ONKOTRONE Concentrate for solution for infusion Ref.[27750] Active ingredients: Mitoxantrone

Precautions to be taken before handling or administering the medicinal product

Mitoxantrone should be given slowly into a freely flowing intravenous infusion. Mitoxantrone must not be given subcutaneously, intramuscularly, or intra-arterially. There have been reports of local/regional neuropathy, some irreversible, following intra-arterial injection. Severe local tissue damage may occur if there is extravasation during administration. To date, only isolated cases of severe local reactions (necroses) have been described due to extravasation. Mitoxantrone must not be given by intrathecal injection. Severe injury with permanent sequelae can result from intrathecal administration. There have been reports of neuropathy and neurotoxicity, both central and peripheral, following intrathecal injection. These reports have included seizures leading to coma and severe neurologic sequelae, and paralysis with bowel and bladder dysfunction.

Cardiac function

Myocardial toxicity, manifested in its most severe form by potentially irreversible and fatal congestive heart failure (CHF), may occur either during therapy with mitoxantrone or months to years after termination of therapy. This risk increases with cumulative dose. Cancer patients who received cumulative doses of 140 mg/m² either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure. In comparative oncology trials, the overall cumulative probability rate of moderate or severe decreases in LVEF at this dose was 13%.

Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic medicinal products may increase the risk of cardiac toxicity. Evaluation of the left-ventricular ejection fraction (LVEF) by echocardiogram or multiple-gated acquisition (MUGA) is recommended prior to administration of the initial dose of mitoxantrone in cancer patients. Cardiac function for cancer patients should be carefully monitored during treatment. LVEF evaluation is recommended at regular intervals and/or if signs or symptoms of congestive heart failure develop. Cardiotoxicity can occur at any time during mitoxantrone therapy, and the risk increases with cumulative dose. Cardiac toxicity with mitoxantrone may occur at lower cumulative doses whether or not cardiac risk factors are present.

Because of the possible danger of cardiac effects in patients previously treated with daunorubicin or doxorubicin, the benefit-to-risk ratio of mitoxantrone therapy in such patients should be determined before starting therapy.

Acute congestive heart failure may occasionally occur in patients treated with mitoxantrone for acute myeloid leukaemia.

Bone marrow suppression

Therapy with mitoxantrone should be accompanied by close and frequent monitoring of haematological and chemical laboratory parameters, as well as frequent patient observation. A complete blood count, including platelets, should be obtained prior to administration of the initial dose of mitoxantrone, 10 days following the administration and prior to each subsequent infusion and in the event that signs and symptoms of infection develop. Patients should be informed about risks, symptoms and signs of acute leukaemia and prompted to seek medical attendance if any such symptoms should occur even after the five year period has passed.

Myelosuppression may be more severe and prolonged in patients with poor general condition, or prior chemotherapy and/or radiotherapy.

Except for the treatment of acute myeloid leukaemia, mitoxantrone therapy generally should not be given to patients with baseline neutrophil counts of less than 1,500 cells/mm³. It is recommended that frequent peripheral blood cell counts are performed on all patients receiving mitoxantrone in order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection.

When mitoxantrone is used in high doses (>14 mg/m²/d x 3 days) such as indicated for the treatment of leukaemia, severe myelosuppression will occur.

Particular care should be given to assuring full haematological recovery before undertaking consolidation therapy (if this treatment is used) and patients should be monitored closely during this phase.

Mitoxantrone administered at any dose can cause myelosuppression.

Secondary acute myeloid leukaemia and myelodysplastic syndrome

Topoisomerase II inhibitors, including mitoxantrone, when used as monotherapy or especially concomitantly with other antineoplastic agents and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia or Myelodysplastic Syndrome. Because of the risk of development of secondary malignancies, the benefit-to-risk ratio of mitoxantrone therapy should be determined before starting therapy.

Non-metastatic breast cancer

In the absence of sufficient efficacy data in the adjuvant treatment of breast cancer and accounting for the increased risk of leukaemia, mitoxantrone should only be used for metastatic breast cancer.

Infections

Patients who receive immunosuppressive agents like mitoxantrone have a reduced immunological response to infection. Systemic infections should be treated concomitantly with or just prior to commencing therapy with mitoxantrone.

Vaccination

Immunisation with live virus vaccines (e.g. yellow fever vaccination) increases the risk of infection and other adverse reactions such as vaccinia gangrenosa and generalised vaccinia, in patients with reduced immunocompetence, such as during treatment with mitoxantrone. 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).

Contraception in males and females

Mitoxantrone is genotoxic and is considered a potential human teratogen. Therefore men under therapy must be advised not to father a child and to use contraceptive measures during and at least 6 months after therapy. Women of childbearing potential should have a negative pregnancy test prior to each dose, and use effective contraception during therapy and for at least 4 months after cessation of therapy.

Breast-feeding

Mitoxantrone has been detected in breast-milk for up to one month after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breast-feeding is contraindicated (see section 4.3) and must be discontinued before starting treatment.

Fertility

Women of childbearing potential should be informed about increased risk of transitory or persistent amenorrhoea (see section 4.6).

Mutagenicity and carcinogenicity

Mitoxantrone was found to be mutagenic in bacterial and mammalian test systems, as well as in vivo in rats. The active substance was carcinogenic in experimental animals at doses below the proposed clinical dose. Therefore, mitoxantrone has the potential to be carcinogenic in humans.

Tumour lysis syndrome

Cases of tumour lysis syndrome were reported with the use of mitoxantrone. Levels of uric acid, electrolytes and urea should be monitored.

Discolouration of urine and other tissues

Mitoxantrone may cause a blue-green colouration to the urine for 24 hours after administration, and patients should be advised to expect this during therapy. Bluish discolouration of the sclera, skin and nails may also occur.

Combining mitoxantrone with potentially cardiotoxic active substances (e.g. anthracyclines) increases the risk of cardiac toxicity.

Topoisomerase II inhibitors, including mitoxantrone, when used concomitantly with other antineoplastic agents and/or radiotherapy, have been associated with the development of Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS) (see section 4.8).

Mitoxantrone causes myelosuppression as an extension of its pharmacological action. Myelosuppresion can be increased when it is used in combination chemotherapy with another myelosuppressive agent such as for treatment of breast cancer.

The combination of mitoxantrone with other immunosuppressive agents may increase the risk of excessive immunodepression and lymphoproliferative syndrome.

Immunisation with live virus vaccines (e.g. yellow fever vaccination) increases the risk of infection and other adverse reactions such as vaccinia gangrenosa and generalised vaccinia, in patients with reduced immunocompetence, such as during treatment with mitoxantrone. 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 4.4).

The combination of vitamin K antagonists and cytotoxic agents may result in an increased risk of bleeding. In patients receiving oral anticoagulant therapy, the prothrombin time ratio or INR should be closely monitored with the addition and withdrawal of treatment with mitoxantrone and should be reassessed more frequently during concurrent therapy. Adjustments of the anticoagulant dose may be necessary in order to maintain the desired level of anticoagulation.

Mitoxantrone has been demonstrated to be a substrate for the BCRP transporter protein in vitro. Inhibitors of the BCRP transporter (e.g. eltrombopag, gefitinib) could result in an increased bioavailability. In a pharmacokinetic study in children with de novo acute myeloid leukaemia, ciclosporin co-medication resulted in a 42% decreased clearance of mitoxantrone. Inducers of the BCRP transporter could potentially decrease mitoxantrone exposure.

Mitoxantrone and its metabolites are excreted in bile and urine, but it is not known whether the metabolic or excretory pathways are saturable, may be inhibited or induced, or if mitoxantrone and its metabolites undergo enterohepatic circulation (see section 5.2).

Contraception in males and females

Mitoxantrone is genotoxic and is considered a potential human teratogen. Therefore men under therapy must be advised not to father a child and to use contraceptive measures during and at least 6 months after therapy. Women of childbearing potential must be advised to avoid becoming pregnant; should have a negative pregnancy test prior to each dose and use effective contraception during therapy and for at least 4 months after cessation of therapy.

Pregnancy

There are very limited data on the use of mitoxantrone in pregnant women. Mitoxantrone was not teratogenic in animal studies at doses below human exposure, but caused reproductive toxicity (see section 5.3). Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents. Mitoxantrone should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If this medicinal product is used during pregnancy or if the patient becomes pregnant while taking mitoxantrone, the patient should be informed of the potential risk to the foetus and genetic counselling should be provided.

Breast-feeding

Mitoxantrone is excreted in breast-milk and has been detected in breast-milk for up to one month after the last administration. Because of the potential for serious adverse reactions in infants from mitoxantrone, breast-feeding is contraindicated (see section 4.3) and must be discontinued before starting treatment.

Fertility

Women treated with Onkotrone Injection have an increased risk of transitory or persistent amenorrhoea and therefore preservation of gametes should be considered prior to therapy. In men, no data are available, but tubular atrophy of the testes and reduced sperm counts were observed in animals (see section 5.3).

Mitoxantrone has minor influence on the ability to drive and use machines. Confusion and fatigue may occur following administration of mitoxantrone (see section 4.8).

Summary of the safety profile

The most serious side effects with mitoxantrone are myocardial toxicity and myelosuppression. The most common side effects with mitoxantrone (seen in more than 1 patient in 10) are anaemia, leucopenia, neutropenia, infections, amenorrhoea, alopecia, nausea and vomiting.

Tabulated list of adverse reactions

The table below is based on safety data derived from clinical trials and spontaneous reporting. Frequencies are defined according to the following convention: 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), not known (cannot be estimated from the available data).

^* Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin. Extravasation can result in tissue necrosis with resultant need for debridement and skin grafting. Phlebitis has also been reported at the site of infusion.

Description of selected adverse reactions

Myocardial toxicity, manifested in its most severe form by potentially irreversible and fatal congestive heart failure (CHF), may occur either during therapy with mitoxantrone or months to years after termination of therapy. This risk increases with cumulative dose. In clinical trials cancer patients who received cumulative doses of 140 mg/m² either alone or in combination with other chemotherapeutic agents had a cumulative 2.6% probability of clinical congestive heart failure.

Myelosuppression is a dose-limiting undesirable effect of mitoxantrone. Myelosuppression can be more pronounced and longer-lasting in patients who have previously received chemotherapy or radiotherapy. In a clinical trial with acute leukaemia patients, significant myelosuppression occurred in all patients who were given mitoxantrone therapy. Amongst the 80 enrolled patients the median values for the lowest white blood cell count and platelet count were 400/µl (WHO grade 4), and 9.500/µl (WHO grade 4), respectively. Haematological toxicity is difficult to evaluate in acute leukaemia because traditional parameters of bone marrow depression such as white blood cell and platelet counts are confounded by marrow replacement with leukemic cells.

Paediatric population

Treatment with mitoxantrone is not recommended in the paediatric population. Safety and efficacy have not been established.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Onkotrone Injection solution must not be mixed together with other drugs in an infusion solution.

Heparin must not be added to Onkotrone Injection solutions as precipitation may occur.