Health and Prostate

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Description. Mitomycin is an antineoplastic antibiotic produced by the growth of Streptomyces caespitosus.

Pharmacopoeias. In China, Europe, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Mitomycin). A substance produced by a strain of Streptomyces caespitotus. Blue-violet crystals or crystalline powder. Slightly soluble in water and in acetone; freely soluble in dimethylacetamide; sparingly soluble in methyl alcohol. A 0.1% solution in water has apH of 5.5 to 7.5. Protect from light.

The United States Pharmacopeia 31, 2008 (Mitomycin). A blue-violet crystalline powder. It has a potency of not less than 970 micrograms/mg. Slightly soluble in water; soluble in acetone, in butyl acetate, in cyclohexanone, and in methyl alcohol. A 0.5% suspension in water has a pH of 6.0 to 7.5. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°. Protect from light.

Incompatibility. Mitomycin may be incompatible with drugs that are acid in solution — for a report of incompatibility with topotecan.

Stability. Mitomycin undergoes degradation in acid solution, and two studies suggested that mitomycin was much less stable in glucose 5% injection than in sodium chloride 0.9%. These findings were queried by a manufacturer (Bristol, USA) whose own results suggested that mitomycin was stable for 48 hours in glucose injection 5% at 25°, and it is uncertain whether different manufacturers’ formulations differ in stability, or, as has been suggested, that an unsuitable assay was used by the manufacturer to measure stability.

Adverse Effects, Treatment, and Precautions

For general discussions see Antineoplastics.

The main adverse effect of mitomycin is delayed cumulative bone-marrow suppression. Profound leucopenia and thrombocytopenia occurs after about 4 weeks with recovery in about 8 to 10 weeks after a dose. Blood counts may not recover in about one-quarter of patients. Other serious adverse effects include renal damage and pulmonary reactions; a potentially fatal haemolytic-uraemic syndrome has been reported in some patients. US licensed product information states that the degree of renal impairment does not appear to be related to dose or duration of therapy although it has been suggested that the incidence of renal toxicity is greatly increased if the total cumulative dose exceeds 120 mg (see also Effects on the Kidneys, below). Gastrointestinal toxicity, dermatitis, alopecia, fever, malaise, and rarely cardiotoxicity may also occur. Local tissue necrosis, ulceration, and cellulitis may follow extravasation.

Mitomycin is contra-indicated in patients with impaired renal function or coagulation disorders. Renal function should be tested before beginning treatment and after each course.

Effects on the bladder. Intravesical instillation ofmitomycin after resection of superficial bladder tumours has led to the development of indolent asymptomatic ulcers at the resection site which may persist for months, and must be distinguished from persistent infiltrating bladder cancer. Persistent ulceration, inflammation, necrosis, and pain has also occurred, possibly because ofmitomycin extravasation at the resection site. There are also a few reports of eosinophilic cystitis, in which eosinophilic infiltration of the mucosa and muscle were accompanied by oedema, inflammation, muscle necrosis and fibrosis. Severe bladder contracture is a rare, and often irreversible, complication of intravesical mitomycin; urinary diversion may be required in cases of intolerable urinary frequency. Formation of papillary-like calcifications at the resection site, and calcification of the bladder wall have also been described after the use ofmitomycin for superficial transitional cell carcinoma of the bladder. See also under Effects on the Skin, below.

Effects on the eyes. Early complications after the topical use of mitomycin with glaucoma filtering surgery (see Glaucoma, below) include hypotony, shallow anterior chamber, cataract formation, choroidal effusions, hypotonous maculopathy, and suprachoroidal haemorrhage. Late complications include bleb leak, blebitis, and endophthalmitis. Complications from the topical use ofmitomycin with or after pterygium surgery (see Ptery-gium, below) commonly include irritation and photophobia. Other effects include delayed epithelial healing, avascularity of the sclera and cornea, scleral calcification and ulceration, necrotising scleritis, corneal or scleral perforation, iridocyclitis, cataract formation, glaucoma, and symblepharon. Some of these effects may be severe and sight-threatening, and require further surgery. Complications most commonly reported after the use of topical mitomycin in ocular surface neoplasia were hypersensitivity reactions and epiphora (an overflow of tears) secondary to stenosis of the lachrymal punctum.

Effects on the kidneys. A syndrome of thrombotic microangiopathy resembling the haemolytic-uraemic syndrome has been seen in patients receiving mitomycin, either alone or more often with other drugs, particularly fluorouracil or tamoxifen. The syndrome is characterised by haemolytic anaemia, thrombocytopenia, and progressive renal failure, and may be accompanied by hypertension, pulmonary oedema, and neurological effects including confusion, headache, and seizures. Onset is usually delayed, sometimes occurring several months after the end of a course ofmitomycin.

There is some uncertainty as to whether mitomycin dose is significant, but one study found that all of 25 cases they reported had received total doses of 70 mg or more, and another reported that 74 of 83 cases had received 60 mg or more. Symptoms may be exacerbated by blood transfusions. The use of erythropoietin allowed the cessation of blood transfusion, with subsequent haematological improvement and slower progression of chronic renal failure in one case report. Plasma exchange has been suggested as possibly helpful, although only a minority of patients may benefit from this treatment. Captopril therapy may also be useful.

Effects on the liver. Hepatic veno-occlusive disease developed in 6 of 29 patients given intensive mitomycin therapy and autologous bone marrow transplantation. The effect was manifest as abdominal pain, hepatomegaly, and ascites, and liver failure was progressive and fatal in 3. A further patient, who had no symptoms, was found to have veno-occlusive disease at post mortem.

Effects on respiratory function. Mitomycin-induced pulmonary toxicity has been reviewed. There have been reports of toxicity at total dosages as low as 20 mg/m ofmitomycin, although others report that the average cumulative dose associated with toxicity is 78 mg. Premedication with corticosteroids may reduce the incidence of lung toxicity. See also Effects on the Lungs. For reference to the respiratory effects ofmitomycin used with a vinca alkaloid see Interactions, Antineoplastics, under Vinblastine Sulfate.

Effects on the skin. Severe eczema of the hands and feet and generalised rash have been reported in patients receiving intravesical mitomycin. These symptoms appear to be due to a delayed hypersensitivity (type IV) reaction, which is probably also responsible for the bladder irritation and cystitis that may follow intravesical mitomycin (see above). Leucocytoclastic vasculitis caused by an immune-complex mediated (type III) reaction and presenting as purpuric papules has also been described.

Interactions

For a general outline of antineoplastic drug interactions.

Antineoplastics. Cardiotoxicity developed in 14 of 91 patients who received mitomycin therapy as second-line treatment for breast cancer after the failure of doxorubicin-contammg regimens, compared with 3 of 89 similar patients whose second-line treatment did not include mitomycin.

For reports of acute bronchospasm after injection of a vinca alkaloid in patients pretreated with mitomycin see Vinblastine Sulfate, p.786. For the increased risk of haemolytic-uraemic syndrome that may occur if mitomycin is given with fluorouracil or tamoxifen see under Effects on the Kidneys, above.

Pharmacokinetics

Mitomycin disappears rapidly from the blood after intravenous injection with an initial (distribution) half-life of 17 minutes. It is widely distributed but does not appear to cross the blood-brain barrier. Mitomycin is metabolised mainly but not exclusively in the liver. The terminal half-life is about 50 minutes. After normal doses about 10% of a dose is excreted unchanged in the urine; small amounts are also present in bile and faeces. With increasing doses metabolic pathways are saturated, and more drug is excreted unchanged in the urine.

Uses and Administration

Mitomycin is a highly toxic antibiotic with antineoplastic properties. It acts as an alkylating agent after activation in vivo and suppresses the synthesis of nucleic acids. It is a cell-cycle non-specific agent, but is most active in the late G1and early S phases.

Mitomycin is used, with other antineoplastic agents, in the treatment of many solid tumours including those of the bladder, breast, cervix, eye, liver, lung, stomach, and prostate as indicated by the cross-references given below. Mitomycin has been tried in other neoplasms including those of the gastrointestinal tract, head and neck, pancreas, in melanoma, sarcomas, and in leukaemias.

Dosage regimens include an initial dose of 10 to 20 mg/m intravenously; subsequent doses are repeated at intervals of 6 to 8 weeks if blood counts permit, and should be reduced according to the previous hae-matological response. Another suggested regimen is 2 mg/m daily for 5 days, repeated after 2 days. Other regimens may be used, particularly in combination. Doses are adjusted according to the effect on bone marrow and treatment should not be repeated until the leucocyte and platelet counts are above acceptable levels (see also Bone-marrow Depression). Mitomycin is also used as a bladder instillation: 10 to 40 mg is instilled once weekly or three times a week for a total of 20 doses in the treatment of superficial bladder tumours. For the prevention of recurrent bladder tumours 20 mg may be instilled every 2 weeks, or 40 mg monthly or 3-monthly. Alternatively 4 to 10 mg may be instilled once weekly or three times a week. These doses are usually given in 10 to 40 mL of water for injection. The solution should be retained in the bladder for at least 1 hour.

Mitomycin has been given by the intra-arterial route in the treatment of liver tumours, sometimes as an infusion of microcapsules designed to produce localised embolisation.

Mitomycin is used for its effect on fibroblasts to improve outcomes and reduce scarring in certain types of surgery, notably in glaucoma (see below).

Glaucoma. Mitomycin, like fluorouracil, is effective in improving the outcome of glaucoma filtering surgery in selected patients when used as an adjunct to prevent the formation of scar tissue. Fluorouracil is usually given as a regimen of multiple injections but mitomycin given as a single intra-operative topical application in usual concentrations ranging from 0.2 to 0.5 mg/mL appears to be of similar efficacy. A systematic review of 11 studies concluded that intra- operative mitomycin reduced the chances of failure in high-risk patients, and in those having their first trabeculectomy. However it was noted that the nature of the data might have led to overestimation of the effect and that there was some evidence of an increased risk of cataract with mitomycin. Late hypotony is also a problem. For other potential complications see Effects on the Eye, above.

Malignant neoplasms. Mitomycin is used in the prevention of recurrent bladder cancer, in the palliative therapy of advanced breast cancer, in malignancies of the cervix, eye, stomach and anus, liver, and non-small cell lung cancer, and has been tried in advanced prostatic cancer.

Pterygium. Pterygium is a degenerative condition of subcon-junctival tissues that results in a vascularised overgrowth of the conjunctiva and cornea. It is cosmetically unappealing but does not usually require treatment. However, if it affects the pupillary area it can be treated surgically. Pterygium often recurs after removal and methods used to prevent recurrence include radiotherapy or the topical application of mitomycin or thiotepa.

Thiotepa has been applied postoperatively as 0.05% eye drops for several weeks, but pterygium may still recur and adverse effects include conjunctival injection, granuloma, hypertrophic conjunctiva, and black deposits in the conjunctival fornix. Depig-mentation of the eyelids may also be a problem, so patients should avoid direct sunlight during thiotepa use.

Mitomycin has been applied topically to the surgical site, or given as eye drops postoperatively. The optimal intra-operative exposure time and concentration are uncertain: concentrations of 0.02 or 0.04% have been applied for up to 5 minutes, and low-dose treatment with mitomycin 0.02% for 30 seconds has been reported to be effective with few complications. Postoperative treatment has generally been given as 0.02, 0.04, or 0.1% eye drops for up to 2 weeks, but the higher concentrations and longer treatment periods have been associated with more adverse effects, some of which may be severe and sight-threatening (see also Effects on the Eyes, above). Comparisons of intra-operative with postoperative use suggest that pterygium recurrence rates are similar.

A range of beta-irradiation doses and fractionation methods have been used. Long-term complications include posterior subcapsular changes of the lens, atrophy and ulceration of the sclera, and scleral necrosis leading to endophthalmitis. In one retrospective study, intra-operative use of 0.04% mitomycin was more effective than beta-irradiation in preventing recurrence after surgery. In another study, postoperative mitomycin 0.02% for one week was less effective than radiation therapy.

Preparations

The United States Pharmacopeia 31, 2008: Mitomycin for Injection.

Proprietary Preparations

Argentina: Asomutan; Crisoflmina; Datisan †; Maximiton; Mitocyna; Mitokebir; Mitonovag; Mitotie; Oncotaxina † Sintemicina; Vetio;

Brazil: Mitocin;

Canada: Mutamycin;

Chile: Metomit †;

Finland: Mitostat; Mutamycin;

France: Ametycine;

Germany; Ametycine; Mitem; Mito-extra; Mito-medac;

India: Mitocin;

Mexico: Ifamit- †; Mitocin-C; Mitolem; Mitotie; Mixandex;

Norway: Mutamycin;

Philippines: Mytoxid;

Sweden: Mutamycin;

Switzerland: Mutamycine †;

United States of America (US and USA): Mitozytrex; Mutamycin.