Mitoxantrone

Mitoxantrone is a synthetic anthracenedione derivative and an established cytotoxic antineoplastic agent, with efficacy reported in many cancers. In multiple sclerosis its presumed mode of action is immunosuppression.

Mechanism of Action

• DNA interaction: mitoxantrone intercalates into DNA by hydrogen bonding, causing cross-links and strand breaks, and it also interferes with RNA.
• Topoisomerase II: it is a potent inhibitor of topoisomerase II, the enzyme that uncoils and repairs damaged DNA.
• Cell-cycle effect: it kills cultured human cells whether or not they are proliferating, which suggests no specificity for a phase of the cell cycle, and it acts on both fast-growing and slow-growing tumours. It blocks the cell cycle in the G2 phase, which raises cellular RNA content and causes polyploidy.
• Immune effects: in vitro it inhibits the proliferation of B cells, T cells and macrophages and reduces antigen presentation and the secretion of interferon gamma, tumour necrosis factor alpha and interleukin-2.

Pharmacokinetics

• Kinetics: after a single dose, mitoxantrone is described by a three-compartment model. Over 15 to 90 mg/m² the area under the curve rises linearly with dose, and no plasma accumulation was apparent with daily dosing for five days or a single dose every three weeks.
• Distribution: tissue distribution is extensive (steady-state volume of distribution above 1,000 L/m²). Plasma concentrations fall quickly over the first two hours and more slowly afterwards. About 78% is bound to plasma proteins, independent of concentration and unaffected by phenytoin, doxorubicin, methotrexate, prednisone, prednisolone, heparin or aspirin. Mitoxantrone does not cross the blood–brain barrier, and distribution to the testes is relatively low.
• Metabolism: the metabolic pathways have not been elucidated.
• Elimination: excretion in urine and faeces is slow, as unchanged drug or inactive metabolites. Over 5 days only 10% (urine) and 18% (faeces) of a dose was recovered; of the urinary recovery, 65% was unchanged mitoxantrone and 35% mono- and dicarboxylic acid derivatives and their glucuronide conjugates. Many reported elimination half-lives are between 10 and 40 hours, but some authors report 7 to 12 days, possibly because of later sampling, data weighting and assay sensitivity.
• Special populations: hepatic impairment may reduce clearance.

Indications as listed in the SmPC of the French 2 mg/mL concentrate (nationally authorised; the list of indications can differ between member states):

• Metastatic breast cancer.
• Non-Hodgkin lymphoma.
• Acute myeloid leukaemia (AML) in adults.
• Chronic myeloid leukaemia in blast crisis: in combination treatment, for induction of remission.
• Advanced castration-resistant prostate cancer: in combination with corticosteroids, for palliative treatment (for example pain relief).
• Multiple sclerosis: highly active relapsing multiple sclerosis associated with rapidly evolving disability, when no alternative therapeutic option exists.

• Hypersensitivity to mitoxantrone or to any of the excipients, including the sulfites that can be produced during the manufacture of mitoxantrone.
• Breastfeeding.
• Treatment of multiple sclerosis in pregnant women.

Live virus vaccines are also contraindicated during treatment (see Drug Interactions).

The most serious adverse effects are myocardial toxicity and myelosuppression. The most frequent (more than 1 patient in 10) are anaemia, leukopenia, neutropenia, infections, amenorrhoea, alopecia, nausea and vomiting. The SmPC tabulates frequencies separately for oncology use and for multiple sclerosis (MS); both are given below where they differ.

Very common (≥1/10): infection (including fatal infection; in MS also urinary tract and upper respiratory tract infection), anaemia, neutropenia and leukopenia (oncology), nausea, vomiting (oncology), alopecia, amenorrhoea (MS; it can be prolonged and may correspond to premature menopause).

Common (≥1/100 to <1/10): oncology: thrombocytopenia, granulocytopenia, anorexia, lethargy, congestive heart failure, myocardial infarction (including fatal), dyspnoea, constipation, diarrhoea, stomatitis, asthenia, fatigue, pyrexia. MS: anaemia, leukopenia, granulocytopenia, abnormal white blood cell count, headache, arrhythmias, electrocardiogram abnormalities, decreased left ventricular ejection fraction, constipation, diarrhoea, stomatitis, vomiting, increased aspartate aminotransferase.

Uncommon (≥1/1,000 to <1/100): septicaemia and opportunistic infections (both settings); urinary and upper respiratory tract infections (oncology); pneumonia (MS); acute myeloid leukaemia and myelodysplastic syndrome; myelosuppression and bone-marrow failure (both settings), abnormal white blood cell count (oncology), thrombocytopenia and neutropenia (MS); anaphylactic or anaphylactoid reactions (including shock); weight changes; tumour lysis syndrome (oncology); anorexia (MS); anxiety, confusion and paraesthesia (both settings), headache (oncology), lethargy (MS); scleral discolouration; cardiac: arrhythmias, sinus bradycardia, electrocardiogram abnormalities and decreased ejection fraction (oncology), congestive heart failure, cardiomyopathy, sinus bradycardia and myocardial infarction including fatal (MS); contusion, haemorrhage, hypotension; dyspnoea (MS); abdominal pain, gastrointestinal haemorrhage, mucosal inflammation, pancreatitis; hepatotoxicity, increased aspartate aminotransferase (oncology); erythema (oncology), nail disorders, rash, skin discolouration, tissue necrosis after extravasation; increased blood creatinine, increased blood urea nitrogen, toxic nephropathy, urine discolouration; amenorrhoea (oncology); oedema, extravasation and dysgeusia (oncology), asthenia, fatigue, oedema, pyrexia, extravasation and sudden death (MS; a causal link has not been firmly established).

Rare (≥1/10,000 to <1/1,000): pneumonia and cardiomyopathy (oncology).

Extravasation at the infusion site can cause erythema, oedema, pain, burning and/or blue discolouration of the skin and can lead to tissue necrosis that needs debridement and skin grafts; phlebitis at the infusion site has also been reported. Myelosuppression is the dose-limiting adverse effect. Myocardial toxicity is described under Special Instructions.

• Cardiotoxic agents (for example anthracyclines): combining them with mitoxantrone increases the risk of cardiac toxicity.
• Other antineoplastic agents and radiotherapy: topoisomerase II inhibitors, including mitoxantrone, combined with other antineoplastic agents and/or radiotherapy have been associated with acute myeloid leukaemia or myelodysplastic syndrome.
• Myelosuppressive agents: mitoxantrone causes myelosuppression, and this can be greater in polychemotherapy with another myelosuppressive agent, for example in breast cancer.
• Other immunosuppressants: may increase the risk of excessive immunosuppression and lymphoproliferative syndrome.
• Live vaccines (for example yellow fever vaccine): they raise the risk of infection and other effects such as progressive vaccinia in patients with reduced immune competence, so live virus vaccines are contraindicated during treatment. After chemotherapy stops, they should be used with caution, and at least 3 months should pass after the last dose before vaccination.
• Vitamin K antagonists: with cytotoxic agents they may increase the risk of bleeding. In patients on oral anticoagulants, prothrombin time or INR must be monitored closely when mitoxantrone is added or stopped and more often during combined treatment.
• Further interactions are listed in section 4.5 of the SmPC.

Treatment must be given under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents; for multiple sclerosis, experience of using cytotoxic agents in that disease is required. Mitoxantrone is for intravenous use only. It is injected slowly into a continuous intravenous infusion of isotonic saline or 5% glucose solution over at least 3 to 5 minutes, with the line preferably in a large vein and, if possible, away from joints or limbs with poor lymphatic or venous drainage. It can also be given as a short infusion (15 to 30 minutes) diluted in 50 to 100 mL of isotonic saline or 5% glucose. It must not be given subcutaneously, intramuscularly, intra-arterially or intrathecally. Administration must stop immediately at any sign of extravasation (burning, pain, itching, redness, swelling, blue skin discolouration or ulceration).

Dose by Indication

• Metastatic breast cancer and non-Hodgkin lymphoma (monotherapy): 14 mg/m² of body surface area as a single intravenous dose, repeated at 21-day intervals. In patients with bone-marrow depression (for example after earlier chemotherapy) or in poor general health, start at 12 mg/m² or less.
• Combination therapy: in metastatic breast cancer, combinations with cyclophosphamide and 5-fluorouracil, or with methotrexate and mitomycin C, have proved effective. In non-Hodgkin lymphoma the data are too limited to recommend specific regimens. Combinations have worked with initial mitoxantrone doses of 7–8 to 10–12 mg/m², depending on the combination and frequency. As a guide, when it is combined with another myelosuppressive agent, the initial dose is reduced by 2 to 4 mg/m² from the monotherapy dose, and later doses follow the myelosuppression-based adjustments below.
• AML, relapse (monotherapy): for induction of remission, 12 mg/m² as a single intravenous dose daily for 5 consecutive days (60 mg/m² in total).
• AML (combination): induction is mitoxantrone 12 mg/m² daily on the first 3 days by intravenous infusion with cytarabine 100 mg/m² by continuous 24-hour infusion for 7 days. If the response is incomplete, a second induction uses mitoxantrone for 2 days and cytarabine for 5 days at the same daily doses; it is postponed if severe or life-threatening non-haematological toxicity occurred in the first course. Consolidation (used in two large randomised studies) is mitoxantrone 12 mg/m² on days 1 and 2 with cytarabine 100 mg/m² by continuous 24-hour infusion on days 1 to 5, the first course about 6 weeks after the last induction and the second usually 4 weeks later. A single regimen of mitoxantrone 6 mg/m² by intravenous bolus, etoposide 80 mg/m² over 1 hour and cytarabine 1 g/m² over 6 hours daily for 6 days showed anti-leukaemic activity as rescue treatment in refractory AML.
• Chronic myeloid leukaemia in blast crisis (combination, relapse): 5 to 12 mg/m² as a single intravenous dose daily for 2 to 4 consecutive days (maximum 48 mg/m²).
• Advanced castration-resistant prostate cancer: 12 to 14 mg/m² by short intravenous infusion at 21-day intervals, together with low-dose oral corticosteroids.
• Multiple sclerosis: usually 12 mg/m² by short intravenous infusion (about 5 to 15 minutes), which may be repeated every 1 to 3 months. The maximum lifetime cumulative dose must not exceed 72 mg/m². Treatment should be used only after the benefit–risk balance has been assessed, particularly for haematological and cardiac risks, and must not be started in patients who have already received mitoxantrone.

Dose Adjustment for Bone-Marrow Suppression

• Breast cancer and non-Hodgkin lymphoma: adjustments and timing follow clinical judgement of the severity and duration of myelosuppression. As a guide, based on the haematological nadir (usually 10 days after the dose): if white cells are above 1,500/µL and platelets above 50,000/µL at the nadir and recovery occurs within 21 days, repeat the previous dose; if recovery takes more than 21 days, wait for recovery and give the same dose as before; if the white cell nadir is below 1,500/µL, reduce the previous dose by 2 mg/m² after recovery; if it is below 1,000/µL, reduce it by 4 mg/m². The platelet criteria for the last two situations are set out in the SmPC table.
• Multiple sclerosis, blood count in the 21 days after an infusion: infection signs and WHO grade 3, next dose 10 mg/m²; grade 4, next dose 8 mg/m².
• Multiple sclerosis, blood count 7 days before an infusion: infection signs and WHO grade 1, next dose 9 mg/m²; grade 2, next dose 6 mg/m²; grade 3 or 4, stop treatment.
• Multiple sclerosis, non-haematological toxicity: WHO grade 2 or 3, next dose 10 mg/m²; grade 4, stop treatment.

Special Populations

• Elderly: dose selection should generally start at the low end of the range, because decreased hepatic, renal or cardiac function, other diseases and other medicines are more frequent.
• Renal impairment: safety has not been established; use with caution.
• Hepatic impairment: safety has not been established. Clearance is reduced, so a dose adjustment may be needed, but the data are insufficient for recommendations and laboratory tests do not predict clearance or dose changes.
• Children and adolescents: safety and efficacy have not been established, and there is no justified use in the paediatric population.

Route of Administration and Extravasation

Mitoxantrone must be given by slow intravenous infusion and never by the subcutaneous, intramuscular or intra-arterial route. Cases of local or regional neuropathy, some irreversible, have been reported after intra-arterial injection. Severe local tissue damage can follow extravasation, although only isolated cases of severe local reactions (necrosis) have been described. It must not be given intrathecally: this can cause severe injury with permanent sequelae, and central and peripheral neuropathy and neurotoxicity have been reported, including seizures progressing to coma, severe neurological consequences, and paralysis with bowel and bladder dysfunction.

Cardiotoxicity and Cumulative Dose

• Heart failure: myocardial toxicity, in its most severe form potentially irreversible and fatal congestive heart failure, can occur during treatment or several months after it stops, and the risk increases with the cumulative dose. Cancer patients who received cumulative doses of 140 mg/m², alone or with other chemotherapy, had a cumulative probability of clinical congestive heart failure of 2.6%. In comparative oncology studies, the overall cumulative probability of moderate or severe reduction in LVEF at that dose was 13%.
• Risk factors: active or dormant cardiovascular disease, earlier or concurrent radiotherapy of the mediastinal or pericardial area, earlier treatment with other anthracyclines or anthracenediones, and other cardiotoxic medicines can raise the risk. Cardiotoxicity can occur at any time during treatment and at lower cumulative doses, whether or not cardiac risk factors are present. In patients previously treated with daunorubicin or doxorubicin, the benefit–risk balance must be judged before starting.
• Monitoring in cancer patients: left ventricular ejection fraction (LVEF) should be assessed by echocardiogram or MUGA scan before the first dose, cardiac function should be monitored closely during treatment, and LVEF should be re-assessed at regular intervals and whenever signs or symptoms of heart failure appear. Acute congestive heart failure can occasionally occur in patients treated for AML.
• Multiple sclerosis: functional cardiac changes can occur and acute heart failure has been reported. LVEF should be assessed before the first dose and before each dose, and once a year for up to 5 years after treatment ends. Patients should normally not receive a lifetime cumulative dose above 72 mg/m², and mitoxantrone should normally not be given if LVEF is below 50% or has fallen to a clinically significant degree.

Bone-Marrow Suppression

Treatment needs careful, frequent monitoring of blood counts and biochemistry. A full blood count including platelets should be taken before the first dose, 10 days after each dose, before each following infusion, and whenever signs or symptoms of infection appear. Myelosuppression can be more severe and longer in patients in poor general condition or with earlier chemotherapy or radiotherapy, and can occur at any dose. Except in AML, mitoxantrone should generally not be given to patients whose neutrophil count at baseline is below 1,500 cells/mm³. High doses (above 14 mg/m² a day for 3 days), as used for leukaemia, cause severe myelosuppression, and full haematological recovery should be confirmed before any consolidation treatment.

Secondary Leukaemia and Myelodysplastic Syndrome

Topoisomerase II inhibitors, including mitoxantrone, used alone or particularly with other anticancer agents and/or radiotherapy, have been associated with acute myeloid leukaemia and myelodysplastic syndrome. The benefit–risk balance should be weighed before starting. Patients should be told about the risks, symptoms and signs of acute leukaemia and should seek medical advice if they appear, even after five years.

Specific Uses

• Breast cancer: because safety data in adjuvant treatment are insufficient and the risk of leukaemia is increased, mitoxantrone should be used only for metastatic breast cancer.
• After other multiple sclerosis treatments: safety and efficacy have not been studied after natalizumab, fingolimod, alemtuzumab, dimethyl fumarate or teriflunomide.

Infections, Vaccination and Tumour Lysis

Patients receiving immunosuppressive agents such as mitoxantrone respond less well to infection, and systemic infections should be treated at the same time as, or just before, starting mitoxantrone. Live vaccines are contraindicated during treatment (see Drug Interactions). Cases of tumour lysis syndrome have been reported, and uric acid, electrolytes and urea should be monitored; acute lymphoblastic leukaemia and non-Hodgkin lymphoma are more often associated with it.

Mutagenicity, Carcinogenicity and Discolouration

Mitoxantrone was mutagenic in bacterial and mammalian test systems in vitro and in rats in vivo, and it was carcinogenic in laboratory animals at doses below the proposed clinical dose, so it has carcinogenic potential in humans. It can turn the urine blue-green for 24 hours after administration, and blue discolouration of the sclera, skin and nails can also occur; patients should be told.

Pregnancy, Contraception, Breastfeeding and Fertility

• Contraception: mitoxantrone is genotoxic and considered a potential human teratogen. Men should be advised not to father a child and to use contraception during treatment and for 5 months after it ends. Women of childbearing potential should avoid pregnancy, must have a negative pregnancy test before each dose, and must use effective contraception during treatment and for 8 months after it ends.
• Pregnancy: data are very limited. Mitoxantrone was not teratogenic in animals at doses below human exposure but was toxic to reproduction, and it is considered a potential human teratogen. It is contraindicated for multiple sclerosis in pregnancy; in other indications it should not be given during pregnancy, particularly the first trimester, and the benefit and the risk to the foetus are weighed case by case. If it is used in pregnancy or the patient becomes pregnant, she should be told of the potential risk to the foetus and offered genetic counselling.
• Breastfeeding: mitoxantrone passes into breast milk and has been detected up to one month after the last dose. Breastfeeding is contraindicated and must stop before treatment starts.
• Fertility: women have an increased risk of temporary or persistent amenorrhoea, so preservation of gametes should be considered before treatment. There are no data in men, but testicular tubular atrophy and reduced sperm counts were seen in animals.

Sodium Content

Each mL contains 3.40 mg of sodium. The 5 mL vial contains less than 1 mmol (23 mg) of sodium and is essentially sodium-free; the 10 mL and 15 mL vials contain more, and the SmPC gives their sodium content.

Effect on Driving

Mitoxantrone has a minor influence on the ability to drive and use machines. Treatment can cause mental confusion and fatigue.

Store unopened vials at a temperature not exceeding 25 °C. Do not refrigerate and do not freeze. No cold chain is needed. The vials are type I glass with a butyl stopper, holding 10 mg/5 mL, 20 mg/10 mL or 30 mg/15 mL, in boxes of 1, 5 or 10 vials; not all presentations may be marketed.

18 months before opening. After dilution, the SmPC gives physico-chemical stability data for the diluted solution; from a microbiological point of view it should be used immediately unless dilution took place under controlled and validated aseptic conditions, and otherwise the user is responsible for the in-use storage time and conditions. See sections 6.3 and 6.4 of the SmPC for the permitted storage of the diluted solution.

Prescription only (Rx). Treatment is given under the supervision of a physician experienced in the use of cytotoxic chemotherapy agents. Mitoxantrone is a hospital infusion, so it is supplied to the hospital or clinic that administers it. It is kept at room temperature (not above 25 °C) and is not refrigerated.