover markers.

Effect on height

In the three-year osteoporosis study standing height was measured annually using a stadiometer. The Aclasta group revealed approximately 2.5 mm less height loss compared to placebo (95% CI: 1.6 mm, 3.5 mm) [p<0.0001].

Days of disability

Aclasta significantly reduced the mean days of limited activity and the days of bed rest due to back pain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the mean days of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectively compared to placebo (all p<0.01).

Clinical efficacy in the treatment of osteoporosis in patients at increased risk of fracture after a recent hip fracture (RFT)

The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 2,127 men and women aged 50-95 years (mean age 74.5 years) with a recent (within 90 days) low-trauma hip fracture who were followed for an average of 2 years on study medication. Approximately 42% of patients had a femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a femoral neck BMD T-score above -2.5. Aclasta was administered once a year, until at least 211 patients in the study population had confirmed clinical fractures. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the majority of patients 2 weeks prior to infusion. All participants received 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementation per day. Ninety-five percent of the patients received their infusion two or more weeks after the hip fracture repair and the median timing of infusion was approximately six weeks after the hip fracture repair. The primary efficacy variable was the incidence of clinical fractures over the duration of the study.

Effect on all clinical fractures

The incidence rates of key clinical fracture variables are presented in Table 4.

Table 4 Between treatment comparisons of the incidence of key clinical fracture variables

Outcome

Aclasta

(N=1,065)

event rate (%)

Placebo

(N=1,062)

event rate (%)

Absolute reduction in fracture event rate % (CI)

Relative risk reduction in fracture incidence % (CI)

Any clinical fracture (1)

8.6

13.9

5.3 (2.3, 8.3)

35 (16, 50)**

Clinical vertebral fracture (2)

1.7

3.8

2.1 (0.5, 3.7)

46 (8, 68)*

Non-vertebral fracture (1)

7.6

10.7

3.1 (0.3, 5.9)

27 (2, 45)*

*p-value <0.05, **p-value <0.01

(1) Excluding finger, toe and facial fractures

(2) Including clinical thoracic and clinical lumbar vertebral fractures

       

The study was not designed to measure significant differences in hip fracture, but a trend was seen towards reduction in new hip fractures.

All cause mortality was 10% (101 patients) in the Aclasta-treated group compared to 13% (141 patients) in the placebo group. This corresponds to a 28% reduction in the risk of all cause mortality (p=0.01).

The incidence of delayed hip fracture healing was comparable between Aclasta (34 [3.2%]


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Anucort-HC cream, ointment, suppository


Generic Name: hydrocortisone rectal (cream, ointment, suppository) (hye dro KORT i zone REK tal)
Brand Names: Anucort-HC, Anumed-HC, Anusol-HC, Cortizone-10 Anal Itch Cream, Hemorrhoidal HC, Hemril-30, Hemril-HC Uniserts, Preparation H Hydrocortisone, Procto-Kit 1%, Procto-Kit 2.5%, Procto-Pak 1%, Proctocort, Proctocream-HC, Proctosert HC, Proctosol-HC, Proctozone HC, Proctozone-H, Recort Plus, Rectasol-HC, Tucks HC

What is hydrocortisone rectal?

Hydrocortisone is a steroid medicine that reduces inflammation in the body.

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Hydrocortisone rectal is used to treat itching or swelling caused by hemorrhoids or other inflammatory conditions of the rectum or anus.

Hydrocortisone rectal is also used together with other medications to treat ulcerative colitis, proctitis, and other inflammatory conditions of the lower intestines and rectal area.

Hydrocortisone rectal may also be used for purposes not listed in this medication guide.

What is the most important information I should know about hydrocortisone rectal?

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Call your doctor at once if you have any bleeding from your rectum, feeling short of breath (even with mild exertion), swelling of your ankles or feet, or rapid weight gain.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

What should I discuss with my health care provider before using hydrocortisone rectal?

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

congestive heart failure;

a history of tuberculosis;

stomach ulcer or diverticulitis;

a colostomy or ileostomy;

fever or any type of infection;

kidney disease;

high blood pressure; or

myasthenia gravis.

Also tell your doctor if you have diabetes. Steroid medicines may increase the glucose (sugar) levels in your blood or urine. You may also need to adjust the dose of your diabetes medications.

FDA pregnancy category C. It is not known whether hydrocortisone rectal will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether hydrocortisone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I use hydrocortisone rectal?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Wash your hands before and after using this medicine.

Try to empty your bowel and bladder just before using hydrocortisone rectal.

Remove the outer wrapper from the suppository before inserting it. Avoid handling the suppository too long or it will melt in your hands. The rectal suppository can stain clothing or other fabrics it comes into contact with.

For best results from the suppository, lie down after inserting it and hold in the suppository. The suppository will melt quickly once inserted and you should feel little or no discomfort while holding it in.

For best results from the cream, use only the applicator provided with the medication. Otherwise, follow the directions provided with your rectal cream.

Avoid using the bathroom for one to three hours after inserting the cream or suppository.

Apply the ointment to the rectum and surrounding skin of the rectal area as directed on the package label.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

Store the rectal cream at room temperature away from moisture and heat. Store the rectal suppositories at cool room temperature away from moisture and heat. Do not refrigerate or freeze them. What happens if I miss a dose?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of hydrocortisone rectal is not expected to produce life-threatening symptoms. However, long-term use of high steroid doses can lead to symptoms such as thinning skin, easy bruising, changes in the shape or location of body fat (especially in your face, neck, back, and waist), increased acne or facial hair, menstrual problems, impotence, or loss of interest in sex.

What should I avoid while using hydrocortisone rectal ?

Avoid getting a vaccine during your treatment with hydrocortisone rectal. Vaccines may not work as well while you are using a steroid medicine.

Hydrocortisone rectal side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

feeling short of breath, even with mild exertion;

swelling of your ankles or feet;

muscle weakness;

rapid weight gain, especially in your face and midsection;

severe rectal pain or burning;

bleeding from your rectum;

severe stomach pain;

sudden and severe headache or pain behind your eyes; or

seizure (convulsions).

Less serious side effects may include:

mild rectal pain or burning;

acne;

changes in your menstrual periods;

increased sweating; or

increased facial or body hair growth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect hydrocortisone rectal ?

Before using hydrocortisone rectal, tell your doctor if you also use insulin or take oral diabetes medication.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Anucort-HC resources Anucort-HC Side Effects (in more detail) Anucort-HC Use in Pregnancy & Breastfeeding Anucort-HC Drug Interactions Anucort-HC Support Group 1 Review for Anucort-HC - Add your own review/rating Compare Anucort-HC with other medications Anal Itching Aphthous Stomatitis, Recurrent Atopic Dermatitis Dermatitis Eczema Gingivitis Hemorrhoids Proctitis Pruritus Psoriasis Seborrheic Dermatitis Where can I get more information? Your pharmacist can provide more information about hydrocortisone rectal cream, ointment, or suppository.

See also: Anucort-HC side effects (in more detail)


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Procto-Pak 1% cream, ointment, suppository


Generic Name: hydrocortisone rectal (cream, ointment, suppository) (hye dro KORT i zone REK tal)
Brand Names: Anucort-HC, Anumed-HC, Anusol-HC, Cortizone-10 Anal Itch Cream, Hemorrhoidal HC, Hemril-30, Hemril-HC Uniserts, Preparation H Hydrocortisone, Procto-Kit 1%, Procto-Kit 2.5%, Procto-Pak 1%, Proctocort, Proctocream-HC, Proctosert HC, Proctosol-HC, Proctozone HC, Proctozone-H, Recort Plus, Rectasol-HC, Tucks HC

What is hydrocortisone rectal?

Hydrocortisone is a steroid medicine that reduces inflammation in the body.

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Hydrocortisone rectal is used to treat itching or swelling caused by hemorrhoids or other inflammatory conditions of the rectum or anus.

Hydrocortisone rectal is also used together with other medications to treat ulcerative colitis, proctitis, and other inflammatory conditions of the lower intestines and rectal area.

Hydrocortisone rectal may also be used for purposes not listed in this medication guide.

What is the most important information I should know about hydrocortisone rectal?

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Call your doctor at once if you have any bleeding from your rectum, feeling short of breath (even with mild exertion), swelling of your ankles or feet, or rapid weight gain.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

What should I discuss with my health care provider before using hydrocortisone rectal?

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

congestive heart failure;

a history of tuberculosis;

stomach ulcer or diverticulitis;

a colostomy or ileostomy;

fever or any type of infection;

kidney disease;

high blood pressure; or

myasthenia gravis.

Also tell your doctor if you have diabetes. Steroid medicines may increase the glucose (sugar) levels in your blood or urine. You may also need to adjust the dose of your diabetes medications.

FDA pregnancy category C. It is not known whether hydrocortisone rectal will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether hydrocortisone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I use hydrocortisone rectal?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Wash your hands before and after using this medicine.

Try to empty your bowel and bladder just before using hydrocortisone rectal.

Remove the outer wrapper from the suppository before inserting it. Avoid handling the suppository too long or it will melt in your hands. The rectal suppository can stain clothing or other fabrics it comes into contact with.

For best results from the suppository, lie down after inserting it and hold in the suppository. The suppository will melt quickly once inserted and you should feel little or no discomfort while holding it in.

For best results from the cream, use only the applicator provided with the medication. Otherwise, follow the directions provided with your rectal cream.

Avoid using the bathroom for one to three hours after inserting the cream or suppository.

Apply the ointment to the rectum and surrounding skin of the rectal area as directed on the package label.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

Store the rectal cream at room temperature away from moisture and heat. Store the rectal suppositories at cool room temperature away from moisture and heat. Do not refrigerate or freeze them. What happens if I miss a dose?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of hydrocortisone rectal is not expected to produce life-threatening symptoms. However, long-term use of high steroid doses can lead to symptoms such as thinning skin, easy bruising, changes in the shape or location of body fat (especially in your face, neck, back, and waist), increased acne or facial hair, menstrual problems, impotence, or loss of interest in sex.

What should I avoid while using hydrocortisone rectal ?

Avoid getting a vaccine during your treatment with hydrocortisone rectal. Vaccines may not work as well while you are using a steroid medicine.

Hydrocortisone rectal side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

feeling short of breath, even with mild exertion;

swelling of your ankles or feet;

muscle weakness;

rapid weight gain, especially in your face and midsection;

severe rectal pain or burning;

bleeding from your rectum;

severe stomach pain;

sudden and severe headache or pain behind your eyes; or

seizure (convulsions).

Less serious side effects may include:

mild rectal pain or burning;

acne;

changes in your menstrual periods;

increased sweating; or

increased facial or body hair growth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect hydrocortisone rectal ?

Before using hydrocortisone rectal, tell your doctor if you also use insulin or take oral diabetes medication.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Procto-Pak 1% resources Procto-Pak 1% Side Effects (in more detail) Procto-Pak 1% Use in Pregnancy & Breastfeeding Procto-Pak 1% Drug Interactions Procto-Pak 1% Support Group 0 Reviews for Procto-Pak% - Add your own review/rating Compare Procto-Pak 1% with other medications Anal Itching Aphthous Stomatitis, Recurrent Atopic Dermatitis Dermatitis Eczema Gingivitis Hemorrhoids Proctitis Pruritus Psoriasis Seborrheic Dermatitis Ulcerative Colitis, Active Where can I get more information? Your pharmacist can provide more information about hydrocortisone rectal cream, ointment, or suppository.

See also: Procto-Pak% side effects (in more detail)


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Proctosol-HC cream, ointment, suppository


Generic Name: hydrocortisone rectal (cream, ointment, suppository) (hye dro KORT i zone REK tal)
Brand Names: Anucort-HC, Anumed-HC, Anusol-HC, Cortizone-10 Anal Itch Cream, Hemorrhoidal HC, Hemril-30, Hemril-HC Uniserts, Preparation H Hydrocortisone, Procto-Kit 1%, Procto-Kit 2.5%, Procto-Pak 1%, Proctocort, Proctocream-HC, Proctosert HC, Proctosol-HC, Proctozone HC, Proctozone-H, Recort Plus, Rectasol-HC, Tucks HC

What is hydrocortisone rectal?

Hydrocortisone is a steroid medicine that reduces inflammation in the body.

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Hydrocortisone rectal is used to treat itching or swelling caused by hemorrhoids or other inflammatory conditions of the rectum or anus.

Hydrocortisone rectal is also used together with other medications to treat ulcerative colitis, proctitis, and other inflammatory conditions of the lower intestines and rectal area.

Hydrocortisone rectal may also be used for purposes not listed in this medication guide.

What is the most important information I should know about hydrocortisone rectal?

The information in this medication guide is specific to hydrocortisone rectal cream, ointment, or suppository.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Call your doctor at once if you have any bleeding from your rectum, feeling short of breath (even with mild exertion), swelling of your ankles or feet, or rapid weight gain.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

What should I discuss with my health care provider before using hydrocortisone rectal?

Ask a doctor or pharmacist if it is safe for you to use this medicine if you have:

congestive heart failure;

a history of tuberculosis;

stomach ulcer or diverticulitis;

a colostomy or ileostomy;

fever or any type of infection;

kidney disease;

high blood pressure; or

myasthenia gravis.

Also tell your doctor if you have diabetes. Steroid medicines may increase the glucose (sugar) levels in your blood or urine. You may also need to adjust the dose of your diabetes medications.

FDA pregnancy category C. It is not known whether hydrocortisone rectal will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether hydrocortisone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. How should I use hydrocortisone rectal?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Do not take hydrocortisone rectal by mouth. It is for use only in your rectum.

This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions. You may need to use this medication for up to 8 weeks.

Wash your hands before and after using this medicine.

Try to empty your bowel and bladder just before using hydrocortisone rectal.

Remove the outer wrapper from the suppository before inserting it. Avoid handling the suppository too long or it will melt in your hands. The rectal suppository can stain clothing or other fabrics it comes into contact with.

For best results from the suppository, lie down after inserting it and hold in the suppository. The suppository will melt quickly once inserted and you should feel little or no discomfort while holding it in.

For best results from the cream, use only the applicator provided with the medication. Otherwise, follow the directions provided with your rectal cream.

Avoid using the bathroom for one to three hours after inserting the cream or suppository.

Apply the ointment to the rectum and surrounding skin of the rectal area as directed on the package label.

Call your doctor if your symptoms do not improve or if they get worse after using this medicine for a few days.

Store the rectal cream at room temperature away from moisture and heat. Store the rectal suppositories at cool room temperature away from moisture and heat. Do not refrigerate or freeze them. What happens if I miss a dose?

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose? Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of hydrocortisone rectal is not expected to produce life-threatening symptoms. However, long-term use of high steroid doses can lead to symptoms such as thinning skin, easy bruising, changes in the shape or location of body fat (especially in your face, neck, back, and waist), increased acne or facial hair, menstrual problems, impotence, or loss of interest in sex.

What should I avoid while using hydrocortisone rectal ?

Avoid getting a vaccine during your treatment with hydrocortisone rectal. Vaccines may not work as well while you are using a steroid medicine.

Hydrocortisone rectal side effects Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have a serious side effect such as:

feeling short of breath, even with mild exertion;

swelling of your ankles or feet;

muscle weakness;

rapid weight gain, especially in your face and midsection;

severe rectal pain or burning;

bleeding from your rectum;

severe stomach pain;

sudden and severe headache or pain behind your eyes; or

seizure (convulsions).

Less serious side effects may include:

mild rectal pain or burning;

acne;

changes in your menstrual periods;

increased sweating; or

increased facial or body hair growth.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect hydrocortisone rectal ?

Before using hydrocortisone rectal, tell your doctor if you also use insulin or take oral diabetes medication.

There may be other drugs that can interact with hydrocortisone rectal. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Proctosol-HC resources Proctosol-HC Side Effects (in more detail) Proctosol-HC Use in Pregnancy & Breastfeeding Proctosol-HC Drug Interactions Proctosol-HC Support Group 2 Reviews for Proctosol-HC - Add your own review/rating Compare Proctosol-HC with other medications Anal Itching Aphthous Stomatitis, Recurrent Atopic Dermatitis Dermatitis Eczema Gingivitis Hemorrhoids Proctitis Pruritus Psoriasis Seborrheic Dermatitis Ulcerative Colitis, Active Where can I get more information? Your pharmacist can provide more information about hydrocortisone rectal cream, ointment, or suppository.

See also: Proctosol-HC side effects (in more detail)


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Cytoxan


Generic Name: cyclophosphamide
Dosage Form: injection, powder, for solution; tablets
Cytoxan®
(cyclophosphamide for injection, USP)
Cytoxan® Tablets
(cyclophosphamide tablets, USP) Cytoxan Description

Cytoxan® (cyclophosphamide for injection, USP) is a sterile white powder containing cyclophosphamide monohydrate. Cytoxan Tablets (cyclophosphamide tablets, USP) are for oral use and contain 25 mg or 50 mg cyclophosphamide (anhydrous). Inactive ingredients in Cytoxan Tablets are: acacia, FD&C Blue No. 1, D&C Yellow No. 10 Aluminum Lake, lactose, magnesium stearate, starch, stearic acid and talc. Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder with the molecular formula C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate. Cyclophosphamide is soluble in water, saline, or ethanol and has the following structural formula:

Cytoxan - Clinical Pharmacology

Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA.

Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is responsible for either the therapeutic or toxic effects of cyclophosphamide. Although elevated levels of metabolites of cyclophosphamide have been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated.

Indications and Usage for Cytoxan Malignant Diseases

Cytoxan, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. The following malignancies are often susceptible to Cytoxan treatment:

Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. Multiple myeloma. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children (Cytoxan given during remission is effective in prolonging its duration). Mycosis fungoides (advanced disease). Neuroblastoma (disseminated disease). Adenocarcinoma of the ovary. Retinoblastoma. Carcinoma of the breast. Nonmalignant Disease
Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children

Cytoxan is useful in carefully selected cases of biopsy proven “minimal change” nephrotic syndrome in children but should not be used as primary therapy. In children whose disease fails to respond adequately to appropriate adrenocorticosteroid therapy or in whom the adrenocorticosteroid therapy produces or threatens to produce intolerable side effects, Cytoxan may induce a remission. Cytoxan is not indicated for the nephrotic syndrome in adults or for any other renal disease.

Contraindications

Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone marrow function. Cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to it. See WARNINGS and PRECAUTIONS.

Warnings Carcinogenesis, Mutagenesis, and Impairment of Fertility

Second malignancies have developed in some patients treated with cyclophosphamide used alone or in association with other antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myeloproliferative, or lymphoproliferative malignancies. Second malignancies most frequently were detected in patients treated for primary myeloproliferative or lymphoproliferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically.

In some cases, the second malignancy developed several years after cyclophosphamide treatment had been discontinued. In a single breast cancer trial utilizing two to four times the standard dose of cyclophosphamide in conjunction with doxorubicin a small number of cases of secondary acute myeloid leukemia occurred within two years of treatment initiation. Urinary bladder malignancies generally have occurred in patients who previously had hemorrhagic cystitis. In patients treated with cyclophosphamide-containing regimens for a variety of solid tumors, isolated case reports of secondary malignancies have been published. One case of carcinoma of the renal pelvis was reported in a patient receiving long-term cyclophosphamide therapy for cerebral vasculitis. The possibility of cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug.

Cyclophosphamide can cause fetal harm when administered to a pregnant woman and such abnormalities have been reported following cyclophosphamide therapy in pregnant women. Abnormalities were found in two infants and a six-month-old fetus born to women treated with cyclophosphamide. Ectrodactylia was found in two of the three cases. Normal infants have also been born to women treated with cyclophosphamide during pregnancy, including the first trimester. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients.

Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a significant proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. Girls treated with cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late prepubescence has been reported. Girls treated with cyclophosphamide during prepubescence subsequently have conceived.

Men treated with cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin but normal testosterone secretion. Sexual potency and libido are unimpaired in these patients. Boys treated with cyclophosphamide during prepubescence develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Men temporarily rendered sterile by cyclophosphamide have subsequently fathered normal children.

Urinary System

Hemorrhagic cystitis may develop in patients treated with cyclophosphamide. Rarely, this condition can be severe and even fatal. Fibrosis of the urinary bladder, sometimes extensive, also may develop with or without accompanying cystitis. Atypical urinary bladder epithelial cells may appear in the urine. These adverse effects appear to depend on the dose of cyclophosphamide and the duration of therapy. Such bladder injury is thought to be due to cyclophosphamide metabolites excreted in the urine. Forced fluid intake helps to assure an ample output of urine, necessitates frequent voiding, and reduces the time the drug remains in the bladder. This helps to prevent cystitis. Hematuria usually resolves in a few days after cyclophosphamide treatment is stopped, but it may persist. Medical and/or surgical supportive treatment may be required, rarely, to treat protracted cases of severe hemorrhagic cystitis. It is usually necessary to discontinue cyclophosphamide therapy in instances of severe hemorrhagic cystitis.

Cardiac Toxicity

Although a few instances of cardiac dysfunction have been reported following use of recommended doses of cyclophosphamide, no causal relationship has been established. Acute cardiac toxicity has been reported with doses as low as 2.4 g/m2 to as high as 26 g/m2, usually as a portion of an intensive antineoplastic multi-drug regimen or in conjunction with transplantation procedures. In a few instances with high doses of cyclophosphamide, severe, and sometimes fatal, congestive heart failure has occurred after the first cyclophosphamide dose. Histopathologic examination has primarily shown hemorrhagic myocarditis. Hemopericardium has occurred secondary to hemorrhagic myocarditis and myocardial necrosis. Pericarditis has been reported independent of any hemopericardium.

No residual cardiac abnormalities, as evidenced by electrocardiogram or echocardiogram appear to be present in patients surviving episodes of apparent cardiac toxicity associated with high doses of cyclophosphamide.

Cyclophosphamide has been reported to potentiate doxorubicin-induced cardiotoxicity.

Infections

Treatment with cyclophosphamide may cause significant suppression of immune responses. Serious, sometimes fatal, infections may develop in severely immunosuppressed patients. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop viral, bacterial, fungal, protozoan, or helminthic infections.

Other

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported.

Precautions General

Special attention to the possible development of toxicity should be exercised in patients being treated with cyclophosphamide if any of the following conditions are present.

Leukopenia Thrombocytopenia Tumor cell infiltration of bone marrow Previous X-ray therapy Previous therapy with other cytotoxic agents Impaired hepatic function Impaired renal function Laboratory Tests

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Drug Interactions

The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high doses of phenobarbital.

The physician should be alert for possible combined drug actions, desirable or undesirable, involving cyclophosphamide even though cyclophosphamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.

Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of succinylcholine chloride.

If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.

Adrenalectomy

Since cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses of both replacement steroids and cyclophosphamide may be necessary for the adrenalectomized patient.

Wound Healing

Cyclophosphamide may interfere with normal wound healing.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

See WARNINGS for information on carcinogenesis, mutagenesis, and impairment of fertility.

Pregnancy

Pregnancy Category D—See WARNINGS.

Nursing Mothers

Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the potential for tumorigenicity shown for cyclophosphamide in humans, 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

The safety profile of Cytoxan in pediatric patients is similar to that of the adult population (see ADVERSE REACTIONS).

Geriatric Use

Insufficient data from clinical studies of Cytoxan for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determine whether they respond differently than younger patients. In two clinical trials in which cyclophosphamide was compared with paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients who received cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, published reports of clinical trials of cyclophosphamide-containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing experience suggest that elderly patients may be more susceptible to cyclophosphamide toxicities. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patient response (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases).

Adverse Reactions

Information on adverse reactions associated with the use of Cytoxan (cyclophosphamide) is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are described in the WARNINGS section.

Reproductive System

See WARNINGS for information on impairment of fertility.

Digestive System

Nausea and vomiting commonly occur with cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. These adverse drug effects generally remit when cyclophosphamide treatment is stopped.

Skin and Its Structures

Alopecia occurs commonly in patients treated with cyclophosphamide. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive causal relationship to cyclophosphamide has not been established.

Hematopoietic System

Leukopenia occurs in patients treated with cyclophosphamide, is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an initial loading dose of the drug, and less frequently in patients maintained on smaller doses. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.

Thrombocytopenia or anemia develop occasionally in patients treated with Cytoxan. These hematologic effects usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy.

Urinary System

See WARNINGS for information on cystitis and urinary bladder fibrosis.

Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with cyclophosphamide. Such lesions usually resolve following cessation of therapy.

Infections

See WARNINGS for information on reduced host resistance to infections.

Carcinogenesis

See WARNINGS for information on carcinogenesis.

Respiratory System

Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of cyclophosphamide over a prolonged period.

Other

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience.

Overdosage

No specific antidote for cyclophosphamide is known. Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.

Cytoxan Dosage and Administration Treatment of Malignant Diseases
Adults and Children

When used as the only oncolytic drug therapy, the initial course of Cytoxan for patients with no hematologic deficiency usually consists of 40 to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 to 15 mg/kg given every 7 to 10 days or 3 to 5 mg/kg twice weekly.

Oral Cytoxan dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Many other regimens of intravenous and oral Cytoxan have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. Transient decreases in the total white blood cell count to 2000 cells/mm3 (following short courses) or more persistent reduction to 3000 cells/mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.

When Cytoxan is included in combined cytotoxic regimens, it may be necessary to reduce the dose of Cytoxan as well as that of the other drugs.

Cytoxan and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. Patients with compromised renal function may show some measurable changes in pharmacokinetic parameters of Cytoxan metabolism, but there is no consistent evidence indicating a need for Cytoxan dosage modification in patients with renal function impairment.

Treatment of Nonmalignant Diseases
Biopsy Proven “Minimal Change’’ Nephrotic Syndrome in Children

An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of oligospermia and azoospermia increases if the duration of Cytoxan treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of Cytoxan therapy. See PRECAUTIONS concerning hematologic monitoring.

Preparation and Handling of Solutions

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

Add the diluent to the vial and shake it vigorously to dissolve. If the powder fails to dissolve immediately and completely, it is advisable to allow the vial to stand for a few minutes. Use the quantity of diluent shown below to constitute the product:

Dosage Strength Cytoxan
Contains
Cyclophosphamide
Monohydrate Quantity of Diluent 500 mg 534.5 mg 25 mL 1 g 1069.0 mg 50 mL 2 g 2138.0 mg 100 mL For Direct Injection

Cytoxan should be prepared for parenteral use by adding 0.9% sterile sodium chloride solution. Solutions of Cytoxan may be injected intravenously, intramuscularly, intraperitoneally, or intrapleurally if constituted by adding 0.9% sterile sodium chloride solution.

For Infusion

Cytoxan may be prepared for parenteral use by infusion using any of the following methods:

Cytoxan constituted with 0.9% sterile sodium chloride may be infused without further dilution. Cytoxan constituted with 0.9% sterile sodium chloride may be infused following further dilution in the following:
    Dextrose Injection, USP (5% dextrose)
    Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride)
    5% Dextrose and Ringer’s Injection
    Lactated Ringer’s Injection, USP
    Sodium Chloride Injection, USP (0.45% sterile sodium chloride)
    Sodium Lactate Injection, USP (1/6 molar sodium lactate)
Cytoxan sterile powder may be prepared for parenteral use by infusion by adding Sterile Water for Injection, USP. Cytoxan, constituted in water, is hypotonic and should not be injected directly. Prior to infusion, solutions of sterile powder constituted in Sterile Water for Injection, USP must be further diluted in one of the following:
    Dextrose Injection, USP (5% dextrose)
    Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride)
    5% Dextrose and Ringer’s Injection
    Lactated Ringer’s Injection, USP
    Sodium Chloride Injection, USP (0.45% sterile sodium chloride)
    Sodium Lactate Injection, USP (1/6 molar sodium lactate)
Stability of Constituted Parenteral Solutions

Cytoxan (prepared for either direct injection or infusion) is chemically and physically stable for 24 hours at room temperature or for six days in the refrigerator; it does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

The osmolarities of solutions of Cytoxan constituted with water and 0.9% sterile sodium chloride solution are found in the following table:

Cytoxan and Diluent mOsm/L 5 mL water per 100 mg cyclophosphamide (anhydrous) 74 5 mL 0.9% sterile sodium chloride solution per 100 mg cyclophosphamide (anhydrous) 374

Isotonic 0.9% sterile sodium chloride solution has an osmolarity of 289 mOsm/L.

For Oral Administration

Extemporaneous liquid preparations of Cytoxan for oral administration may be prepared by dissolving Cytoxan in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used within 14 days.

How is Cytoxan Supplied

Cytoxan® contains cyclophosphamide monohydrate and is supplied in vials for single dose use.

Cytoxan (cyclophosphamide for injection, USP).

NDC 0015-0502-41 500 mg vial, carton of 1 NDC 0015-0505-41 1.0 g vial, carton of 1 NDC 0015-0506-41 2.0 g vial, carton of 1

Store vials at or below 77° F (25° C). During transport or storage of Cytoxan vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide. Vials containing melted substance can be visually differentiated. Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials. Do not use Cytoxan vials if there are signs of melting.

Cytoxan® Tablets, 25 mg and Cytoxan Tablets, 50 mg, are white tablets with blue flecks containing 25 mg and 50 mg cyclophosphamide (anhydrous), respectively.

Cytoxan Tablets (cyclophosphamide tablets, USP).

NDC 0015-0503-01 50 mg, bottles of 100 NDC 0015-0504-01 25 mg, bottles of 100

Store tablets at or below 77° F (25° C); tablets will withstand brief exposure to temperatures up to 86° F (30° C) but should be protected from temperatures above 86° F (30° C).

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Cytoxan sterile powder for injection, or bottles containing Cytoxan tablets. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

REFERENCES ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1592. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983;1:426-428. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J Clin. 1983;33:258-263. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. Controlling occupational exposure to hazardous drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

Vials Manufactured by:
Baxter Healthcare Corporation
Deerfield, Illinois 60015 USA

Vials Made in Germany

Vials Distributed by:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543

Tablets Manufactured by:
Bristol-Myers Squibb Company
Princeton, New Jersey 08543

Tablets Made in Italy

1175025A2
1050971A4
USA 5638 0612 C 669

Rev September 2005

---------------------------------------------
REPRESENTATIVE PACKAGING

See How Supplied section for a complete list of available packages of Cytoxan.

NDC 0015-0502-41
Cytoxan®
(cyclophosphamide for injection, USP)
500 mg
WARNING: CYTOTOXIC AGENT
Store vial at or below 77° F (25° C).
Rx only

NDC 0015-0505-41
Cytoxan®
(cyclophosphamide for injection, USP)
1 gram
WARNING: CYTOTOXIC AGENT
Store vial at or below 77° F (25° C).
Rx only

NDC 0015-0506-41
Cytoxan®
(cyclophosphamide for injection, USP)
2 gram
WARNING: CYTOTOXIC AGENT
Store vial at or below 77° F (25° C).
Rx only

100 TABLETS
NDC 0015-0503-01
Cytoxan®
(cyclophosphamide tablets, USP)
50 mg
Rx only
WARNING: Cytotoxic Agent
Storage at or below 77° F (25° C) is recommended.
NSN 6505-00-733-5246
Bristol-Myers Squibb Company


Cytoxan 
cyclophosphamide  injection, powder, for solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-0502 Route of Administration INTRAVASCULAR, INTRAMUSCULAR, INTRAPERITONEAL, INTRAPLEURAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cyclophosphamide (cyclophosphamide) cyclophosphamide 500 mg  in 25 mL Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0015-0502-41 1 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE 1 25 mL In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (0015-0502-41)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA012141 06/01/2009 10/31/2011
Cytoxan 
cyclophosphamide  injection, powder, for solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-0505 Route of Administration INTRAVASCULAR, INTRAMUSCULAR, INTRAPERITONEAL, INTRAPLEURAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cyclophosphamide (cyclophosphamide) cyclophosphamide 1 g  in 50 mL Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0015-0505-41 1 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE 1 50 mL In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (0015-0505-41)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA012141 06/01/2009 11/30/2011
Cytoxan 
cyclophosphamide  injection, powder, for solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-0506 Route of Administration INTRAVASCULAR, INTRAMUSCULAR, INTRAPERITONEAL, INTRAPLEURAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cyclophosphamide (cyclophosphamide) cyclophosphamide 2 g  in 100 mL Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0015-0506-41 1 VIAL In 1 CARTON contains a VIAL, SINGLE-DOSE 1 100 mL In 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (0015-0506-41)
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA012141 06/01/2009 08/31/2011
Cytoxan 
cyclophosphamide  tablet Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-0503 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cyclophosphamide (cyclophosphamide) cyclophosphamide 50 mg Inactive Ingredients Ingredient Name Strength acacia   FD&C Blue No. 1   aluminum oxide   D&C Yellow No. 10   lactose   magnesium stearate   stearic acid   talc   Product Characteristics Color WHITE Score no score Shape ROUND Size 11mm Flavor Imprint Code MJ;503;50 Contains          Packaging # NDC Package Description Multilevel Packaging 1 0015-0503-01 100 TABLET In 1 BOTTLE None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA012141 06/01/2009 02/14/2010
Cytoxan 
cyclophosphamide  tablet Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-0504 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength cyclophosphamide (cyclophosphamide) cyclophosphamide 25 mg Inactive Ingredients Ingredient Name Strength acacia   FD&C Blue No. 1   aluminum oxide   D&C Yellow No. 10   lactose   magnesium stearate  
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Ibandronate Sodium


Class: Bone Resorption Inhibitors
VA Class: HS900
Chemical Name: [1-Hydroxy-3-(methylpentylamino)propylidene]diphosphonate trihydrogen sodium monohydrate
Molecular Formula: C9H22NNaO7
CAS Number: 138926-19-9
Brands: Boniva

Special Alerts:

[Posted 07/21/2011] ISSUE: FDA notified healthcare professionals and patients about its ongoing review of data from published studies to evaluate whether use of oral bisphosphonate drugs is associated with an increased risk of cancer of the esophagus. FDA has not concluded that taking an oral bisphosphonate drug increases the risk of esophageal cancer. There are insufficient data to recommend endoscopic screening of asymptomatic patients. FDA will continue to evaluate all available data supporting the safety and effectiveness of bisphosphonate drugs and will update the public when more information becomes available.

BACKGROUND: Oral bisphosphonates are commonly used for the prevention and treatment of osteoporosis as well as to treat other bone diseases such as Paget’s disease. There have been conflicting findings from studies evaluating the risk of esophageal cancer. Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates. See the Data Summary in the Drug Safety Communication for additional details at: .

RECOMMENDATION: Patients should talk with their healthcare professional about the benefits and risks of taking oral bisphosphonates and how long they should expect to take them. Patients should talk with their healthcare professional if they develop swallowing difficulties, chest pain, new or worsening heartburn, or have trouble or pain when swallowing. Patients should be instructed to carefully follow the directions for use of the oral bisphosphonate drug they are prescribed. For more information visit the FDA website at: and .

[Posted 10/13/2010] ISSUE: FDA is updating the public regarding information previously communicated describing the risk of atypical fractures of the thigh, known as subtrochanteric and diaphyseal femur fractures, in patients who take bisphosphonates for osteoporosis. This information will be added to the Warnings and Precautions section of the labels approved to treat osteoporosis, including alendronate (Fosamax), alendronate with cholecalciferol (Fosamax Plus D), risedronate (Actonel and Atelvia), risedronate with calcium carbonate (Actonel with Calcium), ibandronate (Boniva), tiludronate (Skelid), and zoledronic acid (Reclast) and their generic products. A Medication Guide will also be required to be given to patients when they pick up their bisphosphonate prescription.

BACKGROUND:Atypical subtrochanteric femur fractures are fractures in the bone just below the hip joint. Diaphyseal femur fractures occur in the long part of the thigh bone. These fractures are very uncommon and appear to account for less than 1% of all hip and femur fractures overall. Although it is not clear if bisphosphonates are the cause, these unusual femur fractures have been predominantly reported in patients taking bisphosphonates.

RECOMMENDATIONS: Patients should continue to take their medication unless told to stop by their healthcare professional. FDA recommends that healthcare professionals should discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture. For more information visit the FDA website at: and .

[Posted 03/11/2010] FDA notified healthcare professionals and patients that at this point, the data that FDA has reviewed have not shown a clear connection between bisphosphonate use and a risk of atypical subtrochanteric femur fractures. FDA is working with outside experts, including members of the recently convened American Society of Bone and Mineral Research Subtrochanteric Femoral Fracture Task Force, to gather more information and evaluate the issue further.

FDA recommends that healthcare professionals follow the recommendations in the drug label when prescribing oral bisphosphonates.

Patients should continue taking oral bisphosphonates unless told by their healthcare professional to stop. Patients should talk to their healthcare professional if they develop new hip or thigh pain or have any concerns with their medications. For more information visit the FDA website at: and .

[Posted 11/12/2008] FDA issued an update to the Agency’s review of safety data regarding the potential increased risk of atrial fibrillation in patients treated with a bisphosphonate drug. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, and to treat bone metastases and lower elevated levels of blood calcium in patients with cancer. FDA reviewed data on 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years. The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Additionally, increasing dose or duration of bisphosphonate therapy was not associated with an increase rate of atrial fibrillation. Healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication. For more information visit the FDA website at: , and .

[Posted 01/07/2008] FDA informed healthcare professionals and patients of the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.

Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. For more information visit the FDA website at: and .

[Posted 10/01/2007] FDA issued an early communication about the ongoing review of new safety data regarding the association of atrial fibrillation with the use of bisphosphonates. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, treat bone metastases, and lower elevated levels of blood calcium in patients with cancer.

FDA reviewed spontaneous postmarketing reports of atrial fibrillation reported in association with oral and intravenous bisphosphonates and did not identify a population of bisphosphonate users at increased risk of atrial fibrillation. In addition, as part of the data review for the recent approval of once-yearly Reclast for the treatment of postmenopausal osteoporosis, FDA evaluated the possible association between atrial fibrillation and the use of Reclast (zoledronic acid). Most cases of atrial fibrillation occurred more than a month after drug infusion. Also, in a subset of patients monitored by electrocardiogram up to the 11th day following infusion, there was no significant difference in the prevalence of atrial fibrillation between patients who received Reclast and patients who received placebo.

Upon initial review, it is unclear how these data on serious atrial fibrillation should be interpreted. Therefore, FDA does not believe that healthcare providers or patients should change either their prescribing practices or their use of bisphosphonates at this time. For more information visit the FDA website at: and .

REMS:

FDA approved a REMS for ibandronate sodium to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Synthetic bisphosphonate; bone resorption inhibitor.1 4

Uses for Ibandronate Sodium

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

Osteoporosis

Prevention of osteoporosis in postmenopausal women.1 Risk factors include a family history of osteoporosis, early menopause, previous fracture, high bone turnover, reduced bone mineral density (?1 standard deviation below premenopausal mean), thin body frame, white or Asian race, excessive alcohol intake, treatment with certain drugs (e.g., corticosteroids), low dietary calcium or vitamin D intake, sedentary lifestyle, and cigarette smoking.1 5 6 8 18

Treatment of osteoporosis in postmenopausal women.1 3 7

Ibandronate Sodium Dosage and Administration General

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

Oral: Provide supplemental calcium and vitamin D1 7 if dietary intake is inadequate.1 18

IV: Supplemental calcium and vitamin D required regardless of the adequacy of dietary intake of calcium and vitamin D.7 18

Administration Oral Administration

Administer orally with a full glass (180–240 mL) of plain water ?60 minutes prior to the first food, beverage (other than plain water), or other orally administered drug or supplement (including vitamins, antacids, and calcium) of the day.1 4 5 16 (See Food under Pharmacokinetics.)

Avoid lying down for ?60 minutes following administration.1 5

Do not to suck or chew tablets; potential for oropharyngeal ulceration.1 5 (See GI Effects under Cautions.)

If a morning daily oral dose is missed, do not take missed dose later that same day.5 Resume the regular schedule the next day.1 5

When administered monthly, take tablets in the morning on the same day each month.1 a If a monthly dose is missed and the next scheduled dose is more than 7 days away, take the missed dose the next morning after it is remembered and resume the regular schedule.1 a If the next scheduled dose is 1–7 days away, maintain the regular schedule;1 do not take more than one 150-mg tablet within the same week.1 a

IV Administration

Administer by IV injection once every 3 months by a health-care professional.7

Injection must only be administered IV.1 7 18 Safety and efficacy of IV injection administered by other routes not established.7

If a dose is missed, reschedule administration with a health-care professional as soon as possible.7 8 Schedule subsequent injections at 3-month intervals; should not be administered more often than once every 3 months.7 8

Administration Risks

Take care to avoid intra-arterial or paravenous injection as such administration could result in tissue damage.7

Rate of Administration

Administer IV over a period of 15–30 seconds.7 8

Dosage

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

Available as ibandronate sodium (as the monosodium monohydrate); dosage expressed in terms of ibandronate.1 7

Adults Osteoporosis Prevention in Postmenopausal Women Oral

2.5 mg once daily.1 Alternatively, a dosage of 150 mg once monthly may be considered.1

Osteoporosis Treatment in Postmenopausal Women Oral

2.5 mg once daily or 150 mg once monthly.1

IV

3 mg once every 3 months.7

Special Populations Hepatic Impairment

Dosage adjustments not necessary.1 7

Renal Impairment Oral

Dosage adjustments not necessary in patients with mild to moderate renal impairment (Clcr ?30 mL/minute); use not recommended in patients with severe renal impairment (Clcr <30 mL/minute).1 4 18

IV

Should not be administered to patients with severe renal impairment (Clcr <30 mL/minute, Scr >2.3 mg/dL).7 18

Geriatric Patients

Dosage adjustments not necessary.1 7

Cautions for Ibandronate Sodium Contraindications

Uncorrected hypocalcemia.1 5 7 8

Known hypersensitivity to ibandronate or any ingredient in the formulation.1 5 7 8

Oral: Inability to stand or sit upright for ?60 minutes.1 5

Warnings/Precautions Warnings

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

GI Effects

Adverse upper GI effects (e.g., dysphagia, esophagitis, esophageal or gastric ulcer) reported with oral bisphosphonates.1 2 (See Administration under Dosage and Administration.)

Route of Administration

Injection must be administered IV by a health-care professional; do not administer by non-IV (e.g., intra-arterial) routes.7 (See Administration Risks under Dosage and Administration.)

General Precautions

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

Renal Effects

Possible renal toxicity (e.g., deterioration of renal function and, rarely, renal failure) with bisphosphonates.7 12 Risk may be greater in patients with coexisting conditions associated with renal impairment, concomitant therapy with other nephrotoxic drugs, preexisting renal disease, dehydration, dosage, infusion volume and rate, and multiple cycles of treatment.4 7 8 9 10 11

Use not recommended in patients with severe renal impairment (Scr >2.3 mg/dL or Clcr <30 mL/minute).1 7

Assess risk factors predisposing patients to renal deterioration.7 8 Measure Scr prior to each IV dose.7 Withhold treatment if deterioration of renal function occurs.7

Musculoskeletal Effects

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

Osteonecrosis and osteomyelitis of the jaw reported in patients receiving bisphosphonates.1 7 13 Most cases associated with dental procedures (e.g., tooth extraction) in cancer patients, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses.1 7 13

Dental examination with appropriate preventive dentistry recommended prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene).13 18 Such patients should avoid invasive dental procedures, if possible, during therapy.13 18

Severe, occasionally incapacitating bone, joint, and/or muscle pain reported infrequently with bisphosphonate therapy.1 5 7 8 18 Time to onset of symptoms varied from 1 day to several months after treatment initiation.1 7 8 Such pain generally improves following discontinuance of the drug, but may recur upon subsequent rechallenge with the same drug or another bisphosphonate.1 5 7 8 18

Metabolic Effects

Correct hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism before initiating therapy.1 7 8 18

Oral: If daily intake inadequate, administer supplemental calcium and vitamin D.1 18 a

IV: May cause a transient decrease in serum calcium concentrations.7 Supplemental calcium and vitamin D required regardless of the adequacy of dietary intake of calcium and vitamin D.7 18

Specific Populations Pregnancy

Category C. 1 7

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 7 Use caution.1 7

Pediatric Use

Safety and efficacy not established in children.1 7 18 Not indicated for use in children.18

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 7 Consider age-related decreases in renal function.18

Renal Impairment

Oral: Use not recommended in patients with severe renal impairment (CLcr <30 mL/minute).1 18

IV: Do not administer in patients with severe renal impairment (Clcr <30 mL/minute, Scr >2.3 mg/dL).7 18

Common Adverse Effects

Oral: Upper respiratory infection,1 back pain,1 dyspepsia,1 2 a bronchitis,1 pain in the extremities,1 a abdominal pain,1 diarrhea,1 a headache,1 hypertension,1 pneumonia,1 myalgia,1 arthralgia,1 urinary tract infection,1 nausea.1

IV: Arthralgia,7 8 16 17 back pain,7 hypertension,7 abdominal pain.7

Interactions for Ibandronate Sodium

Does not induce or inhibit CYP isoenzymes (i.e., CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, or 3A4)4 7 and is not metabolized.1 4 7

Antacids or Mineral Supplements Containing Divalent Cations

Pharmacokinetic interaction (decreased absorption of ibandronate) when tablets are used concomitantly with antacids or mineral supplements containing divalent cations (e.g., aluminum, calcium, magnesium, iron).1 5 b Administer tablets ?60 minutes prior to such drugs or supplements.1 5

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely.1

Drugs Excreted through Renal Tubular Transport

Based on limited data in animals, not excreted through renal tubular transport.1 4 7 Pharmacokinetic interaction unlikely.1 4

Nephrotoxic Agents

Potential pharmacologic interaction (increased risk of renal toxicity). 4 7 8 9 10 11 12 Assess patients taking concomitant nephrotoxic agents.1 7 (See Renal Effects under Cautions.)

Specific Drugs and Tests

Drug

Interaction

Comments

Bone-imaging agents

Potential to interfere with use of bone-imaging agents1 7

Histamine H2-receptor antagonists

Increased oral bioavailability of ibandronate1 4 b

No evidence of increased adverse upper GI effects1 18

Not considered clinically important1 4

Melphalan

Pharmacokinetic interaction unlikely with IV ibandronate7

NSAIAs

No evidence of increased adverse upper GI effects1

Use concomitantly with caution1

Prednisolone

Pharmacokinetic interaction unlikely with IV ibandronate7

Tamoxifen

Pharmacokinetic interaction unlikely with IV ibandronate1 7

Ibandronate Sodium Pharmacokinetics Absorption Bioavailability

Absolute (compared with IV administration) oral bioavailability about 0.6%.1 4 16

Onset

Reduction in bone turnover evident within 1–3 months of treatment initiation; maximal effects observed at 6 months.1 7 b

Duration

Biochemical markers of bone turnover returned to baseline ?12 months after treatment discontinuance.b

Food

Bioavailability decreased by 90% when administered with a standard breakfast compared with administration under fasting conditions.1 Bioavailability and effect on BMD reduced when food and beverages taken <60 minutes following oral administration.1

Special Populations

In patients with renal impairment (Clcr 40–70 mL/minute), AUC is increased by 55% compared with that in patients with normal renal function (Clcr >90 mL/minute).7 Patients with severe renal impairment (Clcr <30 mL/minute) had >2-fold increase in AUC compared with exposure for healthy individuals.7 b

Distribution Extent

Widely distributed throughout the body and redistributed to bone.4 b Subsequently, the drug is released systemically via bone turnover.1 4 Not known whether distributed into milk.7

Plasma Protein Binding

84–99.5% at therapeutic drug concentrations.1 4 7 b

Elimination Metabolism

No evidence of metabolism.7 16

Elimination Route

Excreted in urine (50–60% of circulating dose) as unchanged drug and in feces (unabsorbed drug).1 4 7 b

Half-life

Apparent oral terminal half-life is 37–157 hours; dose-dependent.1

Apparent IV terminal half-life is 4.6–25.5 hours; dose-dependent.7

Special Populations

No race-related pharmacokinetic differences between Asians and whites; other races not studied.b Pharmacokinetics not affected by gender.1 b

Pharmacokinetics not evaluated in pediatric patients.1 b Pharmacokinetics in patients with hepatic impairment not studied as ibandronate is not metabolized in the liver.1

Stability Storage Oral Tablets

25°C (may be exposed to 15–30°C).1

Parenteral Injection

25°C (may be exposed to 15–30°C).7

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Do not admix with calcium-containing solutions or other IV drugs.7

Actions

Incorporates into bone and selectively inhibits osteoclast-mediated bone resorption in a dose-dependent manner.1 4 7 b

Reduces biochemical markers of bone resorption in patients with postmenopausal osteoporosis.1 7 b

Maintains or increases BMD2 3 13 and increases bone mass in postmenopausal women.1 4 5 7

Advice to Patients

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

Importance of providing patient with a copy of the manufacturer’s patient information.1 7

Importance of adhering to recommended life-style modifications (e.g., exercise, calcium and vitamin D supplementation).1 5

Importance of correct oral administration (e.g., avoiding foods and beverages other than plain water [including mineral water] prior to administration, not lying down for ?60 minutes following administration).1 5 18 (See GI Effects under Cautions.)

Importance of not taking vitamins, calcium, or antacids ?60 minutes of taking oral ibandronate.1 5

Necessity of swallowing tablets whole, without chewing or sucking.1 5

Importance of reviewing how to resume therapy in the event of a missed dose.1 5 7

Importance of discontinuing oral ibandronate and informing clinician if symptoms of esophageal disease (e.g., new or worsening dysphagia, difficulty or pain on swallowing, retrosternal pain, heartburn) develop.1 5

Importance of informing a clinician if severe bone pain, joint pain, muscular pain, or jaw problems develop.8 a

Importance of women informing clinicians if they are or plan to become pregnant or to plan to breast-feed.1 5 8

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (vitamins, supplements, antacids), as well as any concomitant illnesses (e.g., preexisting dysphagia, esophageal disorders, renal impairment).1 5 8

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Ibandronate Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg (of ibandronate)

Boniva (with povidone)

Roche (also promoted by GlaxoSmithKline)

150 mg (of ibandronate)

Boniva (with povidone)

Roche (also promoted by GlaxoSmithKline)

Injection, for IV use only

1 mg (of ibandronate) per mL

Boniva (available in prefilled syringe with needle and swabs)

Roche (also promoted by GlaxoSmithKline)

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Boniva 150MG Tablets (GENENTECH): 1/$128.99 or 3/$372.99

Boniva 3MG/3ML Kit (GENENTECH): 3/$469.97 or 9/$1,329.91

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 October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Roche Laboratories. Boniva (ibandronate sodium) tablets prescribing information. Nutley, NJ; 2006 Aug.

2. McClung MR, Wasnich RD, Recker R et al. Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis. J Bone Miner Res. 2004; 19:11-8. [PubMed 14753731]

3. Chesnut CH, Skag A, Christiansen C et al. Effect of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004; 19:1241-9. [PubMed 15231010]

4. Barrett J, Worth E, Bauss F et al. Ibandronate: a clinical pharmacological and pharmacokinetic update. J Clin Pharmacol. 2004; 44:951-65. [IDIS 519745] [PubMed 15317823]

5. Roche Laboratories. Boniva (ibadronate sodium) tablets patient information. Nutley, NJ; 2005 Mar.

6. National Osteoporosis Foundation. Physician’s guide to prevention and treatment of osteoporosis. Washington, DC; 2000. From National Osteoporosis Foundation website ().

7. Roche Pharmceuticals. Boniva (ibandronate sodium) injection prescribing information. Nutley, NJ; 2006 Jan.

8. Roche Pharmceuticals. Boniva (ibandronate sodium) injection patient information. Nutley, NJ; 2006 Jan.

9. Major P, Lortholary A, Han J et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001; 19:558-67. [IDIS 460631] [PubMed 11208851]

10. Brown DL, Robbins R. Developments in the therapeutic applications of bisphosphonates. J Clin Pharmacol. 1999; 39:651-60. [IDIS 430233] [PubMed 10392318]

11. Cheer SM, Noble S. Zoledronic acid. Drugs. 2001; 61:799-805. [PubMed 11398911]

12. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001; 7:377-87. [PubMed 11693896]

13. Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc. 2005; 136:1658-68. [PubMed 16383047]

14. Novartis. Zometa (zoledronic acid) injection prescribing information. East Hanover, NJ; 2005 Apr.

15. Reginster JY, Adami S, Lakatos P et al. Efficacy and tolerability of once-monthy oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis [serial online]. January 26, 2006. Available at .

16. Reginster JY. Oral and intravenous ibandronate in the management of postmenopausal osteoporosis: a comprehensive review. Curr Pharm Des. 2005; 11:3711-28. [PubMed 16305506]

17. Delmas PD, Adami S, Strugala C et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results form the dosing intravenous administration study. Arthritis Rheum. 2006; 54:1838-46. [PubMed 16729277]

18. Roche Pharmaceuticals, Nutley, NJ: Personal communication.

a. Roche Laboratories. Boniva (ibadronate sodium) tablets patient information. Nutley, NJ; 2006 Aug.

b. Kehoe T, Colman E. Boniva (Ibandronate sodium) FDA approval package, Medical review. NDA No. 21-455. Rockville, MD; 2003 May 16.

More Ibandronate Sodium resources Ibandronate Sodium Side Effects (in more detail) Ibandronate Sodium Use in Pregnancy & Breastfeeding Ibandronate Sodium Drug Interactions Ibandronate Sodium Support Group 13 Reviews for Ibandronate Sodium - Add your own review/rating Compare Ibandronate Sodium with other medications Osteoporosis Prevention of Osteoporosis
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Cyclophosphamide



Cyclophosphamide Tablets USP, 25 mg and 50 mg

Rx only

Cyclophosphamide Description

Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder with the molecular formula C7H15Cl2N2O2P • H2O and a molecular weight of 279.1. The chemical name for Cyclophosphamide is 2H-1,3,2-Oxazaphosphorin-2-amine, N,N-bis(2-chloroethyl)tetrahydro-, 2-oxide, monohydrate, (±). Cyclophosphamide is soluble in water, saline, or ethanol and has the following structural formula:

Each tablet for oral administration contains Cyclophosphamide (anhydrous) 25 mg or 50 mg. In addition, each tablet contains the following inactive ingredients: acacia, FD&C Blue No. 1, lactose monohydrate, magnesium stearate, and microcrystalline cellulose.

Cyclophosphamide - Clinical Pharmacology

Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA.

Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5% to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma. Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose. Plasma protein binding of unchanged drug is low but some metabolites are bound to an extent greater than 60%. It has not been demonstrated that any single metabolite is responsible for either the therapeutic or toxic effects of Cyclophosphamide. Although elevated levels of metabolites of Cyclophosphamide have been observed in patients with renal failure, increased clinical toxicity in such patients has not been demonstrated.

Indications and Usage for Cyclophosphamide Malignant Diseases

Cyclophosphamide Tablets USP, 25 mg and 50 mg, although effective alone in susceptible malignancies, are more frequently used concurrently or sequentially with other antineoplastic drugs. The following malignancies are often susceptible to Cyclophosphamide treatment:

Malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin’s disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt’s lymphoma. Multiple myeloma. Leukemias: Chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia in children (Cyclophosphamide given during remission is effective in prolonging its duration). Mycosis fungoides (advanced disease). Neuroblastoma (disseminated disease). Adenocarcinoma of the ovary. Retinoblastoma. Carcinoma of the breast. Nonmalignant Disease Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children:

Cyclophosphamide Tablets USP, 25 mg and 50 mg are useful in carefully selected cases of biopsy proven “minimal change” nephrotic syndrome in children but should not be used as primary therapy. In children whose disease fails to respond adequately to appropriate adrenocorticosteroid therapy or in whom the adrenocorticosteroid therapy produces or threatens to produce intolerable side effects, Cyclophosphamide may induce a remission. Cyclophosphamide is not indicated for the nephrotic syndrome in adults or for any other renal disease.

Contraindications

Continued use of Cyclophosphamide is contraindicated in patients with severely depressed bone marrow function. Cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to it (see WARNINGS and PRECAUTIONS).

Warnings Carcinogenesis, Mutagenesis, and Impairment of Fertility

Second malignancies have developed in some patients treated with Cyclophosphamide used alone or in association with other antineoplastic drugs and/or modalities. Most frequently, they have been urinary bladder, myeloproliferative, or lymphoproliferative malignancies. Second malignancies most frequently were detected in patients treated for primary myeloproliferative or lymphoproliferative malignancies or nonmalignant disease in which immune processes are believed to be involved pathologically.

In some cases, the second malignancy developed several years after Cyclophosphamide treatment had been discontinued. In a single breast cancer trial utilizing two to four times the standard dose of Cyclophosphamide in conjunction with doxorubicin a small number of cases of secondary acute myeloid leukemia occurred within two years of treatment initiation. Urinary bladder malignancies generally have occurred in patients who previously had hemorrhagic cystitis. In patients treated with Cyclophosphamide-containing regimens for a variety of solid tumors, isolated case reports of secondary malignancies have been published. One case of carcinoma of the renal pelvis was reported in a patient receiving long-term Cyclophosphamide therapy for cerebral vasculitis. The possibility of Cyclophosphamide-induced malignancy should be considered in any benefit-to-risk assessment for use of the drug.

Cyclophosphamide can cause fetal harm when administered to a pregnant woman and such abnormalities have been reported following Cyclophosphamide therapy in pregnant women. Abnormalities were found in two infants and a six-month-old fetus born to women treated with Cyclophosphamide. Ectrodactylia was found in two of the three cases. Normal infants have also been born to women treated with Cyclophosphamide during pregnancy, including the first trimester. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes. Development of sterility appears to depend on the dose of Cyclophosphamide, duration of therapy, and the state of gonadal function at the time of treatment. Cyclophosphamide-induced sterility may be irreversible in some patients.

Amenorrhea associated with decreased estrogen and increased gonadotropin secretion develops in a significant proportion of women treated with Cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. Girls treated with Cyclophosphamide during prepubescence generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged Cyclophosphamide treatment in late prepubescence has been reported. Girls treated with Cyclophosphamide during prepubescence subsequently have conceived.

Men treated with Cyclophosphamide may develop oligospermia or azoospermia associated with increased gonadotropin but normal testosterone secretion. Sexual potency and libido are unimpaired in these patients. Boys treated with Cyclophosphamide during prepubescence develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy. Men temporarily rendered sterile by Cyclophosphamide have subsequently fathered normal children.

Urinary System

Hemorrhagic cystitis may develop in patients treated with Cyclophosphamide. Rarely, this condition can be severe and even fatal. Fibrosis of the urinary bladder, sometimes extensive, also may develop with or without accompanying cystitis. Atypical urinary bladder epithelial cells may appear in the urine. These adverse effects appear to depend on the dose of Cyclophosphamide and the duration of therapy. Such bladder injury is thought to be due to Cyclophosphamide metabolites excreted in the urine. Forced fluid intake helps to assure an ample output of urine, necessitates frequent voiding, and reduces the time the drug remains in the bladder. This helps to prevent cystitis. Hematuria usually resolves in a few days after Cyclophosphamide treatment is stopped, but it may persist. Medical and/or surgical supportive treatment may be required, rarely, to treat protracted cases of severe hemorrhagic cystitis. It is usually necessary to discontinue Cyclophosphamide therapy in instances of severe hemorrhagic cystitis.

Cardiac Toxicity

Although a few instances of cardiac dysfunction have been reported following use of recommended doses of Cyclophosphamide, no causal relationship has been established. Acute cardiac toxicity has been reported with doses as low as 2.4 g/m2 to as high as 26 g/m2, usually as a portion of an intensive antineoplastic multi-drug regimen or in conjunction with transplantation procedures. In a few instances with high doses of Cyclophosphamide, severe, and sometimes fatal, congestive heart failure has occurred after the first Cyclophosphamide dose. Histopathologic examination has primarily shown hemorrhagic myocarditis. Hemopericardium has occurred secondary to hemorrhagic myocarditis and myocardial necrosis. Pericarditis has been reported independent of any hemopericardium.

No residual cardiac abnormalities, as evidenced by electrocardiogram or echocardiogram appear to be present in patients surviving episodes of apparent cardiac toxicity associated with high doses of Cyclophosphamide.

Cyclophosphamide has been reported to potentiate doxorubicin-induced cardiotoxicity.

Infections

Treatment with Cyclophosphamide may cause significant suppression of immune responses. Serious, sometimes fatal, infections may develop in severely immunosuppressed patients. Cyclophosphamide treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop viral, bacterial, fungal, protozoan, or helminthic infections.

Other

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported.

Precautions General

Special attention to the possible development of toxicity should be exercised in patients being treated with Cyclophosphamide if any of the following conditions are present:

Leukopenia Thrombocytopenia Tumor cell infiltration of bone marrow Previous X-ray therapy Previous therapy with other cytotoxic agents Impaired hepatic function Impaired renal function Laboratory Tests

During treatment, the patient’s hematologic profile (particularly neutrophils and platelets) should be monitored regularly to determine the degree of hematopoietic suppression. Urine should also be examined regularly for red cells which may precede hemorrhagic cystitis.

Drug Interactions

The rate of metabolism and the leukopenic activity of Cyclophosphamide reportedly are increased by chronic administration of high doses of phenobarbital.

The physician should be alert for possible combined drug actions, desirable or undesirable, involving Cyclophosphamide even though Cyclophosphamide has been used successfully concurrently with other drugs, including other cytotoxic drugs.

Cyclophosphamide treatment, which causes a marked and persistent inhibition of cholinesterase activity, potentiates the effect of succinylcholine chloride.

If a patient has been treated with Cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted.

Adrenalectomy

Since Cyclophosphamide has been reported to be more toxic in adrenalectomized dogs, adjustment of the doses of both replacement steroids and Cyclophosphamide may be necessary for the adrenalectomized patient.

Wound Healing

Cyclophosphamide may interfere with normal wound healing.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

See WARNINGS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Pregnancy Pregnancy Category D:

See WARNINGS.

Nursing Mothers

Cyclophosphamide is excreted in breast milk. Because of the potential for serious adverse reactions and the potential for tumorigenicity shown for Cyclophosphamide in humans, 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

The safety profile of Cyclophosphamide in pediatric patients is similar to that of the adult population (see ADVERSE REACTIONS).

Geriatric Use

Insufficient data from clinical studies of cyclophospamide for malignant lymphoma, multiple myeloma, leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast carcinoma are available for patients 65 years of age and older to determine whether they respond differently than younger patients. In two clinical trials in which Cyclophosphamide was compared with paclitaxel, each in combination with cisplatin, for the treatment of advanced ovarian carcinoma, 154 (28%) of 552 patients who received Cyclophosphamide plus cisplatin were 65 years or older. Subset analyses (<65 versus >65 years) from these trials, published reports of clinical trials of Cyclophosphamide-containing regimens in breast cancer and non-Hodgkin’s lymphoma, and postmarketing experience suggest that elderly patients may be more susceptible to Cyclophosphamide toxicities. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range and adjusting as necessary based on patient response (see DOSAGE AND ADMINISTRATION: Treatment of Malignant Diseases).

Adverse Reactions

Information on adverse reactions associated with the use of Cyclophosphamide is arranged according to body system affected or type of reaction. The adverse reactions are listed in order of decreasing incidence. The most serious adverse reactions are described in the WARNINGS section.

Reproductive System

See WARNINGS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Digestive System

Nausea and vomiting commonly occur with Cyclophosphamide therapy. Anorexia and, less frequently, abdominal discomfort or pain and diarrhea may occur. There are isolated reports of hemorrhagic colitis, oral mucosal ulceration and jaundice occurring during therapy. These adverse drug effects generally remit when Cyclophosphamide treatment is stopped.

Skin and Its Structures

Alopecia occurs commonly in patients treated with Cyclophosphamide. The hair can be expected to grow back after treatment with the drug or even during continued drug treatment, though it may be different in texture or color. Skin rash occurs occasionally in patients receiving the drug. Pigmentation of the skin and changes in nails can occur. Very rare reports of Stevens-Johnson syndrome and toxic epidermal necrolysis have been received during postmarketing surveillance; due to the nature of spontaneous adverse event reporting, a definitive causal relationship to Cyclophosphamide has not been established.

Hematopoietic System

Leukopenia occurs in patients treated with Cyclophosphamide, is related to the dose of drug, and can be used as a dosage guide. Leukopenia of less than 2000 cells/mm3 develops commonly in patients treated with an initial loading dose of the drug, and less frequently in patients maintained on smaller doses. The degree of neutropenia is particularly important because it correlates with a reduction in resistance to infections. Fever without documented infection has been reported in neutropenic patients.

Thrombocytopenia or anemia develop occasionally in patients treated with Cyclophosphamide. These hematologic effects usually can be reversed by reducing the drug dose or by interrupting treatment. Recovery from leukopenia usually begins in 7 to 10 days after cessation of therapy.

Urinary System

See WARNINGS: Urinary System for information on cystitis and urinary bladder fibrosis.

Hemorrhagic ureteritis and renal tubular necrosis have been reported to occur in patients treated with Cyclophosphamide. Such lesions usually resolve following cessation of therapy.

Infections

See WARNINGS: Infections for information on reduced host resistance to infections.

Carcinogenesis

See WARNINGS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Respiratory System

Interstitial pneumonitis has been reported as part of the postmarketing experience. Interstitial pulmonary fibrosis has been reported in patients receiving high doses of Cyclophosphamide over a prolonged period.

Other

Anaphylactic reactions have been reported; death has also been reported in association with this event. Possible cross-sensitivity with other alkylating agents has been reported. SIADH (syndrome of inappropriate ADH secretion) has been reported with the use of Cyclophosphamide. Malaise and asthenia have been reported as part of the postmarketing experience.

Overdosage

No specific antidote for Cyclophosphamide is known. Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.

Cyclophosphamide Dosage and Administration Treatment of Malignant Diseases Adults and Children:

Oral Cyclophosphamide dosing is usually in the range of 1 to 5 mg/kg/day for both initial and maintenance dosing.

Many other regimens of intravenous and oral Cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage. Transient decreases in the total white blood cell count to 2000 cells/mm3 (following short courses) or more persistent reduction to 3000 cells/mm3 (with continuing therapy) are tolerated without serious risk of infection if there is no marked granulocytopenia.

When Cyclophosphamide is included in combined cytotoxic regimens, it may be necessary to reduce the dose of Cyclophosphamide, as well as that of the other drugs.

Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences depending upon the dialysis system being used. Patients with compromised renal function may show some measurable changes in pharmacokinetic parameters of Cyclophosphamide metabolism, but there is no consistent evidence indicating a need for Cyclophosphamide dosage modification in patients with renal function impairment.

Treatment of Nonmalignant Diseases Biopsy Proven “Minimal Change” Nephrotic Syndrome in Children:

An oral dose of 2.5 to 3 mg/kg daily for a period of 60 to 90 days is recommended. In males, the incidence of oligospermia and azoospermia increases if the duration of Cyclophosphamide treatment exceeds 60 days. Treatment beyond 90 days increases the probability of sterility. Adrenocorticosteroid therapy may be tapered and discontinued during the course of Cyclophosphamide therapy (see PRECAUTIONS: Laboratory Tests).

Preparation and Handling of Solutions

Extemporaneous liquid preparations of Cyclophosphamide for oral administration may be prepared by dissolving Cyclophosphamide for injection in Aromatic Elixir, N.F. Such preparations should be stored under refrigeration in glass containers and used within 14 days.

How is Cyclophosphamide Supplied

Cyclophosphamide Tablets USP

25 mg, light blue, round, unscored tablets

(Identified 54 639)

NDC 0054-4129-25: Bottle of 100 tablets.

50 mg, light blue, round, unscored tablets

(Identified 54 980)

NDC 0054-4130-25: Bottle of 100 tablets.

Storage

Storage at or below 25°C (77°F) is recommended; this product will withstand brief exposure to temperatures up to 30°C (86°F) but should be protected from temperatures above 30°C (86°F).

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

To minimize the risk of dermal exposure, always wear impervious gloves when handling bottles containing Cyclophosphamide tablets. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

References ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society; 1999:32-41. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Dept of Health and Human Services, Public Health Service publication NIH 83-2621. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA.1985; 253: 1590-1592. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust.1983;1:426-428. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J Clin.1983;33:258-263. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm.1990;47:1033-1049. Controlling occupational exposure to hazardous drugs. (OSHA Work-Practice Guidelines.) Am J Health- Syst Pharm.1996;53:1669-1685.

4047201//03

Revised September 2007

© RLI, 2007

Package Label - Cyclophosphamide Tablets USP

25 mg

NDC 0054-4129-25

Bottle of 100 tablets.

CYTOTOXIC AGENT

Rx Only

Roxane Laboratories, Inc.

50 mg 

NDC 0054-4130-25

Bottle of 100 tablets.

CYTOTOXIC AGENT

Rx Only

Roxane Laboratories, Inc.


Cyclophosphamide 
Cyclophosphamide  tablet Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0054-4129 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Cyclophosphamide (Cyclophosphamide) Cyclophosphamide 25 mg Inactive Ingredients Ingredient Name Strength ACACIA   FD&C BLUE NO. 1   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   Product Characteristics Color BLUE (Light) Score no score Shape ROUND Size 9mm Flavor Imprint Code 54;639 Contains          Packaging # NDC Package Description Multilevel Packaging 1 0054-4129-25 100 TABLET In 1 BOTTLE, PLASTIC None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA040032 08/17/1999
Cyclophosphamide 
Cyclophosphamide  tablet Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0054-4130 Route of Administration ORAL DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Cyclophosphamide (Cyclophosphamide) Cyclophosphamide 50 mg Inactive Ingredients Ingredient Name Strength ACACIA   FD&C BLUE NO. 1   LACTOSE MONOHYDRATE   MAGNESIUM STEARATE   CELLULOSE, MICROCRYSTALLINE   Product Characteristics Color BLUE (Light) Score no score Shape ROUND Size 11mm Flavor Imprint Code 54;980 Contains          Packaging # NDC Package Description Multilevel Packaging 1 0054-4130-25 100 TABLET In 1 BOTTLE, PLASTIC None
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA040032 08/17/1999
Labeler - Roxane Laboratories, Inc (058839929) Registrant - Roxane Laboratories, Inc (058839929) Establishment Name Address ID/FEI Operations Boehringer Ingelheim Roxane Inc 128407710 MANUFACTURE Revised: 11/2009Roxane Laboratories, Inc More Cyclophosphamide resources Cyclophosphamide Side Effects (in more detail) Cyclophosphamide Dosage Cyclophosphamide Use in Pregnancy & Breastfeeding Drug Images Cyclophosphamide Drug Interactions Cyclophosphamide Support Group 4 Reviews for Cyclophosphamide - Add your own review/rating Cyclophosphamide Professional Patient Advice (Wolters Kluwer) Cyclophosphamide MedFacts Consumer Leaflet (Wolters Kluwer) Cyclophosphamide Monograph (AHFS DI) cyclophosphamide Oral, Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information cyclophosphamide oral/injection Concise Consumer Information (Cerner Multum) Compare Cyclophosphamide with other medications Acute Lymphocytic Leukemia Acute Nonlymphocytic Leukemia Bladder Cancer Brain Tumor Breast Cancer Bullous Pemphigoid Cancer Cervical Cancer Chronic Lymphocytic Leukemia Chronic Myelogenous Leukemia Cogan's Syndrome Dermatomyositis Endometrial Cancer Ewing's Sarcoma Histiocytosis Hodgkin's Lymphoma IgA Nephropathy Multiple Myeloma Multiple Sclerosis Mycosis Fungoides Nephrotic Syndrome Neuroblastoma Non-Hodgkin's Lymphoma Non-Small Cell Lung Cancer Organ Transplant, Rejection Prophylaxis Osteosarcoma Ovarian Cancer Pemphigoid Pemphigus Prostate Cancer Rheumatoid Arthritis Small Cell Lung Cancer Systemic Lupus Erythematosus Systemic Sclerosis Testicular Cancer Wegener's Granulomatosus Wilms' Tumor
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Alkeran


melphalan hydrochloride
Dosage Form: injection
Alkeran®
(melphalan hydrochloride)
for Injection Warning

Melphalan should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation. Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation. Melphalan is leukemogenic in humans. Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans.

Alkeran Description

Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent that is active against selected human neoplastic diseases. It is known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is C13H18Cl2N2O2 and the molecular weight is 305.20. The structural formula is:

Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active against certain animal tumors, and the dose needed to produce effects on chromosomes is larger than that required with the L-isomer. The racemic (DL-) form is known as merphalan or sarcolysin.

Melphalan is practically insoluble in water and has a pKa1 of ?2.5.

Alkeran for Injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single-use vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg povidone. Alkeran for Injection is reconstituted using the sterile diluent provided. Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6.0 mL, ethanol (96%) 0.52 mL, and Water for Injection to a total of 10 mL. Alkeran for Injection is administered intravenously.

Alkeran - Clinical Pharmacology

Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.

Pharmacokinetics

The pharmacokinetics of melphalan after IV administration has been extensively studied in adult patients. Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 75 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m2) were observed. One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the third course. Mean (±SD) peak melphalan plasma concentrations in myeloma patients given IV melphalan at doses of 10 or 20 mg/m2 were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, respectively.

The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The extent of melphalan binding to plasma proteins ranges from 60% to 90%. Serum albumin is the major binding protein, while ?1-acid glycoprotein appears to account for about 20% of the plasma protein binding. Approximately 30% of the drug is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.

Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one study noted an increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 weeks of therapy.

Clinical Trial

A randomized trial compared prednisone plus IV melphalan to prednisone plus oral melphalan in the treatment of myeloma. As discussed below, overall response rates at week 22 were comparable; however, because of changes in trial design, conclusions as to the relative activity of the 2 formulations after week 22 are impossible to make.

Both arms received oral prednisone starting at 0.8 mg/kg/day with doses tapered over 6 weeks. Melphalan doses in each arm were:

Arm 1: Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC began to rise.

Arm 2: IV melphalan 16 mg/m2 q 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks.

Doses of melphalan were adjusted according to the following criteria:

Table 1. Criteria for Dosage Adjustment in a Randomized Clinical Trial

WBC/mm3

Platelets

Percent of Full Dose

?4,000

?100,000

100

?3,000

?75,000

75

?2,000

?50,000

50

<2,000

<50,000

0

One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the IV melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor load (51% versus 34%) on the oral compared to the IV arm (P<0.04). Response rates at week 22 are shown in the following table:

Table 2. Response Rates at Week 22

Initial Arm

Evaluable

Patients

Responders

n (%)

P

Oral melphalan

100

44 (44%)

P>0.2

IV melphalan

195

74 (38%)

 

Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.

Severe myelotoxicity (WBC ?1,000 and/or platelets ?25,000) was more common in the IV melphalan arm (28%) than in the oral melphalan arm (11%).

An association was noted between poor renal function and myelosuppression; consequently, an amendment to the protocol required a 50% reduction in IV melphalan dose if the BUN was ?30 mg/dL. The rate of severe leukopenia in the IV arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) before protocol amendment to 11% (3/28) (P = 0.01) after the amendment.

Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the IV arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1% (1/100) incidence of drug-related death in the oral arm.

Indications and Usage for Alkeran

Alkeran for Injection is indicated for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.

Contraindications

Melphalan should not be used in patients whose disease has demonstrated prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.

Warnings

Alkeran for Injection may cause local tissue damage should extravasation occur, and consequently it should not be administered by direct injection into a peripheral vein. It is recommended that Alkeran for Injection be administered by injecting slowly into a fast-running IV infusion via an injection port, or via a central venous line (see DOSAGE AND ADMINISTRATION: Administration Precautions).

Melphalan should be administered in carefully adjusted dosage by or under the supervision of experienced physicians who are familiar with the drug's actions and the possible complications of its use.

As with other nitrogen mustard drugs, excessive dosage will produce marked bone marrow suppression. Bone marrow suppression is the most significant toxicity associated with Alkeran for Injection in most patients. Therefore, the following tests should be performed at the start of therapy and prior to each subsequent dose of Alkeran: platelet count, hemoglobin, white blood cell count, and differential. Thrombocytopenia and/or leukopenia are indications to withhold further therapy until the blood counts have sufficiently recovered. Frequent blood counts are essential to determine optimal dosage and to avoid toxicity. Dose adjustment on the basis of blood counts at the nadir and day of treatment should be considered.

Hypersensitivity reactions including anaphylaxis have occurred in approximately 2% of patients who received the IV formulation (see ADVERSE REACTIONS). These reactions usually occur after multiple courses of treatment. Treatment is symptomatic. The infusion should be terminated immediately, followed by the administration of volume expanders, pressor agents, corticosteroids, or antihistamines at the discretion of the physician. If a hypersensitivity reaction occurs, IV or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan.

Carcinogenesis

Secondary malignancies, including acute nonlymphocytic leukemia, myeloproliferative syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating agents (including melphalan). Some patients also received other chemotherapeutic agents or radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis increases with chronicity of treatment and with cumulative dose. In one study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after oral melphalan therapy was 19.5% for cumulative doses ranging from 730 to 9,652 mg. In this same study, as well as in an additional study, the 10-year cumulative risk of developing acute leukemia or myeloproliferative syndrome after oral melphalan therapy was less than 2% for cumulative doses under 600 mg. This does not mean that there is a cumulative dose below which there is no risk of the induction of secondary malignancy. The potential benefits from melphalan therapy must be weighed on an individual basis against the possible risk of the induction of a second malignancy.

Adequate and well-controlled carcinogenicity studies have not been conducted in animals. However, intraperitoneal (IP) administration of melphalan in rats (5.4 to 10.8 mg/m2) and in mice (2.25 to 4.5 mg/m2) 3 times per week for 6 months followed by 12 months post-dose observation produced peritoneal sarcoma and lung tumors, respectively.

Mutagenesis

Melphalan has been shown to cause chromatid or chromosome damage in humans. Intramuscular administration of melphalan at 6 and 60 mg/m2 produced structural aberrations of the chromatid and chromosomes in bone marrow cells of Wistar rats.

Impairment of Fertility

Melphalan causes suppression of ovarian function in premenopausal women, resulting in amenorrhea in a significant number of patients. Reversible and irreversible testicular suppression have also been reported.

Pregnancy

Pregnancy Category D. Melphalan may cause fetal harm when administered to a pregnant woman. While adequate animal studies have not been conducted with IV melphalan, oral (6 to 18 mg/m2/day for 10 days) and IP (18 mg/m2) administration in rats was embryolethal and teratogenic. Malformations resulting from melphalan included alterations of the brain (underdevelopment, deformation, meningocele, and encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible and tail, as well as hepatocele (exomphaly). There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Precautions General

In all instances where the use of Alkeran for Injection is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse events. Melphalan should be used with extreme caution in patients whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy or whose marrow function is recovering from previous cytotoxic therapy.

Dose reduction should be considered in patients with renal insufficiency receiving IV melphalan. In one trial, increased bone marrow suppression was observed in patients with BUN levels ?30 mg/dL. A 50% reduction in the IV melphalan dose decreased the incidence of severe bone marrow suppression in the latter portion of this study.

Administration of live vaccines to immunocompromised patients should be avoided.

Information for Patients

Patients should be informed that the major acute toxicities of melphalan are related to bone marrow suppression, hypersensitivity reactions, gastrointestinal toxicity, and pulmonary toxicity. The major long-term toxicities are related to infertility and secondary malignancies. Patients should never be allowed to take the drug without close medical supervision and should be advised to consult their physicians if they experience skin rash, signs or symptoms of vasculitis, bleeding, fever, persistent cough, nausea, vomiting, amenorrhea, weight loss, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant.

Laboratory Tests

Periodic complete blood counts with differentials should be performed during the course of treatment with melphalan. At least 1 determination should be obtained prior to each dose. Patients should be observed closely for consequences of bone marrow suppression, which include severe infections, bleeding, and symptomatic anemia (see WARNINGS).

Drug Interactions

The development of severe renal failure has been reported in patients treated with a single dose of IV melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. IV melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS section.

Pregnancy Teratogenic Effects

Pregnancy Category D: See WARNINGS section.

Nursing Mothers

It is not known whether this drug is excreted in human milk. IV melphalan should not be given to nursing mothers.

Pediatric Use

The safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Alkeran for Injection 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. 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.

ADVERSE REACTIONS (SEE OVERDOSAGE)

 The following information on adverse reactions is based on data from both oral and IV administration of melphalan as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.

Hematologic

The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. White blood cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure has been reported.

Gastrointestinal

Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice have been reported. Hepatic veno-occlusive disease has been reported.

Hypersensitivity

Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients receiving Alkeran for Injection for myeloma (see WARNINGS). These reactions were characterized by urticaria, pruritus, edema, skin rashes, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. These patients appeared to respond to antihistamine and corticosteroid therapy. If a hypersensitivity reaction occurs, IV or oral melphalan should not be readministered since hypersensitivity reactions have also been reported with oral melphalan. Cardiac arrest has also been reported rarely in association with such reports.

Miscellaneous

Other reported adverse reactions include skin hypersensitivity, skin ulceration at injection site, skin necrosis rarely requiring skin grafting, maculopapular rashes, vasculitis, alopecia, hemolytic anemia, allergic reaction, pulmonary fibrosis (including fatal outcomes), and interstitial pneumonitis. Temporary significant elevation of the blood urea has been seen in the early stages of therapy in patients with renal damage. Subjective and transient sensation of warmth and/or tingling.

Overdosage

Overdoses resulting in death have been reported. Overdoses, including doses up to 290 mg/m2, have produced the following symptoms: severe nausea and vomiting, decreased consciousness, convulsions, muscular paralysis, and cholinomimetic effects. Severe mucositis, stomatitis, colitis, diarrhea, and hemorrhage of the gastrointestinal tract occur at high doses (>100 mg/m2). Elevations in liver enzymes and veno-occlusive disease occur infrequently. Significant hyponatremia caused by an associated inappropriate secretion of ADH syndrome has been observed. Nephrotoxicity and adult respiratory distress syndrome have been reported rarely. The principal toxic effect is bone marrow suppression. Hematologic parameters should be closely followed for 3 to 6 weeks. An uncontrolled study suggests that administration of autologous bone marrow or hematopoietic growth factors (i.e., sargramostim, filgrastim) may shorten the period of pancytopenia. General supportive measures together with appropriate blood transfusions and antibiotics should be instituted as deemed necessary by the physician. This drug is not removed from plasma to any significant degree by hemodialysis or hemoperfusion. A pediatric patient survived a 254-mg/m2 overdose treated with standard supportive care.

Alkeran Dosage and Administration

 The usual IV dose is 16 mg/m2. Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ?30 mg/dL) (see PRECAUTIONS: General). The drug is administered as a single infusion over 15 to 20 minutes. Melphalan is administered at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. Available evidence suggests about one third to one half of the patients with multiple myeloma show a favorable response to the drug. Experience with oral melphalan suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned prematurely. Dose adjustment on the basis of blood cell counts at the nadir and day of treatment should be considered.

Administration Precautions

As with other toxic compounds, caution should be exercised in handling and preparing the solution of Alkeran. Skin reactions associated with accidental exposure may occur. The use of gloves is recommended. If the solution of Alkeran contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not use this product.

Care should be taken to avoid possible extravasation of melphalan and in cases of poor peripheral venous access, consideration should be given to use of a central venous line (see WARNINGS).

Preparation for Administration/Stability Alkeran for Injection must be reconstituted by rapidly injecting 10 mL of the supplied diluent directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. This provides a 5-mg/mL solution of melphalan. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater than 0.45 mg/mL. Administer the diluted product over a minimum of 15 minutes. Complete administration within 60 minutes of reconstitution.

The time between reconstitution/dilution and administration of Alkeran should be kept to a minimum because reconstituted and diluted solutions of Alkeran are unstable. Over as short a time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted material from the reaction of Alkeran with Sterile Diluent for Alkeran. Upon further dilution with saline, nearly 1% label strength of melphalan hydrolyzes every 10 minutes.

A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.

How is Alkeran Supplied

Alkeran for Injection is supplied in a carton containing one single-use clear glass vial of freeze-dried melphalan hydrochloride equivalent to 50 mg melphalan and one 10-mL clear glass vial of sterile diluent (NDC 0173-0130-93).

Store at controlled room temperature 15° to 30°C (59° to 86°F) and protect from light.

REFERENCES ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: Oncology Nursing Society;1999:32-41. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, Clinical Center Pharmacy Department and Cancer Nursing Services, National Institutes of Health; 1992. US Dept of Health and Human Services. Public Health Service publication NIH 92-2621. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-263. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.) Am J Health-Syst Pharm. 1996;53:1669-1685.

Alkeran is registered trademark of GlaxoSmithKline.

Alkeran and Diluent manufactured by:

GlaxoSmithKline

Research Triangle Park, NC 27709

©2008, GlaxoSmithKline. All rights reserved.

October 2008

ALJ:4PI

Principal Display Panel

NDC 0173-0130-93

Alkeran®

(melphalan hydrochloride)

for Injection

SINGLE-USE

Rx only

One vial of Alkeran for Injection containing sterile, nonpyrogenic, freeze-dried melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg povidone.

One vial of sterile, nonpyrogenic diluent containing 0.2 g sodium citrate, 6.0 mL propylene glycol, 0.52 mL ethanol (96%), and Water for Injection to a total of 10 mL.

For intravenous infusion.

Reconstitute with enclosed diluent. See enclosed package insert for additional reconstitution and administration instructions.

See prescribing information for Dosage and Administration.

Store at controlled room temperature, 15o to 30oC (59o to 86oF) and protect from light.

Add diluent rapidly.

Immediately shake vial vigorously.

Made in UK

Alkeran and Diluent

Manufactured by

GlaxoSmithKline

RTP, NC 27709

10000000061802


Alkeran 
melphalan hydrochloride  kit Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0173-0130 Packaging # NDC Package Description Multilevel Packaging 1 0173-0130-93 1 KIT In 1 CARTON None QUANTITY OF PARTS Part # Package Quantity Total Product Quantity Part 1 1 VIAL, SINGLE-DOSE   10 mL Part 2 1 VIAL, SINGLE-USE   10 mL Part 1 of 2 Alkeran 
melphalan hydrochloride  injection, powder, for solution Product Information       Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength MELPHALAN HYDROCHLORIDE (MELPHALAN) MELPHALAN HYDROCHLORIDE 50 mg  in 10 mL Inactive Ingredients Ingredient Name Strength POVIDONE   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 10 mL In 1 VIAL, SINGLE-DOSE None Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020207 03/16/1993
Part 2 of 2 DILUENT 
water  injection Product Information       Route of Administration INTRAVENOUS DEA Schedule      Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength No Active Ingredients Found Inactive Ingredients Ingredient Name Strength WATER   SODIUM CITRATE   PROPYLENE GLYCOL   ALCOHOL   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 10 mL In 1 VIAL, SINGLE-USE None Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020207 03/16/1993
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA020207 03/16/1993 05/31/2012
Labeler - GlaxoSmithKline LLC (167380711) Revised: 01/2011GlaxoSmithKline LLC
More Alkeran resources Alkeran Side Effects (in more detail) Alkeran Use in Pregnancy & Breastfeeding Drug Images Alkeran Drug Interactions Alkeran Support Group 0 Reviews for Alkeran - Add your own review/rating Alkeran Concise Consumer Information (Cerner Multum) Alkeran MedFacts Consumer Leaflet (Wolters Kluwer) Alkeran Monograph (AHFS DI) Alkeran Advanced Consumer (Micromedex) - Includes Dosage Information Melphalan Professional Patient Advice (Wolters Kluwer) Compare Alkeran with other medications Multiple Myeloma Ovarian Cancer
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Oilatum Emollient


1. Name Of The Medicinal Product

Oilatum Bath Formula

Oilatum Emollient

2. Qualitative And Quantitative Composition

Light Liquid Paraffin 63.4% w/w

3. Pharmaceutical Form

Liquid Bath Additive

4. Clinical Particulars 4.1 Therapeutic Indications

Oilatum Emollient is indicated in the treatment of contact dermatitis, atopic dermatitis, senile pruritus, ichthyosis and related dry skin conditions. Oilatum Emollient replaces oil and water and hydrates the keratin. Oilatum Emollient is particularly suitable for infant bathing. The preparation also overcomes the problem of cleansing the skin in conditions where the use of soaps, soap substitutes and colloid or oatmeal baths proves irritating.

4.2 Posology And Method Of Administration

Oilatum Emollient should always be used with water, either added to the water or applied to wet skin.

Adult bath:

Add 1-3 capfuls to an 8-inch bath of water, soak for 10-20 minutes. Pat dry.

Infant bath:

Add ?-2 capfuls to a basin of water, Apply gently over entire body with a sponge. Pat dry.

Skin cleansing:

Rub a small amount of oil into wet skin. Rinse and pat dry.

Where conditions permit, and particularly in cases of extensive areas of dry skin, Oilatum Emollient should be used as a bath oil, ensuring complete coverage by immersion. In addition to the therapeutic benefits, this method of use provides a means of sedating tense patients, particularly relevant in cases of acute pruritic dermatoses where relaxation of tension appears to relieve symptoms.

The product is suitable for use in adults, children and the elderly.

4.3 Contraindications

None

4.4 Special Warnings And Precautions For Use

The patient should be advised to use care to avoid slipping in the bath. If a rash or skin irritation occurs, stop using the product and consult your doctor.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known

4.6 Pregnancy And Lactation

There is no, or inadequate, evidence of the safety of Oilatum Emollient in human pregnancy or lactation, but it has been in wide use for many years without ill consequence.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

None

4.9 Overdose

Not applicable

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Light liquid paraffin exerts an emollient effect by forming an occlusive oil film on the stratum corneum. This prevents excessive evaporation of water from the skin surface and aids in the prevention of dryness.

5.2 Pharmacokinetic Properties

Not applicable

5.3 Preclinical Safety Data

Not applicable

6. Pharmaceutical Particulars 6.1 List Of Excipients

Acetylated Lanolin Alcohols

Isopropyl Palmitate

Polyethylene Glycol 400 dilaurate

Polyoxyethylene 40 sorbital septaoleate

Floral Spice

6.2 Incompatibilities

None

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

None

6.5 Nature And Contents Of Container

High density polyethylene bottles with a screw cap. Capacity: 25ml, 150ml, 200ml, 250ml, 300ml, 350ml, 400ml, 500ml, 600ml, 1000ml.

6.6 Special Precautions For Disposal And Other Handling

There are no special instructions for use or handling

7. Marketing Authorisation Holder

GlaxoSmithKline UK Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

Trading as Stiefel

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

8. Marketing Authorisation Number(S)

PL 19494/0078

9. Date Of First Authorisation/Renewal Of The Authorisation

8th December 1989 / 8th July 2008

10. Date Of Revision Of The Text

16 December 2010


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Gallium



Dosage Form: Injection

Rx Only.

Diagnostic – For Intravenous Use

Gallium Description

Gallium Citrate Ga 67 Injection is supplied in a 10 milliliter vial as an isotonic, sterile, non-pyrogenic solution. Each milliliter of the isotonic solution contains 74 megabecquerels (2 millicuries) of Gallium Ga 67 on the calibration date as a complex formed from 8.3 nanograms Gallium chloride Ga 67, 1.9 milligrams of sodium citrate dihydrate, 7.8 milligrams of sodium chloride and 0.9 percent benzyl alcohol (v/v) as a preservative. The pH is adjusted to between 5.5 to 8.0 with hydrochloric acid and/or sodium hydroxide solution.

Gallium Ga 67, with a half-life of 78.26 hours, is cyclotron produced by the proton irradiation of enriched zinc. At the time of calibration the drug contains no more than 0.02% Gallium Ga 66 and no more than 0.2% Zinc Zn 65. The concentration of each radionuclidic impurity changes with time. At expiration, the drug contains no more than 0.001% Gallium Ga 66 and no more than 1.0% Zinc Zn 65. No carrier has been added.

Gallium Citrate has the following chemical structure:

PHYSICAL CHARACTERISTICS

Gallium Ga 67 with a physical half-life of 78.26 hours1 decays by electron capture to stable Zinc Zn 67. Photons that are useful for imaging studies are listed in Table 1.

Table 1. Principal Radiation Emission Data1 Radiation Mean % Per
Disintegration Energy Gamma-2 2.9 91.3 Gamma-3 35.7 93.3 Gamma-4 19.7 184.6 Gamma-5 2.2 209.0 Gamma-6 16.0 300.2 Gamma-7 4.5 393.5 1 Kocher, D.C., Radioactive Decay Tables, Health and Safety Research Division, National Technical Information Service, DOE/TIC-11026, pg. 80, 1981. EXTERNAL RADIATION

The specific gamma ray constant for Gallium Ga 67 is 1.6 R/mCi-hour at 1 cm. The first half-value thickness of lead (Pb) is 0.066 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of lead is shown in Table 2. For example, the use of 1.2 cm of lead will decrease the radiation exposure by a factor of about 100.

Table 2. Radiation Attenuation by Lead Shielding Shield Thickness (Pb), cm Coefficient of Attenuation 0.066 0.5 0.41 10-1 1.2 10-2 2.5 10-3 4.8 10-4

To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the time of calibration are shown in Table 3.

Table 3. Physical Decay Chart Gallium Ga 67 Half-Life 78.26 Hours

*Calibration Time

Hours Fraction Remaining Hours Fraction Remaining 0* 1.000 72 (3d) 0.529 6 0.948 78 0.501 12 0.899 84 0.475 18 0.853 90 0.451 24 (1d) 0.809 96 (4d) 0.427 30 0.767 108 0.384 36 0.727 120 (5d) 0.345 42 0.689 132 0.311 48 (2d) 0.654 144 (6d) 0.279 54 0.620 156 0.251 60 0.588 168 (7d) 0.226 66 0.557 Gallium - Clinical Pharmacology

Gallium Citrate Ga 67, with no carrier added, has been found to concentrate in certain viable primary and metastatic tumors as well as focal sites of infection. The mechanism of concentration is unknown, but investigational studies have shown that Gallium Ga 67 accumulates in lysosomes and is bound to a soluble intracellular protein.

It has been reported in the scientific literature that following intravenous injection, the highest tissue concentration of Gallium Ga 67 - other than tumors and sites of infection - is the renal cortex. After the first day, the maximum concentration shifts to bone and lymph nodes and after the first week, to liver and spleen. Gallium Ga 67 is excreted relatively slowly from the body. The average whole body retention is 65 percent after seven days, with 26 percent having been excreted in the urine and 9 percent in the stools.

Indications and Usage for Gallium

Gallium Citrate Ga 67 Injection may be useful to demonstrate the presence and extent of Hodgkin's disease, lymphoma, and bronchogenic carcinoma. Positive Gallium Ga 67 uptake in the absence of prior symptoms warrants follow-up as an indication of a potential disease state. Gallium Citrate Ga 67 Injection may be useful as an aid in detecting some acute inflammatory lesions.

Contraindications

None.

Warnings

None known.

Precautions General

A thorough knowledge of the normal distribution of intravenously administered Gallium Citrate Ga 67 Injection is essential in order to accurately interpret pathologic states. The finding of an abnormal Gallium Ga 67 concentration usually implies the existence of underlying pathology, but further diagnostic studies should be done to distinguish benign from malignant lesions. Gallium Citrate Ga 67 Injection is intended for use as an adjunct in the diagnosis of certain neoplasms as well as focal areas of infection. Certain pathologic conditions may yield up to 40 percent false negative Gallium Ga 67 studies. Therefore, a negative study cannot be definitely interpreted as ruling out the presence of disease.

Lymphocytic lymphoma frequently does not accumulate Gallium Ga 67 sufficiently for unequivocal imaging and the use of Gallium with this histologic type of lymphoma is not recommended at this time.

Gallium Ga 67 localization cannot differentiate between tumor and acute inflammation, and other diagnostic studies must be added to define the underlying pathology.

As in the use of any radioactive material, care should be taken to minimize radiation exposure to the patient consistent with proper management and to insure minimum radiation exposure to occupational workers.

The vial contents are sterile and non-pyrogenic. It is essential that the user follow the directions carefully and adhere to strict aseptic procedures.

Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides produced by nuclear reactor or particle accelerator and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to evaluate carcinogenic or mutagenic potential or whether this drug affects fertility in males or females.

Pregnancy Category C

Animal reproductive studies have not been conducted with Gallium Citrate Ga 67. It is also not known whether Gallium Citrate Ga 67 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gallium Citrate Ga 67 should be given to a pregnant woman only if clearly needed.

Ideally, examinations using radiopharmaceuticals, especially those elective in nature of women of childbearing capability, should be performed during the first few (approximately ten) days following the onset of menses.

Nursing Mothers

This drug is known to be excreted in human milk during lactation, therefore, formula feedings should be substituted for breast feedings.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 have not been established.

Adverse Reactions

Rare occurrences of allergic reactions, skin rash and nausea have been reported in association with Gallium Citrate Ga 67 use.

Gallium Dosage and Administration

The recommended adult (70 kg) dose of Gallium Citrate Ga 67 Injection is 74 to 185 megabecquerels (2 to 5 millicuries). Gallium Citrate Ga 67 Injection is intended for intravenous administration only.

Approximately 10 percent of the administered dose is excreted in the feces during the first week after injection. Daily laxatives and/or enemas are recommended from the day of injection until the final images are obtained in order to cleanse the bowel of radioactive material and minimize the possibility of false positive studies.

Studies indicate the optimal tumor to background concentration ratios are often obtained 48 hours post injection. However, considerable biological variability may occur in individuals and acceptable images may be obtained as early as 6 hours and as late as 120 hours after injection.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if contents are turbid.

Instructions for the handling of Gallium Citrate Ga 67:

Waterproof gloves should be used during the entire handling and administration procedure.
Using proper shielding, the vial containing the Gallium Citrate Ga 67 should be visually inspected to insure that it is free of particulate matter and discoloration prior to use.
Maintain adequate shielding during the life of the product and use a sterile, shielded syringe for withdrawing and injecting the preparation. RADIATION DOSIMETRY

The estimated absorbed radiation doses2 from an intravenous injection of 185 megabecquerels (5 millicuries) of Gallium Citrate Ga 67 are shown in Table 4.

Table 4. Absorbed Radiation Doses Tissue mGy/
185MBq rads/
5mCi Whole Body 13.0 1.30 Skeleton 22.0 2.20 Liver 23.0 2.30 Bone Marrow 29.0 2.90 Spleen 26.5 2.65 Kidney 20.5 2.05 Ovaries 14.0 1.40 Testes 12.0 1.20 Gastrointestinal Tract    Stomach 11.0 1.10    Small Intestine 18.0 1.80    Upper Large Intestine 28.0 2.80    Lower Large Intestine 45.0 4.50 2 MIRD Dose Estimate Report No. 2, J. Nucl. Med. 14; 755-6 (1973). How is Gallium Supplied

Catalog Number 180.

Gallium Citrate Ga 67 Injection is supplied sterile and non-pyrogenic for intravenous use. Each milliliter contains 74 megabecquerels (2 millicuries) of Gallium Ga 67 on the calibration date, as a complex formed from 8.3 nanograms Gallium chloride Ga 67, 1.9 milligrams of sodium citrate dihydrate, 7.8 milligrams of sodium chloride, and 0.9 percent benzyl alcohol (v/v) as a preservative. The pH is adjusted to between 5.5 to 8.0 with hydrochloric acid and/or sodium hydroxide solution.

Gallium Citrate Ga 67 Injection is available in vials containing 111 MBq, 222 MBq and 444 MBq (3 mCi, 6 mCi and 12 mCi) on the calibration date.

STORAGE AND HANDLING

The contents of the vial are radioactive, and adequate shielding and handling precautions must be maintained. Store at controlled room temperature 20-25°C (68-77°F) [see USP].

Storage and disposal of Gallium Citrate Ga 67 Injection should be controlled in a manner that is in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide.

Revised 4/2005
Mallinckrodt Inc.
St. Louis, MO 63134

MALLINCKRODT
A180I0


Gallium CITRATE GA-67 
Gallium citrate, ga-67  injection, solution Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0019-N180 Route of Administration INTRAVENOUS DEA Schedule      INGREDIENTS Name (Active Moiety) Type Strength Gallium Citrate, Ga-67 (Gallium Citrate, Ga-67) Active 2 MILLICURIE  In 1 MILLILITER sodium citrate dihydrate Inactive 1.9 MILLIGRAM  In 1 MILLILITER sodium chloride Inactive 7.8 MILLIGRAM  In 1 MILLILITER benzyl alcohol Inactive   hydrochloric acid Inactive   sodium hydroxide Inactive   Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains          Packaging # NDC Package Description Multilevel Packaging 1 0019-N180-D0 1 VIAL In 1 CAN contains a VIAL, MULTI-DOSE 1 1.65 mL (MILLILITER) In 1 VIAL, MULTI-DOSE This package is contained within the CAN (0019-N180-D0) 2 0019-N180-G0 1 VIAL In 1 CAN contains a VIAL, MULTI-DOSE 2 3.3 mL (MILLILITER) In 1 VIAL, MULTI-DOSE This package is contained within the CAN (0019-N180-G0) 3 0019-N180-M0 1 VIAL In 1 CAN contains a VIAL, MULTI-DOSE 3 6.6 mL (MILLILITER) In 1 VIAL, MULTI-DOSE This package is contained within the CAN (0019-N180-M0)
Revised: 03/2007Mallinckrodt Inc. More Gallium resources Gallium Drug Interactions Gallium Support Group 0 Reviews · Be the first to review/rate this drug
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