Mitomycin
Mitomycin 20mg/40mg Injection

WHAT MITOMYCIN IS AND WHAT IT IS USED FOR

As a single medicine or in a combination with other medicines, 'Mitomycin  can be used to treat different types of cancers in many different parts of the body as described below:-

• In bladder cancer 'Mitomycin' can be given by injection or, alternatively introduced directly into the bladder after surgery to reduce the chances of a recurrence of the condition
• Breast cancer and cancer of the neck of the womb (the cervix).
• It shows some activity in cancers of the stomach, pancreas, lung, liver, head and neck, prostate, leukaemia (a disease of the blood) and certain other types of tumours.
• It has a possible role with other anti-cancer medicines in cancer of the lower bowel, skin cancer and sarcomas (cancers of a particular kind of body tissue called connective tissue).
• It has been successfully used in combination with surgery, before operations (in cases of cancer of the upper digestive tract) and after operations (in cases of cancer of the stomach).
• It has been shown to be effective when used in combination with radiotherapy.

WHAT YOU NEED TO KNOW BEFORE YOU USE MITOMYCIN

Do not use Mitomycin if you:

• are allergic (hypersensitive) to mitomycin or any of the other ingredients of Mitomycin (listed in section 6)
• have certain types of blood disorders (ask your doctor for advice).

Take special care with Mitomycin if you:

• have liver or kidney problems; side effects of mitomycin may be more noticeable
• are capable of child-bearing as mitomycin may affect your ability to have children in the future
• have been told that you have bone marrow depression (your bone marrow is not able to make the blood cells that you need); it may be made worse (especially in the elderly); infection (including chickenpox) may be aggravated due to bone marrow depression and may lead to fatal conditions.

Special attention will be paid if this product is given to the elderly or to children due to the possible side effects in these age groups.

You will be given the treatment under the supervision of a healthcare professional who is experienced in this particular branch of medicine to minimise any unwanted side effects in the injection site.

Other medicines and Mitomycin
Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription, or been given other treatments (e.g. radiotherapy).

When given together with certain other cancer treatment there have been some reports of problems related to bone marrow and the occurrence of cancer involving various types of blood cells.

Pregnancy and breast-feeding
You should not be given 'Mitomycin'  if you are pregnant, may be pregnant or if you are breast -feeding. Ask your doctor for advice before taking any medicine.

Driving and using machines
A few people have reported that they feel tired or weak after the treatment. Do not drive or use any tools or machines if you are affected.

HOW TO USE MITOMYCIN

Always use the medicine as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

'Mitomycin' is usually given by injection or as an infusion (with a drip). However in the treatment or the prevention of the recurrence of bladder cancer, a solution of 'Mitomycin' will be given directly into the bladder through a type of tube called a catheter.

The precise dosage, frequency of dosing and duration of treatment with 'Mitomycin'  will depend on your age, weight, medical condition and whether 'Mitomycin' is being given in combination with other drug treatment.

For example, when given by injection the recommended dose is in the range of 4-10 mg given at 1-6 weekly intervals. A course ranging from 40-80 mg is often required for a satisfactory result when used alone or in combination with other treatments. Thus, the period of treatment could last from just a few weeks up to a number of months, depending on the condition being treated.

In the treatment of bladder cancer, the recommended dose is 20-40mg administered into the bladder, weekly or three times a week for a total of 20 doses. The dosage may be decreased if side effects are a problem.

If during treatment you develop a dry cough, breathlessness, rapid breathing or anything else which suggests your lungs might be affected, you may require to be monitored by X-rays of your chest that could continue up to 4 weeks after the end of treatment.

If you are given more Mitomycin than you should
If you have been accidentally given a higher dose you may experience symptoms such as fever, nausea, vomiting and blood disorders. Your doctor may give you supportive treatment for any symptoms that may occur.

POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you notice any of the following severe reactions tell your doctor immediately:

• severe breathlessness
• pneumonia – fever, chills, shortness of breath or a cough
• severe allergic reaction – you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint.

If you experience any of the following tell your doctor as soon as possible:

• fever on the day of treatment
• loss of appetite and weight loss
• tiredness, weakness and headache
• feeling or being sick (this may shortly disappear during treatment)
• high blood pressure or flushing
• pain, swelling, redness or tenderness at the site of the injection
• sores mouth and mouth ulcers
• diarrhoea, abdominal discomfort or constipation
• hardening, thickening, redness, tenderness or swelling of the tips of the fingers and hair loss
• changes in urinating or pain when urinating
• ridging of nails, blisters on pressure points e.g. elbows
• easily pick up infections
• reduced blood flow to the fingers, toes and tip of the nose
• bleeding and bruising
• severe damage and potentially rupture of the wall of the bladder resulting in severe lower abdominal pain, difficulty or inability to pass urine, and possibly blood in the urine.
• severe damage to the penis resulting in pain in the penis, abnormal colour of the penis and potential difficulty in passing urine.

Kidney or liver problems have also been reported. Your doctor will monitor your kidney (urine test) and liver (blood test) regularly.

HOW TO STORE MITOMYCIN

Keep out of the sight and reach of children.
Mitomyicin should be kept in its original packaging.

Do not use this medicine after the expiry date which is stated on the label after “Exp Date”. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

CONTENTS OF THE PACK AND OTHER INFORMATION

What Mitomycin contains

-        The active substance is Mitomycin
-        The other ingredient is sodium chloride

What Mitomycin looks like and contents of the pack
Mitomycin is a powder which is mixed before injection. It is packaged in glass vials with a rubber stopper and aluminium seal.

Mitomycin
Mitomycin 20mg/40mg Injection

DESCRIPTION

Mitomycin (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.

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. Each mL of reconstituted solution will contain 0.5 mg mitomycin and have a pH between 6.0 and 8.0.

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;

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.

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.

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 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 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.

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.

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.

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 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

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. Mitomycin produces cumulative myelosuppression.

This has occurred in approximately 4% of patients treated with mitomycin. 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 Mitomycin for Injection USP, 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).

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.

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 mitomycin-induced pulmonary toxicity. If other etiologies are eliminated, 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 mitomycin in combination with other chemotherapy and maintained at FlO2 concentrations greater than 50% perioperatively.

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 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 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 mitomycin. Of 83 patients studied, 72 developed the syndrome at total doses exceeding 60 mg of mitomycin. Consequently, patients receiving ≥60 mg of 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.

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 Mitomycin were fever, anorexia, nausea, and vomiting. They occurred in about 14% of 1,281 patients.

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.

DOSAGE AND ADMINISTRATION

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

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 mitomycin 20 mg and mannitol 40 mg or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 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 a 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.

1. Unreconstituted 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, 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:

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

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

HOW SUPPLIED

Mitomycin for Injection USP

Each amber vial contains 20 mg mitomycin, individually packed in single carton.
Each amber vial contains 40 mg mitomycin, individually packed in single carton.

Storage:Store dry powder at 25°C, excursion permitted between 15°C and 30°C, 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.

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.