MUTAMYCIN - mitomycin injection, powder, for solution 
E.R. Squibb & Sons, L.L.C.

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MUTAMYCIN®
(mitomycin for injection, USP)

DESCRIPTION

MUTAMYCIN® (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.

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 percent increase in tumor incidence in male Sprague-Dawley rats, and a greater than 50 percent increase in tumor incidence in female Swiss mice.

INDICATIONS

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.

CONTRAINDICATIONS

MUTAMYCIN (mitomycin for injection, USP) 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.

WARNINGS

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.

PRECAUTIONS

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.

Geriatric Use

Insufficient data from clinical studies of MUTAMYCIN are available for patients 65 years of age and older to determine whether they respond differently than younger patients. Postmarketing surveillance suggests that elderly patients may be more susceptible than younger patients to injection site reactions (see ADVERSE REACTIONS: Integument and Mucous Membrane Toxicity) and hypersensitivity reactions. In general, caution should be exercised when prescribing to elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

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. 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. Elderly patients may be more susceptible than younger patients to injection site reactions (see PRECAUTIONS: Geriatric Use).

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 (mitomycin for injection, USP) 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).

DOSAGE AND ADMINISTRATION

MUTAMYCIN should be given intravenously only, using care to avoid extravasation 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:

Nadir After Prior Dose
Leukocytes/mm3	Platelets/mm3	Percentage of Prior Dose to be Given
>4000	>100,000	100%
3000-3999	75,000-99,999	100%
2000-2999	25,000-74,999	70%
<2000	<25,000	50%

No repeat dosage should be given until leukocyte count has returned to 4000/mm3 and a 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:

   I.V. Fluid	Stability
   5% Dextrose Injection	3 hours
   0.9% Sodium Chloride Injection	12 hours
   Sodium Lactate Injection	24 hours

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.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

HOW SUPPLIED

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. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, PA: Oncology Nursing Society; 1999:32-41.
2. 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.
3. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985;253:1590-1591.
4. 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.
5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.
6. 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.
7. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
8. Controlling Occupational Exposure to Hazardous Drugs. (OSHA Work-Practice Guidelines.). Am J Health SystPharm. 1996;53:1669-1685.

Bristol-Myers Squibb Oncology

A Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA

Revised May 2004

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REPRESENTATIVE PACKAGING

See HOW SUPPLIED section for a complete list of available packages of MUTAMYCIN.

NDC 0015-3002-20
NSN 6505-01-125-4597
MUTAMYCIN® (mitomycin for injection, USP)
20 mg
Rx only
©1977, Bristol-Myers Squibb Company

MUTAMYCIN  mitomycin   injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3001 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength mitomycin (mitomycin) mitomycin 5 mg  in 10 mL

Inactive Ingredients Ingredient Name Strength mannitol 10 mg  in 10 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0015-3001-20 1 VIAL In 1 CARTON contains a VIAL 1 10 mL In 1 VIAL This package is contained within the CARTON (0015-3001-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA062336	08/24/1981	06/30/2008

MUTAMYCIN  mitomycin   injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3002 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength mitomycin (mitomycin) mitomycin 20 mg  in 40 mL

Inactive Ingredients Ingredient Name Strength mannitol 40 mg  in 40 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0015-3002-20 1 VIAL In 1 CARTON contains a VIAL 1 40 mL In 1 VIAL This package is contained within the CARTON (0015-3002-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA062336	08/24/1981	12/31/2007

MUTAMYCIN  mitomycin   injection, powder, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0015-3059 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength mitomycin (mitomycin) mitomycin 40 mg  in 80 mL

Inactive Ingredients Ingredient Name Strength mannitol 80 mg  in 80 mL

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0015-3059-20 1 VIAL In 1 CARTON contains a VIAL 1 80 mL In 1 VIAL This package is contained within the CARTON (0015-3059-20)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA062336	03/10/1988	05/31/2008

Labeler - E.R. Squibb & Sons, L.L.C. (006370092)

Revised: 01/2010E.R. Squibb & Sons, L.L.C.