MITOCIN

Posology Mitomycin should only be used by doctors experienced in this therapy if there is a strict indication and with continual monitoring of the haematological parameters. It is essential that the injection is administered intravenous.

If the medicinal product is injected perivasally, extensive necrosis occurs in the area concerned.

Unless otherwise prescribed, mitomycin is dosed as follows:

Intravenous administration In cytostatic monochemotherapy mitomycin is usually administered intravenously as a bolus injection. The recommended dosage is 10 - 20 mg/m2 of body surface every 6 - 8 weeks, 8 - 12 mg/m2 of body surface every 3 - 4 weeks or 5-10 mg/m2 of body surface every 1-6 weeks, depending on the therapeutic scheme used.

In combination therapy the dosage is considerably lower. Because of the risk of additive myelotoxicity, proven treatment protocols may not be deviated from without a specific reason. 9%) solution, is instilled weekly into the bladder.

In the case of intravesical administration the urine pH should be higher than pH 6. 15 mg/kg of body weight) instilled into the bladder though a urethral catheter 1 or 3 times per week. Special population The dose must be reduced in patients who have undergone extensive previous cytostatic therapy, in case of myelosuppression or in elderly patients.

Insufficient data from clinical studies are available concerning the use of mitomycin in patients ≥65 years of age. 3) The product is not recommended in patients with hepatic impairment due to lack efficacy and safety data in this group of patients.

Paediatric population The safety and efficacy of mitomycin in children have not been established. Method of administration Mitomycin is intended for intravenous injection or infusion or for intravesical instillation after being dissolved.

Partial use is applicable. Preparation of ready-to-use solution for injection or infusion The contents of one vial of Mitocin 20 mg are dissolved in 40 ml of water for injections by swirling. Shake until the reconstituted solution becomes clear and free of particles.

For intravenous infusion the solution of Mitocin 20 mg in 40 ml of water for injections can be diluted with isotonic sodium chloride infusion solution down to a concentration of 20 - 40 micrograms of mitomycin/ml. 9%) solution. Notes • Mitocin 20 mg must not be used in mixed injections.

• Other injection solutions or infusion solutions must be administered separately. • It is essential that the injection is administered intravenous.

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 Hepatobiliary 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 erythema 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, bladder wall fibrosis, bladder perforation.

Not known in case of extravasation:

Bladder perforation, (fat) tissue necrosis of the surrounding area, vesical fistula, abscesses. 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. uk/yellowcard.

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.

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.

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. Extravasation following intravesical administration Symptoms of extravasation after intravesical mitomycin administration might present straight after the application or weeks or months later.

It can be unclear if the extravasation occurred due to unnoticed perforation, a thinned muscularis propria or if the medicinal product was not administered correctly. First symptoms present as pelvic or abdominal pain that are refractory to simple analgesia.

(Fat) tissue necrosis in the surrounding area as a consequence of the extravasation was observed in most cases. 8). Therefore, physicians should consider the possibility that extravasation occurred if the patient complains about pelvic or abdominal pain to prevent serious consequences.

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

1. • Breastfeeding Systemic therapy Pancytopenia or isolated leucopoenia/thrombopenia, haemorrhagic diathesis and acute infections are absolute contraindications. Restrictive or obstructive disturbances to pulmonary ventilation, renal function, liver function and/or a poor general state of health are relative contraindications.

Temporal connection with radiotherapy or other cytostatic may be a further contraindication. Intravesical therapy Perforation of the bladder wall is an absolute contraindication. Cystitis is a relative contraindication