Mitomycin – Mutamycin®

Mitomycin - Mutamycin®

Usual Diluents

Dilution Data

Mitomycin should be given intravenously only, using care to avoid extravasation of the compound. If extravasation occurs, cellulitis, ulceration, and slough may result.1  Administer slow I.V. push or by slow (15-30 minute) infusion via a freely-running dextrose or saline infusion. Consider using a central venous catheter 2.

Stability1
-------------------------------------------------
1.   Unreconstituted mitomycin stored at controlled room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C).
2.   Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, mitomycin is stable for 14 days refrigerated or 7 days at room temperature. Protect reconstituted solution from light.
3.   Diluted in various IV fluids at room temperature, to a concentration of 20 to 40 micrograms per mL    
                (0.02 - 0.04  mg/ml)

4.   The combination of mitomycin (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.

Store vials of unreconstituted product at controlled room temperature, 15° to 30°C (59° to 86°F)1.

DESCRIPTION
Mitomycin (also known as 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.

Mitomycin for Injection is a sterile dry mixture of mitomycin and mannitol, which, when reconstituted with Sterile Water for Injection, provides a solution for intravenous administration. Each vial contains either mitomycin 5 mg and mannitol 10 mg, or mitomycin 20 mg and mannitol 40 mg, or mitomycin 40 mg and mannitol 80 mg.

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 IV, the maximal serum concentrations were 2.4 mcg/mL,

1.7 mcg/mL, and 0.52 mcg/mL, respectively. Clearance is affected 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% increase in tumor incidence in male Sprague-Dawley rats, and a greater than 50% increase in tumor incidence in female Swiss mice.

INDICATIONS AND USAGE
Mitomycin for Injection 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. Mitomycin is not recommended to replace appropriate surgery and/or radiotherapy.

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

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

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 8 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 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 have 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 FlO2 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 found in human milk. Because many drugs are found in milk, it is recommended that women receiving mitomycin not breast feed because of the potential for serious adverse reactions from mitomycin in nursing infants.

Pediatric Use
Safety and effectiveness in pedriatric patients have not been established.

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

-------------------------------------------------
Stability
-------------------------------------------------
1.   Unreconstituted mitomycin stored at controlled room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C).
2.   Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, mitomycin is stable for 14 days refrigerated or 7 days at room temperature. Protect reconstituted solution from light.
3.   Diluted in various IV fluids at room temperature, to a concentration of 20 to 40 micrograms per mL

4.   The combination of mitomycin (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. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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

HOW SUPPLIED
Mitomycin for Injection is supplied in the following package strengths:

NDC 55390-251-01 5 mg; individually-boxed vial

NDC 55390-252-01 20 mg; individually-boxed vial

NDC 55390-253-01 40 mg; individually-boxed vial

Store vials of unreconstituted product at controlled room temperature, 15° to 30°C (59° to 86°F).

2) Solimando, Dominic A. Drug Information Handbook for Oncology: A Complete Guide to Combination Chemotherapy Regimens, 8th ed. Hudson, OH: Lexi-Comp, Inc.; 2010.