Idarubicin

Idarubicin is an anthracycline that intercalates into DNA, interacts with topoisomerase II and inhibits nucleic acid synthesis. A modification at position 4 of the anthracycline structure makes it highly lipophilic, which increases cellular uptake compared with doxorubicin and daunorubicin.

Mechanism of Action

• DNA intercalation and topoisomerase II: idarubicin inserts between DNA base pairs and stabilises the DNA–topoisomerase II complex, preventing the re-ligation step the enzyme normally completes. This gives antimitotic and cytotoxic activity.
• Other proposed effects: it may also inhibit polymerase activity, alter gene expression and cause free-radical damage to DNA. Anthracyclines are not specific to a phase of the cell cycle.
• Cross-resistance: in laboratory studies of anthracycline-resistant murine and human cells, idarubicin showed less cross-resistance than doxorubicin or daunorubicin.
• Active metabolite: idarubicinol has antitumour activity in vitro and in vivo; in rats, at the same doses, it is clearly less cardiotoxic than idarubicin.

Pharmacokinetics

• Distribution: in leukaemia patients, peak idarubicin concentrations in nucleated blood and bone marrow cells are reached a few minutes after injection. Because of its lipophilicity it is extensively bound to plasma proteins (97% for idarubicin, 94% for idarubicinol) and distributed into tissues, including tumours. Concentrations in nucleated blood and bone marrow cells are about 100 times plasma concentrations, and the volume of distribution is around 1,500 L/m².
• Metabolism: extensively converted to the active metabolite idarubicinol, in the liver and other tissues (the SmPC names CYP2C9 and CYP2D6).
• Elimination: after intravenous dosing with normal liver and kidney function, the terminal plasma half-life of idarubicin is 11–25 hours and that of idarubicinol 41–69 hours. In cells the half-lives are about 15 hours (idarubicin) and 72 hours (idarubicinol). Elimination is biliary and renal (less than 10% of drug and metabolites in urine), mainly as idarubicinol.
• Special populations: kidney or liver impairment can raise plasma concentrations. In seven children given intravenous idarubicin the median half-life was 8.5 hours, and that of idarubicinol 43.7 hours.

• Acute myeloid leukaemia (AML) in adults (formerly called acute non-lymphoblastic leukaemia): induction of remission as first-line therapy, or induction of remission in relapsed or refractory patients.
• AML in children: in combination with cytarabine, induction of remission as first-line therapy in previously untreated children.
• Acute lymphoblastic leukaemia (ALL): in adults and children, second-line treatment of relapsed ALL.
• Idarubicin is commonly used in chemotherapy regimens together with other cytotoxic agents.

• Hypersensitivity to idarubicin, to any excipient, or to other anthracyclines or anthracenediones.
• Severe hepatic impairment.
• Severe renal impairment.
• Uncontrolled infections.
• Severe cardiomyopathy, acute inflammatory heart disease, severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias.
• Persistent myelosuppression.
• Previous treatment with the maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones.
• Haemorrhagic diathesis.
• Stomatitis.
• Breastfeeding.
• Combination with yellow fever vaccine.

Severe bone marrow suppression and cardiac toxicity are two of the most important adverse effects. Reactions are similar in adults and children, except that children are more susceptible to anthracycline-induced cardiac toxicity.

Very common (≥1/10): infection; anaemia, severe leucopenia, neutropenia, thrombocytopenia and pancytopenia; anorexia; nausea, vomiting, mucositis/stomatitis, diarrhoea, and abdominal pain or burning sensation; alopecia (usually reversible); red colouring of the urine for 1–2 days after treatment; fever, headache and chills.

Common (≥1/100 to <1/10): congestive heart failure, cardiomyopathy, bradycardia, sinus tachycardia, tachyarrhythmia and asymptomatic falls in left ventricular ejection fraction; local phlebitis, thrombophlebitis and haemorrhage; gastrointestinal haemorrhage and belly ache; raised liver enzymes and bilirubin; erythema, pruritus and hypersensitivity of irradiated skin (radiation recall).

Uncommon (≥1/1,000 to <1/100): sepsis and septicaemia; secondary leukaemia (acute myeloid leukaemia and myelodysplastic syndrome); dehydration; hyperuricaemia and tumour lysis syndrome; ECG abnormality (non-specific ST-T changes) and myocardial infarction; shock; oesophagitis and colitis (including severe enterocolitis or neutropenic enterocolitis with perforation); hyperpigmentation of skin and nails, urticaria, cellulitis (which can be severe) and tissue necrosis.

Rare (≥1/10,000 to <1/1,000): cerebral haemorrhage.

Very rare (<1/10,000): anaphylaxis; myocarditis, atrioventricular block, right bundle branch block and pericarditis; thromboembolism (including pulmonary embolism) and flushes; gastric erosion or ulceration; acral erythema.

Not known: local reaction.

Marked bone marrow suppression is the most serious effect, though it is needed to eradicate leukaemic cells. Life-threatening congestive heart failure is the most severe anthracycline cardiomyopathy and represents the cumulative dose-limiting toxicity. Severe stomatitis can progress to mucosal ulceration, with dehydration from continued vomiting and diarrhoea and a risk of colonic perforation. Paravenous leakage can cause pain, severe cellulitis and tissue necrosis. Hydration, urine alkalinisation and allopurinol prophylaxis can minimise the risk of tumour lysis.

• Other myelosuppressive treatment: idarubicin is a potent myelosuppressant, so combination with other chemotherapy of similar action gives additive effects. Additive myelosuppression also occurs with radiotherapy given at the same time or in the 2–3 weeks before.
• Cardiotoxic or cardioactive medicines: with other cardiotoxic chemotherapy or cardioactive medicines (for example calcium channel blockers), cardiac function must be monitored throughout treatment. Anthracyclines should not be given until 27 weeks after the end of trastuzumab where possible; if given earlier, monitor cardiac function carefully.
• Changes in liver or kidney function caused by other treatment can alter the metabolism, pharmacokinetics, efficacy and toxicity of idarubicin.
• Live attenuated vaccines (for example yellow fever): not recommended, because of the risk of fatal systemic disease, which is higher in immunosuppressed patients; use an inactivated vaccine where available. Combination with yellow fever vaccine is contraindicated.
• Oral anticoagulants: check the INR more often during chemotherapy, as an interaction cannot be excluded.
• Ciclosporin A: given as a single chemosensitiser it raised the AUC of idarubicin 1.78-fold and of idarubicinol 2.46-fold in acute leukaemia. The clinical relevance is unknown, and a dose adjustment may be needed in some patients.

Idarubicin is given only by the intravenous route, never intrathecally, under the supervision of physicians experienced in cytotoxic chemotherapy. Doses are calculated on body surface area and are general guidelines; individual protocols should be consulted.

Acute Myeloid Leukaemia

• Adults: 12 mg/m² daily intravenously for 3 days in combination with cytarabine, or 8 mg/m² daily intravenously for 5 days as a single agent and/or in combination.
• Children: in combination with cytarabine, 10–12 mg/m² body surface area daily for 3 days by slow intravenous injection.

Acute Lymphoblastic Leukaemia

• Adults: 12 mg/m² daily intravenously for 3 days in suitable combination regimens.
• Children: 10 mg/m² daily intravenously for 3 days in suitable combination regimens.

Dose Adjustments

• Take the patient’s haematological status and the doses of other cytotoxic medicines into account.
• In patients who develop severe mucositis, delay a second dose until recovery and reduce the dose by 25%.
• Do not exceed a maximum dose of 120 mg/m² body surface area.
• Dose adjustment may be needed in renal or hepatic impairment; serum bilirubin and creatinine are checked before and during treatment (see Special Instructions).

Method of Administration

The infusion can be prepared by dilution with 0.9% sodium chloride or 5% glucose. Alternatively, the required undiluted volume can be given slowly over 5 to 10 minutes into the tubing of a freely running intravenous infusion of 0.9% sodium chloride or 5% glucose. Direct injection is not recommended because of the risk of extravasation, which can occur even when blood is aspirated back from the needle. Dilution instructions are in section 6.6 of the SmPC.

General

Idarubicin is given only under the supervision of physicians experienced in cytotoxic chemotherapy, so that serious complications of the disease or its treatment (such as haemorrhage and repeated infections) can be treated at once. Patients should have recovered from acute toxicities of earlier cytotoxic treatment (stomatitis, neutropenia, thrombocytopenia, generalised infection), and systemic infections should be controlled before starting. Protective recommendations for health professionals handling this cytotoxic medicine are in section 6.6.

Cardiotoxicity

• Early effects: sinus tachycardia and/or ECG changes (non-specific ST-T changes), tachyarrhythmias including premature ventricular contractions and ventricular tachycardia, bradycardia, and atrioventricular and bundle branch block. They do not usually predict later cardiotoxicity, rarely matter clinically and are generally not a reason to stop.
• Delayed effects: usually late in treatment or 2–3 months after it ends, though events months to years later have been reported. They show as a lower left ventricular ejection fraction (LVEF) and/or signs of congestive heart failure (dyspnoea, pulmonary oedema, peripheral oedema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, gallop rhythm); pericarditis/myocarditis has also occurred. Life-threatening congestive heart failure is the cumulative dose-limiting toxicity.
• Cumulative dose: limits have not been defined for intravenous or oral idarubicin hydrochloride. Treatment-related cardiomyopathy was reported in 5% of patients who received intravenous cumulative doses between 150 and 290 mg/m². Data in patients given cumulative oral doses up to 400 mg/m² suggest a low probability of cardiotoxicity. Cardiotoxicity can still occur at lower cumulative doses, whether or not cardiac risk factors are present.
• Monitoring: assess cardiac function before treatment, with an ECG and either a MUGA scan or echocardiography, especially in patients at higher risk, and repeat LVEF measurements by the same method during treatment, particularly at high cumulative anthracycline doses. Stop idarubicin at the first sign of impaired function.
• Risk factors: active or latent cardiovascular disease, previous or concomitant radiotherapy to the pericardial or mediastinal area, earlier anthracyclines or anthracenediones, and medicines that suppress cardiac contractility (for example trastuzumab). Anthracyclines should not be combined with other cardiotoxic agents unless cardiac function is closely monitored.
• Children: infants and children appear more susceptible, so long-term periodic cardiac assessment is needed.

Bone Marrow Suppression

Severe myelosuppression occurs in all patients at therapeutic doses. A blood count with white cell differential is needed before treatment and during each cycle. Reversible, dose-dependent leucopenia and/or neutropenia is the most common dose-limiting toxicity; thrombocytopenia and anaemia may also occur. Neutrophil and platelet nadirs are usually reached on days 10–14 and counts normalise by the third week. Deaths from infection and/or haemorrhage have occurred during severe myelosuppression, and intravenous antibiotics are recommended for febrile neutropenia.

Other Warnings

• Secondary leukaemia: reported with anthracyclines, with or without a pre-leukaemic phase, more often when combined with DNA-damaging antineoplastic agents, after intensive cytotoxic pre-treatment or with escalated anthracycline doses; latency is 1–3 years.
• Gastrointestinal: idarubicin is emetogenic. Mucositis (mainly stomatitis) generally appears soon after administration and, if severe, can progress to ulceration within days; most patients recover by the third week.
• Liver and kidney function: impaired function can alter idarubicin availability. Serum bilirubin and creatinine are assessed before and during treatment. In several phase III trials the drug was contraindicated when either exceeded 2.0 mg/dL, and with other anthracyclines the dose is generally reduced by 50% at levels of 1.2–2.0 mg/dL.
• Injection site and extravasation: injection into a small vessel or repeated injection into the same vein may cause phlebosclerosis. Extravasation causes local pain and serious tissue injury (blistering, severe cellulitis, necrosis); stop the infusion at once if it is suspected. Dexrazoxane can be used to prevent or reduce tissue injury.
• Tumour lysis syndrome: idarubicin can cause hyperuricaemia. Check uric acid, potassium, calcium phosphate and creatinine after the first treatment; hydration, urine alkalinisation and allopurinol prophylaxis can minimise complications.
• Vaccines: live or live-attenuated vaccines (such as yellow fever) can cause serious or fatal infection in patients immunocompromised by chemotherapy and should be avoided; inactivated vaccines may be given but the response may be reduced.
• Other: thrombophlebitis and thromboembolic events, including pulmonary embolism, have occurred. The urine may turn red for 1–2 days, and patients should be told.

Pregnancy, Breastfeeding and Fertility

• Fertility: idarubicin can cause chromosomal damage in human sperm. Men should use effective contraception during treatment and for at least 3.5 months after it ends, and should be advised to ask about sperm storage before starting, as the treatment may cause irreversible infertility. There are no human data on female fertility; adverse effects were seen in animals.
• Contraception: women of childbearing potential should avoid pregnancy and use effective contraception during treatment and for at least 6.5 months after the last dose. Men with female partners of childbearing potential should use effective contraception during treatment and for at least 3.5 months after the last dose.
• Pregnancy: embryotoxic potential has been shown in vitro and in vivo, and there are no adequate, well-controlled studies in pregnant women. Idarubicin should be used in pregnancy only if the potential benefit justifies the risk to the foetus, and the patient must be told of the potential harm.
• Breastfeeding: contraindicated.

Effect on Driving

The effect on the ability to drive and use machines has not been systematically evaluated, but the ability may be impaired in weaker patients.

Store in a refrigerator at 2–8 °C, with the vial kept in the original package to protect it from light. As a refrigerated product it needs cold-chain handling in transport and storage. The vials are clear type I glass with a fluoropolymer-coated halobutyl rubber stopper, with or without a protective plastic coating (Onco-Safe or sleeving) that adds protection in transport. Packs hold 1, 5 or 10 vials of 5 mg/5 mL, 10 mg/10 mL or 20 mg/20 mL; not all pack sizes may be marketed.

2 years for unopened vials. After dilution, chemical and physical stability in use has been shown for 14 days at 2–8 °C and at 25 °C. From a microbiological point of view the product should be used immediately; if not, in-use times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx). Idarubicin is a cytotoxic medicine prescribed and given under the supervision of a physician experienced in cytotoxic chemotherapy, in hospital. It is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.