MITOMYCIN

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

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

Unless otherwise prescribed, mitomycin is dosed as follows:

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

Mitomycin 10 mg, powder for solution for injection/infusion may not be reconstituted in water. A dose greater than 20 mg/m2 gives more toxic manifestations without therapeutic benefits. The maximum cumulative dose of mitomycin is 60 mg/m2.

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 or Water for Injection (WFI), is instilled weekly into the bladder.

The treatment period is 8 to 12 weeks. 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. The solution should be retained in the bladder for 1-2 hours.

Special population The dose must be reduced in patients who have undergone extensive previous cytostatic therapy, in case of myelosuppression or in elderly patients (only valid for intravenous use of mitomycin). Older patients Insufficient data from clinical studies are available concerning the use of mitomycin in patients ≥ 65 years of age.

3). Paediatric population The safety and efficacy of mitomycin in children aged from 0 to 17 years have not been established. No data are available. Method of administration Mitomycin is only intended for intravenous injection or infusion into a blood vessel (intravenous use) or for intravesical instillation after being dissolved.

Partial use is applicable (only valid for intravenous use of mitomycin). Intravenous administration Precautions to be taken before handling or administering the medicinal product • Mitomycin 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. Intravesical administration It is advised to use this medicinal product at its optimal pH (urinary pH > 6) and to maintain the concentration of mitomycin by reducing fluid intake before, during and after instillation.

The bladder must be emptied before instillation. Mitomycin is introduced into the bladder by means of a catheter and at low pressure. The length of individual instillation should be 1 – 2 hours. During this period the solution should have sufficient contact with the entire mucosal surface of the bladder.

Therefore the patient should be mobilised as much as possible. After 2 hours the patient should void the instilled solution, preferably in a sitting position. 6.

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. As the effect in prolonged use is cumulative, bone marrow suppression is often dose limiting. 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 Haemolytic anaemia, thrombotic microangiopathy (TMA), incl. thrombotic thrombocytopenic purpura (TTP) Not known Anaemia Infections and infestations Rare Life-threatening infection, sepsis Not known Infection 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 erythrodysaesthesia (PPE) 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 Adverse reactions may result either from the solution for intravesical instillation or after deep resection.

g. contact dermatitis, also in the form of palmar and plantar erythema), and cystitis. Skin and subcutaneous tissue disorders Common Pruritus, allergic skin rash, contact After intravesical administration, only minor amounts of mitomycin reach the systemic circulation.

Nevertheless, in very rare cases the following systemic adverse reactions have been reported: Possible systemic adverse reactions occurring very rarely following intravesical administration: Blood and lymphatic system disorders Leukocytopenia, thrombocytopenia Respiratory, thoracic and mediastinal disorders Interstitial lung disease Gastrointestinal disorders Nausea, vomiting, diarrhoea Hepatobiliary disorders Transaminases increased Skin and subcutaneous tissue disorders Alopecia Renal and urinary disorders Renal dysfunction General disorders and administration site conditions Fever 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 or search for MHRA Yellow Card in the Google Play or Apple App Store

Extravasation following systemic administration 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, immediate topical use of dimethylsulfoxide (DMSO 99%), repeated every 4-8 hours as well as the use of dry, cold compresses is recommended. A (plastic) surgeon should be consulted at an early stage (within 72 hours).

A systemic injection of 200 mg of Vitamin B6 may be of some value in promoting the regrowth of tissues that have been damaged. 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.

General hygiene for the patient following instillation It is recommended to wash hands and genital area after micturition. This applies especially to the first micturitions following mitomycin administration. Mitomycin is a mutagenic and potentially carcinogenic substance in humans.

Contact with the skin and mucous membranes is to be avoided. If cystitis does occur, symptomatic treatment with local anti-inflammatories and analgesics should be given. In most cases the mitomycin therapy can be continued, if necessary at a reduced dose.

8). Elderly 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. Bone marrow toxicity 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.

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.

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

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).

The occurrence of a haemolytic- uraemic syndrome (HUS: irreversible renal failure, microangiopathic haemolytic anaemia [MAHA syndrome] and thrombocytopenia) is commonly fatal. At doses of > 30 mg of mitomycin/m2 of body surface microangiopathic-haemolytic anaemia has been observed.

Close monitoring of renal function is recommended. No cases of MAHA have been observed so far after intravesical use of mitomycin. 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 immunoadsorption with staphylococcal protein A columns.

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.

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

1. 6) Systemic therapy Pancytopenia, isolated leucopoenia/thrombocytopenia, haemorrhagic diathesis and acute infections are absolute contraindications. Restrictive or obstructive disturbances to pulmonary ventilation, renal dysfunction, hepatic dysfunction and/or a poor general state of health are relative contraindications.

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