MITOXANTRONE

Posology Mitoxantrone should be administered under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. Metastatic breast cancer, non-Hodgkin’s lymphoma Single agent therapy The recommended initial dosage of mitoxantrone used as a single agent is 14 mg/m2 of body surface area, given as a single intravenous dose, which may be repeated at 21-day intervals.

g. due to prior chemotherapy or poor general condition. Dosage modification and the timing of subsequent dosing should be determined by clinical judgment depending on the degree and duration of myelosuppression. For subsequent courses, the prior dose can usually be repeated if white blood cell and platelet counts have returned to normal levels after 21 days.

The following table is suggested as a guide to dosage adjustment, in the treatment of metastatic breast cancer and non-Hodgkin’s lymphoma according to haematological nadir (which usually occurs about 10 days after dosing). WBC and platelet nadir Time to recovery Subsequent dosing If WBC nadir > 1,500 μl and platelet nadir > 50,000 μl Recovery ≤ 21 days Repeat prior dose If WBC nadir > 1,500 μl and platelet nadir > 50,000 μl Recovery > 21 days Withhold until recovery, then repeat prior dose.

If WBC nadir < 1,500 μl or platelet nadir < 50,000 μl Any duration Decrease by 2 mg/m2 from prior dose, after recovery. If WBC nadir < 1,000 μl or platelet nadir < 25,000 μl Any duration Decrease by 4 mg/m2 from prior dose, after recovery.

Combination therapy Mitoxantrone has been given as part of combination therapy. In metastatic breast cancer, combinations of mitoxantrone with other cytotoxic agents including cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C have been shown to be effective.

Mitoxantrone has also been used in various combinations for non-Hodgkin’s lymphoma; however, data are presently limited and specific regimens cannot be recommended. In combination regimens mitoxantrone, in starting doses ranging from 7 to 8 to 10 to 12 mg/m2, dependent on the combination and frequency used, has shown effectiveness.

As a guide, when mitoxantrone is used in combination chemotherapy with another myelosuppressive agent, the initial dose of mitoxantrone should be reduced by 2 to 4 mg/m2 below the doses recommended for single agent usage; subsequent dosing, as outlined in the table above, depends on the degree and duration of myelosuppression.

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 in oncological indications and from clinical trials, post authorisation safety studies and spontaneous reporting for patients treated for multiple sclerosis.

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).

Frequency Oncology Multiple Sclerosis Infections and Infestations Very common Infection (including fatal outcome) Infection (including fatal outcome) Urinary tract infection Upper respiratory tract infection Uncommon Urinary tract infection Upper respiratory tract infection Sepsis Opportunistic infections Pneumonia Sepsis Opportunistic infections Rare Pneumonia Neoplasms benign and malignant (including cysts and polyps) Uncommon Acute myeloid leukaemia, myelodysplastic syndrome, acute leukaemia Acute myeloid leukaemia, myelodysplastic syndrome, acute leukaemia Frequency Oncology Multiple Sclerosis Blood and lymphatic system disorders Very common Anaemia Neutropenia Leukopenia Common Thrombocytopenia Granulocytopenia Anaemia Leukopenia Granulocytopenia White blood cell count abnormal Uncommon Myelosuppression Bone marrow failure White blood cell count abnormal Bone marrow failure Myelosuppression Thrombocytopenia Neutropenia Immune system disorders Uncommon Anaphylaxis/anaphylactoid reactions (including shock) Anaphylaxis/anaphylactoid reactions (including shock) Metabolism and nutrition disorders Common Anorexia Uncommon Weight fluctuations Tumour lysis syndrome* Anorexia Weight fluctuations * Acute T and B lymphoblastic leukaemia and non-Hodgkin lymphomas (NHL) are most commonly associated with TLS Nervous system disorders Common Lethargy Headache Uncommon Anxiety Confusion Headache Paraesthesia Anxiety Confusion Paraesthesia Lethargy Eye disorders Uncommon Scleral discolouration Scleral discolouration Cardiac disorders Common Congestive heart failure Myocardial infarction (including fatal events) Arrhythmia Electrocardiogram abnormal Left ventricular ejection fraction decreased Uncommon Arrhythmia Congestive heart failure Sinus bradycardia Electrocardiogram abnormal Left ventricular ejection fraction decreased Cardiomyopathy Sinus bradycardia Myocardial infarction (including fatal events) Rare Cardiomyopathy Vascular disorders Uncommon Contusion Haemorrhage Hypotension Contusion Haemorrhage Hypotension Frequency Oncology Multiple Sclerosis Respiratory, thoracic and mediastinal disorders Common Dyspnoea Uncommon Dyspnoea Gastrointestinal disorders Very common Nausea Vomiting Nausea Common Constipation Diarrhoea Stomatitis Constipation Diarrhoea Stomatitis Vomiting Uncommon Abdominal pain Gastrointestinal haemorrhage Mucosal inflammation Pancreatitis Abdominal pain Gastrointestinal haemorrhage Mucosal inflammation Pancreatitis Hepatobiliary disorders Common Elevated aspartate aminotransferase levels Uncommon Hepatotoxicity Elevated aspartate aminotransferase levels Hepatotoxicity Skin and subcutaneous tissue disorders Very common Alopecia Alopecia Uncommon Erythema Nail disorders Rash Skin discolouration Tissue necrosis (after extravasation) Nail disorders Rash Skin discolouration Tissue necrosis (after extravasation) Renal and urinary disorders Uncommon Elevated serum creatinine Elevated blood urea nitrogen levels Nephropathy toxic Urine discolouration Elevated serum creatinine Elevated blood urea nitrogen levels Nephropathy toxic Urine discolouration Reproductive system and breast disorders Very common Amenorrhoea* Uncommon Amenorrhoea * Amenorrhea may be prolonged and may be consistent with premature menopause General disorders and administration site conditions Common Asthenia Fatigue Pyrexia Frequency Oncology Multiple Sclerosis Uncommon Oedema Extravasation* Dysgeusia Asthenia Fatigue Oedema Pyrexia Extravasation* Sudden death** * Extravasation at the infusion site has been reported, which may result in erythema, swelling, pain, burning and/or blue discolouration of the skin.

Careful supervision is recommended when treating patients with severe hepatic insufficiency. Sulphites can cause allergic-type reactions including anaphylactic symptoms and bronchospasm in susceptible people, especially those with a history of asthma or allergy.

Mitoxantrone is an active cytotoxic drug which should be used by clinicians familiar with the use of antineoplastic agents, and having the facilities for regular monitoring of clinical, haematological and biochemical parameters during and after treatment.

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. 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.

1, including sulphites that may be produced during the manufacturing of mitoxantrone. 6). 6).