Mitoxantrone

Registered South African indications:

• Breast cancer
• Non-Hodgkin's lymphoma
• Acute non-lymphocytic leukaemia
• Relapse and chronic myelogenous leukaemia
• Advanced hormone refractory prostate cancer

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to sulphites that may be produced during the manufacturing of mitoxantrone
• Breastfeeding
• Multiple sclerosis in pregnant women

Cautions

• Pregnancy
• Men and women of childbearing potential
• Renal impairment
• Hepatic impairment
• Elderly
• Cumulative dosing
• Active or dormant cardiovascular disease
• Radiotherapy or history thereof
• Previous therapy with other anthracyclines or anthracenediones
• Multiple sclerosis
• Use after other multiple sclerosis-specific treatments
• Non-metastatic breast cancer
• Patients with poor general condition
• Prior chemotherapy
• High doses
• Baseline neutrophil count <1500 cells/mm³
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj

Used for the treatment of

• Breast cancer (including metastatic or locally advanced)
• Non-Hodgkin's lymphoma
• Acute non-lymphocytic leukaemia
• Relapse and chronic myelogenous leukaemia (additional agent required)
  - In blast crisis
• Acute myeloid leukaemia
• Prostate cancer (additional agent required)
  - Initial chemotherapy for patients with intractable pain related to advanced castrate resistant prostate cancer
• Multiple sclerosis
  - Highly active and relapsing associated with rapidly evolving disability where no alternative therapeutic options exist

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Consult specialist for dosages and regimens

Not established for use in children

Pregnancy

• Caution; positive evidence of risk
• Contraindicated (multiple sclerosis)
• There is very limited data on the use of mitoxantrone in pregnant women. Mitoxantrone was not teratogenic in animal studies at doses below human exposure
• Mitoxantrone is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents
• For this reason, the use of mitoxantrone to treat multiple sclerosis is contraindicated for pregnant women. When used for treatment in other indications, 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
• Mitoxantrone is genotoxic. 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

Breastfeeding

• Contraindicated
• Mitoxantrone is excreted in breastmilk and has been detected in breastmilk for up to one month after the last administration
• Because of the potential for serious adverse effects in infants from mitoxantrone, breastfeeding is contraindicated and must therefore be discontinued before starting treatment

Fertility

• Women treated with mitoxantrone have an increased risk of transitory or persistent amenorrhoea and therefore preservation of gametes should be considered prior to therapy
• In men, no data is available, but tubular atrophy of the testes and reduced sperm counts were observed in animals

Renal Impairment

• Caution; no information available
  Safety has not been established

Hepatic Impairment

• Caution; no information available
  Dose adjustment may be necessary as mitoxantrone clearance is reduced by hepatic impairment. There is insufficient data that allows for dose adjustment recommendations. Mitoxantrone is not recommended in multiple sclerosis patients with hepatic impairment

Elderly

• Caution; no dose adjustment recommended
  Initiate at the low end of the dosing range

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Lethargy
• Headache
• Anxiety
• Confusion
• Paraesthesia
• Fatigue

Cardiovascular Disorders

• Congestive cardiac failure
• Myocardial infarction (including fatal events)
• Arrhythmia
• Abnormal electrocardiogram
• Decreased left ventricular ejection fraction
• Sinus bradycardia
• Cardiomyopathy
• Contusion
• Haemorrhage
• Hypotension

Respiratory Disorders

• Dyspnoea
• Interstitial pneumonitis

Gastrointestinal Disorders

• Nausea and vomiting
• Stomatitis
• Constipation
• Diarrhoea
• Abdominal pain
• Gastrointestinal haemorrhage
• Mucosal inflammation
• Pancreatitis

Hepatobiliary Disorders

• Increased aspartate aminotransferase levels
• Hepatotoxicity

Genitourinary Disorders

• Increased serum creatinine
• Increased blood urea nitrogen levels
• Toxic nephropathy
• Urine discolouration
• Amenorrhoea

Endocrine and Metabolic Disorders

• Anorexia
• Weight fluctuations
• Tumour lysis syndrome
  - Acute T and B lymphoblastic leukaemia and non-Hodgkin lymphomas

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Erythema
• Skin discolouration
• Nail disorders
• Rash
• Tissue necrosis (after extravasation)
• Oedema

Immune, Blood and Lymphatic System Disorders

• Infection (including fatal outcome)
• Urinary tract infection
• Upper respiratory tract infection
• Pneumonia
• Sepsis
• Opportunistic infections
• Acute myeloid leukaemia
• Myelodysplastic syndrome
• Acute leukaemia
• Anaemia
• Neutropenia
• Leukopenia
• Thrombocytopenia
• Granulocytopenia
• Abnormal white blood cell count
• Myelosuppression
• Bone marrow failure
• Anaphylaxis/anaphylactoid reactions (including shock)
• Fever

Sensory Disorders

• Scleral discolouration
• Dysgeusia

Other

• Sudden death

• Live virus vaccines
• Potentially cardiotoxic active substances
• Anthracyclines
• Other antineoplastic agents
• Chemotherapy with another myelosuppressive agent 
• Immunosuppressive agents
• Vitamin K antagonists 
• Oral anticoagulants
• Breast cancer resistance protein (BCRP) transport inhibitors
• Eltrombopag
• Gefitinib
• Ciclosporin

• Full blood count with differential
• ECG
• Echocardiogram/ Multiple-gated acquisition (MUGA) / Magnetic resonance imaging (MRI)

Specific cases may require

• Blood urea nitrogen (BUN) level
• Electrolytes
• Serum uric acid
• International normalised ratio
• Hepatic function
• Pregnancy test

Mitoxantrone, a DNA-reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, causes crosslinks and strand breaks. Mitoxantrone also interferes with ribonucleic acid (RNA) and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and non-proliferating cultured human cells, suggesting lack of cell cycle phase specificity and activity against rapidly proliferating and slow-growing neoplasms. Mitoxantrone blocks the cell cycle in G2-phase leading to an increase of cellular RNA and polyploidy. Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, tumour necrosis factor alpha, and interleukin-2.

Injection (per 10ml) 20mg

• Mitoxantrone-Hexal (Sandoz)