MITOMYCIN Powder for solution for injection or infusion Ref.[8897] Active ingredients: Mitomycin

Due to the toxic effects on the bone marrow of mitomycin, other myelotoxic therapy modalities (in particular other cytostatics, radiation) must be administered with particular caution in order to minimise the risk of additive myelosuppression.

It is essential that the injection is administered intravenous. If the medicinal product is injected perivasally, extensive necrosis occurs in the area concerned. To avoid necrosis following recommendations apply:

• Always inject into large veins in the arms.
• Do not directly inject intravenously, but rather into the tube of a good and securely running infusion.
• Before removing the cannula after central venous administration, flush it through for a few minutes using the infusion in order to release any residual mitomycin.

If extravasation occurs, it is recommended that the area is immediately infiltrated with sodium bicarbonate 8.4% solution, followed by an injection of 4 mg dexamethasone. A systemic injection of 200 mg of Vitamin B6 may be of some value in promoting the regrowth of tissues that have been damaged.

Long-term therapy may result in cumulative bone marrow toxicity. Bone marrow suppression may only manifest itself after a delay, being expressed most strongly after 4-6 weeks, accumulating after prolonged use and therefore often requiring an individual dose adjustment.

Elderly patients often have reduced physiological function, bone marrow depression, which may be protracted, so administer mitomycin with special caution in this population while closely monitoring patient’s condition.

Particular caution is required when possible occurrence or aggravation of infectious disease and bleeding tendency.

Mitomycin is a mutagenic and potentially carcinogenic substance in humans. Contact with the skin and mucous membranes is to be avoided.

In the case of pulmonary symptoms, which cannot be attributed to the underlying disease, therapy should be stopped immediately. Pulmonary toxicity can be well treated with steroids.

Therapy should be stopped immediately also if there are symptoms of haemolysis or indications of renal dysfunction (nephrotoxicity).

At doses of >30 mg of mitomycin/m² of body surface microangiopathic-haemolytic anaemia has been observed. Close monitoring of renal function is recommended.

New findings suggest a therapeutic trial may be appropriate for the removal of immune complexes that seem to play a significant role in the onset of symptoms by means of staphylococcal protein A.

Occurrence of acute leukaemia (in some cases following preleukaemic phase) and myelodysplastic syndrome has been reported in the patients treated concomitantly with other antineoplastic agents.

Immunisation with live virus vaccines (e.g. yellow fever vaccination) increases the risk of infection and other adverse reactions such as vaccinia gangrenosa and generalized vaccinia, in patients with reduced immunocompetence, such as during treatment with mitomycin. Therefore, live virus vaccines should not be administered during therapy. It is advised to use live virus vaccines with caution after stopping chemotherapy, and vaccinate not sooner than 3 months after the last dose of chemotherapy (see section 4.5).

Recommended check-ups and safety measures in the case of intravenous administration:

Before the start of treatment:

• Complete blood count.
• Pulmonary function test if pre-existing lung dysfunction is suspected.
• Renal function test in order to exclude renal insufficiency.
• Liver function test in order to exclude liver insufficiency.

During therapy:

• Regular checks of the blood count.
• Close monitoring of renal function.

Myelotoxic interactions with other bone marrow-toxic treatment modalities (especially other cytotoxic medicinal products, radiation) are possible.

Combination with vinca alkaloids or bleomycin may reinforce pulmonary toxicity.

An increased risk of haemolytic-uremic syndrome has been reported in patients receiving a concomitant administration of mitomycin and fluorouracil or tamoxifen.

In animal experiments, pyridoxine hydrochloride (vitamin B₆) resulted in the loss of effect of mitomycin.

No injections with live vaccines should be carried out in connection with mitomycin treatment (see section 4.4).

The cardiotoxicity of Adriamycin (doxorubicin) may be reinforced by mitomycin.

Pregnancy

There are no data from the use of mitomycin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Mitomycin has a mutagenic, teratogenic and carcinogenic effect and therefore may impair the development of an embryo. Mitomycin should not be used during pregnancy. In the case of a vital indication for the treatment of a pregnant patient a medical consultation should be carried out with respect to the risk of the harmful effects on the child, which are associated with the treatment.

Breastfeeding

It is suggested that mitomycin is excreted in breast milk. Due to its proven mutagenic, teratogenic and carcinogenic effects, mitomycin should not be administered during breastfeeding. Breastfeeding women must first discontinue breastfeeding before initiating treatment with mitomycin.

Fertility / Contraception in males and females

Female patients of a sexually mature age should take contraceptive measures during and up to 6 months after the end of chemotherapy or refrain from sexual intercourse.

Mitomycin has a genetically harmful effect. Men who are being treated with mitomycin are therefore advised not to father a child during treatment and up to 6 months thereafter and to seek advice on the preservation of sperm before the start of therapy due to the possibility of irreversible infertility caused by the therapy with mitomycin.

Even when used in accordance with instructions these medicinal products may cause nausea and vomiting and thereby reduce reaction times to such an extent that the ability to drive a motor vehicle or operate machinery is impaired. This applies even more in connection with alcohol.

Undesirable effects are listed below by system organ class and frequency. Frequencies below are defined as: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) or not known (cannot be estimated from the available data)

Possible side-effects under systemic therapy

The most common side effects of mitomycin administered systemically are gastrointestinal symptoms like nausea and vomiting and bone marrow suppression with leukopenia and mostly dominant thrombocytopenia. This bone marrow suppression occurs in up to 65% of patients.

In up to 10% of patients serious organ toxicity in the form of interstitial pneumonia or nephrotoxicity must be expected.

Mitomycin is potentially hepatotoxic.

Blood and the lymphatic system disorders

Very common: Bone marrow suppression, leucopenia thrombocytopenia

Rare: Life-threatening infection, sepsis, haemolytic anaemia

Immune system disorders

Very rare: Severe allergic reaction

Cardiac disorders

Rare: Heart failure after previous therapy with anthracyclines

Respiratory, thoracic and mediastinal disorders

Common: Interstitial pneumonia, dyspnoe, cough, shortness of breath

Rare: Pulmonary hypertension, pulmonary veno-occlusive disease (PVOD)

Gastrointestinal disorders

Very common: Nausea, vomiting,

Uncommon: Mucositis, stomatitis, diarrhoea, anorexia

Hepato-biliary disorders

Rare: Liver dysfunction, increased transaminases, jaundice, veno-occlusive disease (VOD) of the liver

Skin and subcutaneous tissue disorders

Common: Exanthema, allergic skin rash, contact dermatitis, palmar-plantar erythema

Uncommon: Alopecia

Rare: Generalised exanthema

Renal and urinary disorders

Common: Renal dysfunction, increase in serum creatinine, glomerulopathy, Nephrotoxicity

Rare: Haemolytic uraemic syndrome(HUS) (commonly fatal), microangiopathic-haemolytic anaemia (MAHA syndrome)

General disorders and administration site conditions

Common: Following Extravasation: Cellulitis, tissue necrosis

Uncommon: Fever

Possible side-effects under intravesical therapy

Skin and subcutaneous tissue disorders

Common: Pruritus, allergic skin rash, contact dermatitis, Palmar plantar erythrodysaesthesia (PPE)

Rare: Generalised exanthema

Renal and urinary disorders

Common: Cystitis (possibly haemorrhagic), dysuria, nocturia, pollakisuria, hematuria, local irritation of the bladder wall

Very rare: necrotizing cystitis, allergic (eosinophilic) cystitis, stenosis of the efferent urinary tract, reduction in bladder capacity, bladder wall calcification, and bladder wall fibrosis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.