Drugs List

Therapeutic Indications

Uses

Leukaemia - acute myeloid
Monotherapy of advanced breast cancer after failure of first line agents

Treatment of acute myelogenous leukaemia (AML) (previously known as acute non-lymphoblastic leukaemia (ANLL)).
Whenever intravenous idarubicin cannot be employed (for example, for medical, psychological or social reasons) oral idarubicin can be used for remission induction in patients with previously untreated, relapsed or refractory acute non-lymphocytic leukaemia.

As a single agent in the treatment of advanced breast cancer after failure of front line chemotherapy not including anthracyclines.

Administration

The capsules should be swallowed whole, with water, and should not be sucked, bitten or chewed.

They may be taken with a light meal.

Contraindications

Children under 18 years
Uncontrolled systemic infection
Breastfeeding
Pregnancy
Recent myocardial infarction
Serious cardiac arrhythmias
Severe cardiac disorder
Severe hepatic impairment
Severe myelosuppression
Severe renal impairment

Precautions and Warnings

Concurrent radiotherapy
History of anthracycline therapy
History of cardiotoxic drug therapy
History of mediastinal radiotherapy
History of pericardial irradiation
Within 7 months of discontinuing trastuzumab
Cardiovascular disorder
Gastrointestinal disorder
Hepatic impairment
Myelosuppression
Renal impairment

Administration of live vaccines is not recommended
Reduce dose in patients with glomerular filtration rate below 50ml/min
Advise ability to drive/operate machinery may be affected by side effects
Cardiotoxic -Avoid anthracyclines for up to 7 months after last trastuzumab
Give pre-treatment counselling and consideration of oocyte cryopreservation
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration during therapy
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Baseline & follow-up ECGs during & immediately after administration advised
Measurement of LV ejection fraction recommended before and during treatment
Monitor haematological parameters before and during treatment
Monitor hepatic function before treatment and regularly during treatment
Monitor renal function before treatment and regularly during treatment
Monitor patients for signs of tumour lysis syndrome
Monitor serum phosphate levels
Monitor serum potassium and calcium
Monitor uric acid levels
Consider treatments to prevent hyperuricaemia
Delayed myocardial toxicity may occur
Risk of cardiomyopathy increases with high cumulative dosage
May colour urine red
Discontinue if cardiomyopathy occurs
Discontinue or review if symptoms of congestive heart failure occur
Consider dose reduction in hepatic impairment
Lifetime cumulative dose should be limited to 400mg/m squared
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 3 months after treatment

Neutrophil and platelet counts usually reach their nadir 10 to 14 days following administration. However, cell counts generally return to normal levels during the third week.

Acute cardiotoxicity is usually a transient disturbance of cardiac function marked by ECG abnormalities (including severe arrhythmias) and does not usually predict subsequent development of delayed cardiomyopathy or require treatment discontinuation.

Delayed cardiotoxicity may manifest towards the end of therapy, within 2 to 3 months of finishing treatment or even years following the completion of treatment. Delayed cardiotoxicity is usually irreversible dose related cardiomyopathy, which may result in cardiac failure. Severe cardiac failure may occur precipitously without ECG changes. Delayed cardiomyopathy is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF). Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

The risk of delayed cardiomyopathy rises with increasing exposure to anthracyclines. Cumulative dose limits for intravenous idarubicin have not been defined. Idarubicin-related cardiomyopathy was reported in 5% of patients who received cumulative intravenous doses of 150 to 290 mg/ metre squared. Above cumulative dose limits for the anthracyclines the risk of irreversible congestive cardiac failure increases greatly. However, cardiotoxicity may occur at doses lower than the recommended cumulative limit. Idarubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines and anthracenediones.

Cardiac function should be carefully assessed before treatment with idarubicin and must be monitored during treatment in order to minimise the risk of severe cardiac impairment. The risk may be decreased through regular monitoring of the left ventricular ejection fraction during the course of treatment and idarubicin promptly discontinued at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes Multiple Gated Acquisition (MUGA) scan or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of drugs with the ability to suppress cardiac contractility or cardiotoxic drugs. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives (such as trastuzumab), may also be at an increased risk of developing cardiotoxicity. Therefore, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab when possible.

Infants and children appear to be more susceptible to anthracycline induced cardiac toxicity and long term periodic evaluation of cardiac function has to be performed.

Hyperuricaemia secondary to rapid lysis of leukaemic cells may be induced (tumour lysis syndrome). Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome.

Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling first if appropriate and available.

Pregnancy and Lactation

Pregnancy

Idarubicin is contraindicated during pregnancy.

Limited experience in second trimester has demonstrated significant foetal toxicity including cardiac anomalies.

Studies in rats have shown embryotoxicity and teratogenicity. Studies in rabbits only showed embryotoxicity. Idarubicin is less likely to cause cardiac abnormalities than other anthracyclines but the lipophilicity of idarubicin means that it will pass through the placenta more easily.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Idarubicin is contraindicated while breastfeeding.

At the time of writing there are no published reports concerning the use of idarubicin while breastfeeding. The molecular weight of idarubicin is low enough that it should be expected to be present in the breast milk.

The effect of concurrent therapies must also be considered.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acute myeloid leukaemia
Alopecia
Anaemia
Anaphylaxis
Anorexia
Atrioventricular block
Bradycardia
Bundle branch block
Burning sensation
Cardiomyopathy
Cellulitis
Cerebral haemorrhage
Chills
Colitis
Congestive cardiac failure
Decreased ejection fraction
Dehydration
Diarrhoea
ECG changes
Enterocolitis
Erythema
Febrile neutropenia
Fever
Flushing
Gastric erosions
Gastro-intestinal perforation
Gastro-intestinal ulceration
Gastrointestinal bleeding
Haemorrhage
Headache
Hyperpigmentation of skin
Hypersensitivity reactions
Hyperuricaemia
Hypoxia
Increases in hepatic enzymes
Infections
Itching
Leukopenia
Mucositis
Myelodysplastic syndrome
Myelosuppression
Myocardial infarction
Myocarditis
Nausea
Neutropenia
Neutropenic colitis
Oesophagitis
Pancytopenia
Pericarditis
Phlebitis
Pigmentation of nails
Radiation recall dermatitis
Rash
Red urine
Secondary leukaemia
Sepsis
Septic shock
Septicaemia
Serum bilirubin increased
Shock
Sinus tachycardia
Skin necrosis
Stomatitis
Tachyarrhythmia
Thrombocytopenia
Thromboembolism
Thrombophlebitis
Tumour lysis syndrome
Urticaria
Vomiting

Presentation

Idarubicin oral formulations

Drugs List

Therapeutic Indications

Uses

Leukaemia - acute myeloid
Monotherapy of advanced breast cancer after failure of first line agents

Treatment of acute myelogenous leukaemia (AML) (previously known as acute non-lymphoblastic leukaemia (ANLL)).
Whenever intravenous idarubicin cannot be employed (for example, for medical, psychological or social reasons) oral idarubicin can be used for remission induction in patients with previously untreated, relapsed or refractory acute non-lymphocytic leukaemia.

As a single agent in the treatment of advanced breast cancer after failure of front line chemotherapy not including anthracyclines.

Dosage

Due to the complexity and specialist nature of dosage regimens for the treatment of malignant disease, specific dosing information on this agent is not included.

Doses may vary significantly if this agent is used as monotherapy or different combinations.

When using this agent, specialist literature, national guidelines, cancer networks protocols and Trust chemotherapy protocols should be consulted.

Maximum cumulative dose by mouth for all indications is 400 mg/metres squared.

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

The capsules should be swallowed whole, with water, and should not be sucked, bitten or chewed.

They may be taken with a light meal.

Contraindications

Children under 18 years
Uncontrolled systemic infection
Breastfeeding
Pregnancy
Recent myocardial infarction
Serious cardiac arrhythmias
Severe cardiac disorder
Severe hepatic impairment
Severe myelosuppression
Severe renal impairment

Precautions and Warnings

Concurrent radiotherapy
History of anthracycline therapy
History of cardiotoxic drug therapy
History of mediastinal radiotherapy
History of pericardial irradiation
Within 7 months of discontinuing trastuzumab
Cardiovascular disorder
Gastrointestinal disorder
Hepatic impairment
Myelosuppression
Renal impairment

Administration of live vaccines is not recommended
Reduce dose in patients with glomerular filtration rate below 50ml/min
Advise ability to drive/operate machinery may be affected by side effects
Cardiotoxic -Avoid anthracyclines for up to 7 months after last trastuzumab
Give pre-treatment counselling and consideration of oocyte cryopreservation
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration during therapy
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Treatment to be administered by or under supervision of specialist
Baseline & follow-up ECGs during & immediately after administration advised
Measurement of LV ejection fraction recommended before and during treatment
Monitor haematological parameters before and during treatment
Monitor hepatic function before treatment and regularly during treatment
Monitor renal function before treatment and regularly during treatment
Monitor patients for signs of tumour lysis syndrome
Monitor serum phosphate levels
Monitor serum potassium and calcium
Monitor uric acid levels
Consider treatments to prevent hyperuricaemia
Delayed myocardial toxicity may occur
Risk of cardiomyopathy increases with high cumulative dosage
May colour urine red
Discontinue if cardiomyopathy occurs
Discontinue or review if symptoms of congestive heart failure occur
Consider dose reduction in hepatic impairment
Lifetime cumulative dose should be limited to 400mg/m squared
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 3 months after treatment

Neutrophil and platelet counts usually reach their nadir 10 to 14 days following administration. However, cell counts generally return to normal levels during the third week.

Acute cardiotoxicity is usually a transient disturbance of cardiac function marked by ECG abnormalities (including severe arrhythmias) and does not usually predict subsequent development of delayed cardiomyopathy or require treatment discontinuation.

Delayed cardiotoxicity may manifest towards the end of therapy, within 2 to 3 months of finishing treatment or even years following the completion of treatment. Delayed cardiotoxicity is usually irreversible dose related cardiomyopathy, which may result in cardiac failure. Severe cardiac failure may occur precipitously without ECG changes. Delayed cardiomyopathy is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF). Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.

The risk of delayed cardiomyopathy rises with increasing exposure to anthracyclines. Cumulative dose limits for intravenous idarubicin have not been defined. Idarubicin-related cardiomyopathy was reported in 5% of patients who received cumulative intravenous doses of 150 to 290 mg/ metre squared. Above cumulative dose limits for the anthracyclines the risk of irreversible congestive cardiac failure increases greatly. However, cardiotoxicity may occur at doses lower than the recommended cumulative limit. Idarubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines and anthracenediones.

Cardiac function should be carefully assessed before treatment with idarubicin and must be monitored during treatment in order to minimise the risk of severe cardiac impairment. The risk may be decreased through regular monitoring of the left ventricular ejection fraction during the course of treatment and idarubicin promptly discontinued at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes Multiple Gated Acquisition (MUGA) scan or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.

Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of drugs with the ability to suppress cardiac contractility or cardiotoxic drugs. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives (such as trastuzumab), may also be at an increased risk of developing cardiotoxicity. Therefore, physicians should avoid anthracycline-based therapy for up to 27 weeks after stopping trastuzumab when possible.

Infants and children appear to be more susceptible to anthracycline induced cardiac toxicity and long term periodic evaluation of cardiac function has to be performed.

Hyperuricaemia secondary to rapid lysis of leukaemic cells may be induced (tumour lysis syndrome). Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome.

Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling first if appropriate and available.

Pregnancy and Lactation

Pregnancy

Idarubicin is contraindicated during pregnancy.

Limited experience in second trimester has demonstrated significant foetal toxicity including cardiac anomalies.

Studies in rats have shown embryotoxicity and teratogenicity. Studies in rabbits only showed embryotoxicity. Idarubicin is less likely to cause cardiac abnormalities than other anthracyclines but the lipophilicity of idarubicin means that it will pass through the placenta more easily.

The effect of concurrent therapies must also be considered.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Idarubicin is contraindicated while breastfeeding.

At the time of writing there are no published reports concerning the use of idarubicin while breastfeeding. The molecular weight of idarubicin is low enough that it should be expected to be present in the breast milk.

The effect of concurrent therapies must also be considered.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Acute myeloid leukaemia
Alopecia
Anaemia
Anaphylaxis
Anorexia
Atrioventricular block
Bradycardia
Bundle branch block
Burning sensation
Cardiomyopathy
Cellulitis
Cerebral haemorrhage
Chills
Colitis
Congestive cardiac failure
Decreased ejection fraction
Dehydration
Diarrhoea
ECG changes
Enterocolitis
Erythema
Febrile neutropenia
Fever
Flushing
Gastric erosions
Gastro-intestinal perforation
Gastro-intestinal ulceration
Gastrointestinal bleeding
Haemorrhage
Headache
Hyperpigmentation of skin
Hypersensitivity reactions
Hyperuricaemia
Hypoxia
Increases in hepatic enzymes
Infections
Itching
Leukopenia
Mucositis
Myelodysplastic syndrome
Myelosuppression
Myocardial infarction
Myocarditis
Nausea
Neutropenia
Neutropenic colitis
Oesophagitis
Pancytopenia
Pericarditis
Phlebitis
Pigmentation of nails
Radiation recall dermatitis
Rash
Red urine
Secondary leukaemia
Sepsis
Septic shock
Septicaemia
Serum bilirubin increased
Shock
Sinus tachycardia
Skin necrosis
Stomatitis
Tachyarrhythmia
Thrombocytopenia
Thromboembolism
Thrombophlebitis
Tumour lysis syndrome
Urticaria
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: August 2013

Reference Sources

British National Formulary, 65th Edition (2013) Pharmaceutical Press, London.

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia

Summary of Product Characteristics: Zavedos 5mg Capsules. Pfizer Limited. Revised September 2014.
Summary of Product Characteristics: Zavedos 10mg Capsules. Pfizer Limited. Revised September 2014.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.