MUTAMYCIN® (mitomycin for injection, USP) (also known as mitomycin and/or mitomycin-C) is an antibiotic isolated from the broth of Streptomyces caespitosus which has been shown to have antitumor activity. The compound is heat stable, has a high melting point, and is freely soluble in organic solvents.

MUTAMYCIN is not recommended as single-agent, primary therapy. It has been shown to be useful in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed. MUTAMYCIN is not recommended to replace appropriate surgery and/or radiotherapy.

MUTAMYCIN should be given intravenously only, using care to avoid extrava-sation of the compound. If extravasation occurs, cellulitis, ulceration, and slough may result.

Each vial contains either mitomycin 5 mg and mannitol 10 mg, mitomycin 20 mg and mannitol 40 mg, or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 10 mL, 40 mL, or 80 mL respectively. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained.

After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy, the following dosage schedule may be used at 6 to 8 week intervals:

20 mg/m² intravenously as a single dose via a functioning intravenous catheter.

Because of cumulative myelosuppression, patients should be fully reevaluated after each course of MUTAMYCIN, and the dose reduced if the patient has experienced any toxicities. Doses greater than 20 mg/m² have not been shown to be more effective, and are more toxic than lower doses.

The following schedule is suggested as a guide to dosage adjustment:

No repeat dosage should be given until leukocyte count has returned to 4000/mm³ and platelet count to 100,000/mm³.

When MUTAMYCIN is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of MUTAMYCIN, the drug should be stopped since chances of response are minimal.

Stability

1. Unreconstituted MUTAMYCIN stored at room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C, 104°F).
2. Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, MUTAMYCIN is stable for 14 days refrigerated or 7 days at room temperature.
3. Diluted in various I.V. fluids at room temperature, to a concentration of 20 to 40 micrograms per mL:
4. The combination of MUTAMYCIN (5 mg to 15 mg) and heparin (1,000 units to 10,000 units) in 30 mL of 0.9% Sodium Chloride Injection is stable for 48 hours at room temperature.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

MUTAMYCIN® (mitomycin for injection, USP)

NDC 0015-3001-20 – Each vial contains 5 mg mitomycin.
NDC 0015-3002-20 – Each vial contains 20 mg mitomycin.
NDC 0015-3059-20 – Each vial contains 40 mg mitomycin.

For information on package sizes available, refer to the current price schedule.

REFERENCES

1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.

2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253 (11):1590-1592.

3. National Study Commission on Cytotoxic Exposure–Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.

4. Clinical Oncological Society of Australia. Guidelines and Recommen- dations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428.

5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA–A Cancer Journal for Clinicians 1983; (Sept/Oct) 258-263.

6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033–1049.

7. Controlling Occupational Exposure to Hazardous Drugs (OSHA WORK PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996;53:1669-1685.

Bristol-Myers Sqibb Company, Princeton, NJ 08543 U.S.A. Revised January 2000. FDA Rev date: 11/2/2000

Bone Marrow Toxicity: This was the most common and most serious toxicity, occurring in 605 of 937 patients (64.4%). Thrombocytopenia and/or leukopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of the leukopenic or thrombocytopenic episodes did not recover. MUTAMYCIN produces cumulative myelosuppression.

Integument and Mucous Membrane Toxicity: This has occurred in approximately 4% of patients treated with MUTAMYCIN (mitomycin for injection, USP). Cellulitis at the injection site has been reported and is occasionally severe. Stomatitis and alopecia also occur frequently. Rashes are rarely reported. The most important dermatological problem with this drug, however, is the necrosis and consequent sloughing of tissue which results if the drug is extravasated during injection. Extravasation may occur with or without an accompanying stinging or burning sensation and even if there is adequate blood return when the injection needle is aspirated. There have been reports of delayed erythema and/or ulceration occurring either at or distant from the injection site, weeks to months after MUTAMYCIN, even when no obvious evidence of extravasation was observed during administration. Skin grafting has been required in some of the cases.

Renal Toxicity: 2% of 1,281 patients demonstrated a statistically significant rise in creatinine. There appeared to be no correlation between total dose administered or duration of therapy and the degree of renal impairment.

Pulmonary Toxicity: This has occurred infrequently but can be severe and may be life threatening. Dyspnea with a nonproductive cough and radiographic evidence of pulmonary infiltrates may be indicative of MUTAMYCIN-induced pulmonary toxicity. If other etiologies are eliminated, MUTAMYCIN therapy should be discontinued. Steroids have been employed as treatment of this toxicity, but the therapeutic value has not been determined. A few cases of adult respiratory distress syndrome have been reported in patients receiving MUTAMYCIN in combination with other chemotherapy and maintained at FIO₂ concentrations greater than 50% perioperatively.

Hemolytic Uremic Syndrome (HUS): This serious complication of chemotherapy, consisting primarily of microangiopathic hemolytic anemia (hematocrit ≤ 25%), thrombocytopenia ( ≤ 100,000/mm³), and irreversible renal failure (serum creatinine ≥ 1.6 mg/dL) has been reported in patients receiving systemic MUTAMYCIN. Microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears has occurred in 98% of patients with the syndrome. Other less frequent complications of the syndrome may include pulmonary edema (65%), neurologic abnormalities (16%), and hypertension. Exacerbation of the symptoms associated with HUS has been reported in some patients receiving blood product transfusions. A high mortality rate (52%) has been associated with this syndrome.

The syndrome may occur at any time during systemic therapy with MUTAMYCIN as a single agent or in combination with other cytotoxic drugs. Less frequently, HUS has also been reported in patients receiving combinations of cytotoxic drugs not including MUTAMYCIN. Of 83 patients studied, 72 developed the syndrome at total doses exceeding 60 mg of MUTAMYCIN. Consequently, patients receiving ≥ 60 mg of MUTAMYCIN should be monitored closely for unexplained anemia with fragmented cells on peripheral blood smear, thrombocytopenia, and decreased renal function.

The incidence of the syndrome has not been defined.

Therapy for the syndrome is investigational.

Cardiac Toxicity: Congestive heart failure, often treated effectively with diuretics and cardiac glycosides, has rarely been reported. Almost all patients who experienced this side effect had received prior doxorubicin therapy.

Acute Side Effects Due to MUTAMYCIN were fever, anorexia, nausea, and vomiting. They occurred in about 14% of 1,281 patients.

Other: Headache, blurring of vision, confusion, drowsiness, syncope, fatigue, edema, thrombophlebitis, hematemesis, diarrhea, and pain. These did not appear to be dose related and were not unequivocally drug related. They may have been due to the primary or metastatic disease processes. Malaise and asthenia have been reported as part of postmarketing surveillance. Bladder fibrosis/contraction has been reported with intravesical administration (see PRECAUTIONS).

No information provided.

Patients being treated with MUTAMYCIN must be observed carefully and frequently during and after therapy.

The use of MUTAMYCIN results in a high incidence of bone marrow suppression, particularly thrombocytopenia and leukopenia. Therefore, the following studies should be obtained repeatedly during therapy and for at least eight weeks following therapy: platelet count, white blood cell count, differential, and hemoglobin. The occurrence of a platelet count below 100,000/mm³ or a WBC below 4,000/mm³ or a progressive decline in either is an indication to withhold further therapy until blood counts have recovered above these levels.

Patients should be advised of the potential toxicity of this drug, particularly bone marrow suppression. Deaths have been reported due to septicemia as a result of leukopenia due to the drug.

Patients receiving MUTAMYCIN should be observed for evidence of renal toxicity. MUTAMYCIN should not be given to patients with a serum creatinine greater than 1.7 mg percent.

Usage in Pregnancy

Safe use of MUTAMYCIN in pregnant women has not been established. Teratological changes have been noted in animal studies. The effect of MUTAMYCIN on fertility is unknown.

Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received MUTAMYCIN. The onset of this acute respiratory distress occurred within minutes to hours after the vinca alkaloid injection. The total number of doses for each drug has varied considerably. Bronchodilators, steroids and/or oxygen have produced symptomatic relief.

A few cases of adult respiratory distress syndrome have been reported in patients receiving MUTAMYCIN in combination with other chemotherapy and maintained at FIO₂ concentrations greater than 50% perioperatively. Therefore, caution should be exercised using only enough oxygen to provide adequate arterial saturation since oxygen itself is toxic to the lungs. Careful attention should be paid to fluid balance and overhydration should be avoided.

Bladder fibrosis/contraction has been reported with intravesical administration (not an approved route of administration), which in rare cases has required cystectomy.

Nursing Mothers

It is not known if mitomycin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from mitomycin, it is recommended that nursing be discontinued when receiving mitomycin therapy.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

No information provided.

MUTAMYCIN is contraindicated in patients who have demonstrated a hypersensitive or idiosyncratic reaction to it in the past.

MUTAMYCIN is contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes.

Action

MUTAMYCIN selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of MUTAMYCIN-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.

In humans, MUTAMYCIN is rapidly cleared from the serum after intravenous administration. Time required to reduce the serum concentration by 50% after a 30 mg bolus injection is 17 minutes. After injection of 30 mg, 20 mg, or 10 mg I.V., the maximal serum concentrations were 2.4 µg/mL, 1.7 µg/mL, and 0.52 µg/mL, respectively. Clearance is effected primarily by metabolism in the liver, but metabolism occurs in other tissues as well. The rate of clearance is inversely proportional to the maximal serum concentration because, it is thought, of saturation of the degradative pathways.

Approximately 10% of a dose of MUTAMYCIN is excreted unchanged in the urine. Since metabolic pathways are saturated at relatively low doses, the percent of a dose excreted in urine increases with increasing dose. In children, excretion of intravenously administered MUTAMYCIN is similar.

Animal Toxicology

MUTAMYCIN has been found to be carcinogenic in rats and mice. At doses approximating the recommended clinical dose in man, it produces a greater than 100% increase in tumor incidence in male Sprague-Dawley rats, and a greater than 50% increase in tumor incidence in female Swiss mice.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

MITOMYCIN - INJECTION

(mitt-oh-MY-sin)

COMMON BRAND NAME(S): Mutamycin

WARNING: Mitomycin may cause serious blood and bone marrow disorders (e.g., low red blood cells/white blood cells/platelets). These problems can affect your body's ability to stop bleeding or fight infection. Tell your doctor immediately if you develop easy bleeding/bruising or signs of an infection (e.g., fever, chills, persistent sore throat).

This drug may cause a certain serious, sometimes fatal side effect (hemolytic uremic syndrome). This condition may result in anemia, low platelet counts, and kidney disease. Blood transfusions may make the symptoms worse. Tell your doctor immediately if you notice symptoms such as pink/bloody urine or change in amount of urine.

USES: Mitomycin is used with other drugs to treat various types of cancer (e.g., stomach/pancreas/lung cancer). It works by slowing or stopping the growth of cancer cells.

HOW TO USE: This medication is given by injection into a vein as directed by your doctor. Dosage is based on your medical condition, body size, and response to treatment.

Read and learn all preparation and usage instructions supplied by the manufacturer. Follow all instructions for proper handling and mixing with the correct IV fluids. Before using, check the product visually for particles or discoloration. If either is present, do not use the liquid.

Learn how to store and discard needles and medical supplies safely. Consult your pharmacist for details.

SIDE EFFECTS: See also Warning section.

Nausea, vomiting, stomach/abdominal pain, or loss of appetite may occur. Nausea and vomiting can be severe. In some cases, your doctor may prescribe medication to prevent or relieve nausea and vomiting. Eating several small meals, not eating before treatment, or limiting activity may help lessen some of these effects. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Severe nausea and vomiting may infrequently result in a loss of too much body water (dehydration). Contact your doctor promptly if you notice any symptoms of dehydration such as unusual decreased urination, unusual dry mouth/increased thirst, lack of tears, dizziness/lightheadedness, or pale/wrinkled skin.

Temporary hair loss may occur. Normal hair growth should return after treatment has ended.

Many people using this medication have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unusual bleeding/bruising (e.g., small red spots on the skin, black/bloody stools, vomit that looks like coffee grounds), numbness/tingling feelings, unusual tiredness/weakness.

Pain or sores in the mouth and throat may occur. Brush your teeth gently/carefully, avoid using mouthwash that contains alcohol, and rinse your mouth frequently with cool water mixed with baking soda or salt. It may also be best to eat soft, moist foods.

If this medication accidentally leaks into the skin/muscle around the injection site, it may cause severe damage. Symptoms may occur both during treatment or weeks to months after receiving a dose. Tell your doctor immediately if you notice redness, pain, or swelling at or near the injection site.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching, swelling, severe dizziness, trouble breathing (especially with cough).

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before receiving mitomycin, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood/bleeding disorders (e.g., anemia, low blood cell counts), current infection, kidney disease, liver disease, radiation treatment.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. Wash your hands well to prevent the spread of infections.

To lower your risk of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

Before having surgery, tell your doctor or dentist that you are using this medication.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. If you become pregnant or think you may be pregnant, tell your doctor immediately. To avoid pregnancy, both males and females using this drug should use reliable form(s) of birth control (e.g., birth control pills, condoms) during treatment. Consult your doctor for details and to discuss effective forms of birth control.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other anti-cancer drugs (especially vinca alkaloids such as vinblastine).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (e.g., complete blood counts, kidney function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule. Do not double the dose to catch up.

STORAGE: Store the unmixed vials at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Avoid exposing this medication to high heat. After mixing, store at room temperature or in the refrigerator. Consult the package instructions or your pharmacist for other storage details. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.