CLINICAL PHARMACOLOGY

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

In humans, mitomycin 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 mcg/mL, 1.7 mcg/mL, and 0.52 mcg/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 mitomycin 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 mitomycin is similar.

Animal Toxicology

Mitomycin 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.

WARNINGS

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

The use of mitomycin 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/mm 3 or a WBC below 4,000/mm 3 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 mitomycin should be observed for evidence of renal toxicity. Mitomycin should not be given to patients with a serum creatinine greater than 1.7 mg percent.

Usage in Pregnancy

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

PRECAUTIONS

Acute shortness of breath and severe bronchospasm has been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received mitomycin. 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 mitomycin in combination with other chemotherapy and maintained at FIO 2 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 mitomycin are available for patients 65 years of ages 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.

HOW SUPPLIED

Mitomycin for injection, USP

NDC 72819-152-05 5 mg; individually-boxed amber vial
NDC 72819-153-02 20 mg; individually-boxed amber vial
NDC 72819-154-04 40 mg; individually-boxed amber vial

Storage: Store dry powder at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.], protected from light. Avoid excessive heat, over 40°C

(104°F). Protect reconstituted solution from light. Store solution under refrigeration 2° to 8°C (36° to 46°F), discard after 14 days. If unrefrigerated, discard after 7 days.