Mitomycin

Mitomycin is an antibiotic isolated from the broth of Streptomyces verticillus Yingtanensis which has been shown to have antimetabolic activity.

Mitomycin is a blue-violet crystalline powder with the molecular formula of C15H18N4O5 and a molecular weight of 334.33. Its chemical name is 7-amino-9α-methoxymitosane and it has the following structural formula:

Mitosol® is a sterile lyophiliized mixture of mitomycin and mannitol, which, when reconstituted with Sterile Water for Injection, provides a solution for application in glaucoma filtration surgery. Mitosol® is supplied in vials containing 0.2 mg of mitomycin. Each vial also contains mannitol 0.4 mg, at a 1:2 ratio of mitomycin to mannitol. Each mL of reconstituted solution contains 0.2 mg mitomycin and has a pH between 5.0 and 8.0.

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.

Mitomycin can lower the activity of the immune system making you more susceptible to infection. Avoid contact with people who have colds, the flu, or other contagious illnesses. In addition, do not receive vaccines that contain a live strain of the virus (e.g., live oral polio vaccine) and avoid contact with individuals who have recently been vaccinated with a live virus.

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).

Read the entire FDA prescribing information for Mutamycin (Mitomycin)

Mitomycin may be found in some form under the following brand names:

• Mitosol

• Mutamycin

Before taking mitomycin, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to mitomycin or to any of its ingredients
• have a blood or bleeding disorder
• have or have had kidney disease
• are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Topical:

• Store mitomycin for topical application at room temperature.

Injectable:

• Store mitomycin for injection at 25ºC.
• Protect from exposure to heat and light.
• Keep this and all medicines out of the reach of children.

WARNING

Mitomycin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of mitomycin.

Hemolytic Uremic Syndrome (HUS) a serious complication of chemotherapy, consisting primarily of microangiopathic hemolytic anemia, thrombocytopenia, and irreversible renal failure has been reported in patients receiving systemic mitomycin. The syndrome may occur at any time during systemic therapy with mitomycin as a single agent or in combination with other cytotoxic drugs, however, most cases occur at doses ≥60 mg of mitomycin. Blood product transfusion may exacerbate the symptoms associated with this syndrome.

The incidence of the syndrome has not been defined.

Mitomycin can weaken (suppress) your immune system, and you may get an infection more easily. Call your doctor if you have signs of infection (fever, weakness, cold or flu symptoms, skin sores, frequent or recurring illness).

Mitomycin can also damage red blood cells, which may cause irreversible kidney failure. Call your doctor right away if you have unusual bruising or bleeding, pale skin, confusion, tiredness or irritability, stomach pain, bloody diarrhea, red or pink urine, swelling, rapid weight gain, and little or no urinating.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Mitomycin can damage red blood cells, which may cause irreversible kidney failure. Call your doctor right away if you have:

• pale skin, unusual bruising or bleeding;

• confusion, tiredness or irritability;

• stomach pain, bloody diarrhea, red or pink urine;

• swelling, rapid weight gain; or

• little or no urinating.

Call your doctor at once if you have:

• signs of infection (fever, weakness, cold or flu symptoms, skin sores, frequent or recurring illness);

• wheezing, chest tightness, new or worsening cough, trouble breathing;

• blisters or ulcers in your mouth, red or swollen gums, trouble swallowing; or

• pain, burning, redness, irritation, or skin changes where the injection was given.

Common side effects may include:

• fever or other signs of infection;

• nausea, vomiting, diarrhea, loss of appetite;

• mouth sores;

• drowsiness, headache;

• blurred vision; or

• temporary hair loss.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Adenocarcinoma of Stomach and Pancreas

Component of combination chemotherapeutic regimens for treatment of disseminated adenocarcinoma of the stomach or pancreas and as palliative treatment of these tumors when other treatment modalities are ineffective.100 121 d

Response rates generally low (10–17%) and of short duration.c

Not recommended for use as single-agent, primary therapy or as a replacement for appropriate surgery and/or radiation therapy.100 d

Anal Cancer

A preferred regimen, in combination with fluorouracil, for primary treatment of anal cancer†.121

Bladder Cancer

Has been used for intravesical† treatment of residual tumor and/or as adjuvant therapy for prophylaxis of superficial bladder cancer†.113 115 120 121 130 131 138

Causes regression of existing papillary tumor and reduces the rate of short-term tumor recurrence but has no effect on disease progression or overall survival.119 123 124 129 139

Cervical Cancer

Has been used in cisplatin-containing combination chemotherapy regimens (e.g., bleomycin, cisplatin, mitomycin, and vincristine) for treatment of metastatic or recurrent cervical cancer†.132 135

Other agents generally preferred for treatment of advanced cervical cancer†.136 137

Non-small Cell Lung Cancer

Has been used for treatment of non-small cell lung cancer† in combination with cisplatin and vinblastine (MVP) 121 146 149 or ifosfamide with mesna (MIC).121 150

Other chemotherapeutic regimens (e.g., cisplatin with paclitaxel, vinorelbine, or gemcitabine) currently preferred for treatment of advanced non-small cell lung cancer†.121 146

Malignant Mesothelioma

Has been used for treatment of malignant mesothelioma†.121

Head and Neck Carcinoma

Has been used as an adjunct to radiation therapy for treatment of squamous cell carcinoma of head and neck†.147

Breast Cancer

Has shown activity for treatment of metastatic breast cancer†.148

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.100 d

• Administer mitomycin only after complete hematologic recovery from any previous chemotherapy occurs.100

Administration

Administer IV.100 c d

Has been administered intravesically†; notan approved route of administration.100 115 120 121 130 131 138 d

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer via a functioning IV catheter;100 c d some clinicians recommend administering the drug through tubing of an IV infusion.c Use care to avoid extravasation.100 d (See Mucocutaneous Effects under Cautions.)

Reconstitute vial containing 5, 20, or 40 mg of mitomycin with 10, 40, or 80 mL of sterile water for injection, respectively, to provide a solution containing approximately 0.5 mg/mL.100 c d

Shake vial to dissolve.100 c d If the powder does not dissolve immediately, allow the vial to stand at room temperature until complete dissolution occurs.100 c d

Dosage

Consult published protocols for dosages of mitomycin and other chemotherapeutic agents and the method and sequence of administration.c

Individualize dosage based on clinical and hematologic response and tolerance of the patient and whether or not other myelosuppressive therapy also is being used.100 c d

Reevaluate patients after each course of therapy and adjust dosages as needed.100 d

Adults

Initially, 20 mg/m2 as a single IV dose every 6–8 weeks.100 d Doses >20 mg/m2 are not more effective and increase risk of toxicity.100 d

Adjust subsequent dosages according to the hematologic response to the previous dose.100 d (See Table 1.)Do not administer repeat dosage until leukocyte count has returned to 4000/mm3 and platelet count to 100,000/mm3.100 d

If disease continues to progress after 2 courses of therapy, discontinue the drug since likelihood of response is minimal.100 d

Usual dosage: 20–60 mg once weekly,115 116 118 120 125 126 127 128 administered as soon as possible following transurethral resection (TUR).117 128 For patients treated within 6–24 hours following TUR, a 6-month course of therapy generally is sufficient; however, for patients in whom intravesical therapy is instituted ≥24 hours following surgery, a 12-month course usually is recommended.117 128 No additional benefit demonstrated for continued maintenance therapy.115 116 120 124 128 131

Special Populations

Hepatic Impairment

No special dosage recommendations at this time.100 d

Renal Impairment

Do not administer if Scr >1.7 mg/dL.100 d (See Renal Effects under Cautions.)

Geriatric Patients

No special dosage recommendations at this time.100 d

• Importance of advising patients of potentially life-threatening hematologic (e.g., myelosuppression), respiratory, and renal toxicities associated with mitomycin therapy.100 c d

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.100 d

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., bleeding disorders).100 d

• Importance of informing patients of other important precautionary information.100 d (See Cautions.)

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.

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.

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 FlO 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.

Data not available