Mutamycin

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

MUTAMYCIN (mitomycin) 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 (mitomycin) is not recommended to replace appropriate surgery and/or radiotherapy.

MUTAMYCIN (mitomycin) 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 (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 MUTAMYCIN (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 MUTAMYCIN (mitomycin) , the drug should be stopped since chances of response are minimal.

Stability

1. Unreconstituted MUTAMYCIN (mitomycin) 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 (mitomycin) 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 (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.^1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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

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

WARNINGS

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

The use of MUTAMYCIN (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/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 (mitomycin) should be observed for evidence of renal toxicity. MUTAMYCIN (mitomycin) should not be given to patients with a serum creatinine greater than 1.7 mg percent.

Usage in Pregnancy

Safe use of MUTAMYCIN (mitomycin) in pregnant women has not been established. Teratological changes have been noted in animal studies. The effect of MUTAMYCIN (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 MUTAMYCIN (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 MUTAMYCIN (mitomycin) 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.

SIDE EFFECTS

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 (mitomycin) 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 (mitomycin) , 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 (mitomycin) -induced pulmonary toxicity. If other etiologies are eliminated, MUTAMYCIN (mitomycin) 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 (mitomycin) 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 (mitomycin). 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) 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 (mitomycin). Of 83 patients studied, 72 developed the syndrome at total doses exceeding 60 mg of MUTAMYCIN (mitomycin). Consequently, patients receiving ≥ 60 mg of MUTAMYCIN (mitomycin) 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 (mitomycin) 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).

DRUG INTERACTIONS

No information provided.

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 (mitomycin) 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 (mitomycin) , 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 (mitomycin) -induced pulmonary toxicity. If other etiologies are eliminated, MUTAMYCIN (mitomycin) 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 (mitomycin) 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 (mitomycin). 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) 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 (mitomycin). Of 83 patients studied, 72 developed the syndrome at total doses exceeding 60 mg of MUTAMYCIN (mitomycin). Consequently, patients receiving ≥ 60 mg of MUTAMYCIN (mitomycin) 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 (mitomycin) 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.