Drugs List

Therapeutic Indications

Uses

Carcinoma of breast
Carcinoma-in-situ of the bladder
Leukaemia
Lymphoma
Myeloma - multiple
Prophylaxis of bladder cancer recurrences after transurethral resection
Treatment of carcinoma of the ovary
Treatment of colorectal carcinoma
Treatment of gastric carcinoma
Treatment of lung carcinoma
Treatment of papillary transitional cell carcinoma of the bladder

Unlicensed Uses

Acute lymphoblastic leukaemia in relapsed or refractory paediatric patients
Childhood rhabdomyosarcoma
Soft tissue tumours of childhood

Administration

For intravenous infusion or injection via tubing of fast running infusion.

Alternatively, it may be given intravesically for superficial bladder carcinoma and carcinoma-in-situ. This route is not suitable for tumours that have penetrated the bladder wall.

Contraindications

Acute infection
Breastfeeding
Cardiac impairment
Cystitis - if for intravesical use
Haematuria - if for intravesical use
History of myocardial infarction
Large residual volume of urine - if for intravesical use
Long QT syndrome
Myelosuppression
Myocardial infarction
Pregnancy
Severe hepatic impairment
Torsade de pointes
Urethral stenosis preventing urethral catheterisation-If intravesical use
Urinary tract infection - if for intravesical use

Precautions and Warnings

Children under 18 years
Family history of long QT syndrome
History of cardiotoxic drug
History of mediastinal radiotherapy
History of treatment with anthracyclines
Within 7 months of discontinuing trastuzumab
Dehydration
Electrolyte imbalance
Hepatic impairment
History of torsade de pointes
Renal impairment - glomerular filtration rate below 10ml/minute

Administration of live vaccines is not recommended
Correct electrolyte disorders before treatment
Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Cardiotoxic -Avoid anthracyclines for up to 7 months after last trastuzumab
Consider premedication with hypouricaemic agent
Exclude invasive tumours penetrating the bladder wall before treatment
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of anti-cancer drugs
Do not use intravesical route if bladder is contracted
Do not use intravesical route if catheterisation problems occur
If extravasation occurs follow local policy & seek expert help immediately
Staff: Not to be handled by pregnant staff
Baseline & follow-up ECGs during & immediately after administration advised
Measurement of LV ejection fraction recommended before and during treatment
Monitor full blood count and differential WBC before and during therapy
Perform echocardiography before commencing therapy
Perform liver function tests before commencing therapy and during therapy
Consider monitoring ECG in patients at risk of QT prolongation
Monitor cardiac function
Monitor patients for signs of tumour lysis syndrome
Monitor serum creatinine
Monitor serum electrolytes
Monitor uric acid levels
Advise patient to report symptoms of infection immediately
Risk of cardiomyopathy increases with high cumulative dosage
May colour urine red
Not licensed for use in children under 18 years
Lifetime cumulative dose should be limited to 1000mg/m squared
May cause impaired fertility
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 6 months after treatment
Breastfeeding: Do not breastfeed & discard milk for 1 week after therapy

Cardiotoxicity
Treatment in the presence of pre-existing heart disease or reduced cardiac function should be carefully considered. Cardiac function should be assessed before patients undergo treatment and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment (e.g. by LVEF, ECG, ECHO, MUGA as appropriate). The risk of cardiotoxicity may be decreased through regular monitoring and prompt discontinuation of epirubicin at the first sign of impaired function.

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.

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 cardiomyopathy is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF). Subacute effects such as pericarditis/myocarditis have also been reported. 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 (e.g. doxorubicin). The maximum cumulative lifetime doses of epirubicin is 900 mg/square. Above this dosage, the risk of irreversible congestive cardiac failure increases greatly, however cardiotoxicity may occur at doses lower than the recommended cumulative limit. Epirubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines and anthracenediones (e.g. mitoxantrone).

Myelosuppression
White blood cell count reaches a nadir between days 10 to 14 after administration, and usually recovers by about 21 days.

Malignancy
Secondary leukaemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pre-treated with cytotoxic drugs or when doses of the anthracyclines have been escalated. These leukaemias can have a 1 to 3 year latency period.

Pregnancy and Lactation

Pregnancy

Epirubicin is contraindicated in pregnancy.

Reports of epirubicin in combination with other cytotoxic agents in human pregnancy has resulted in miscarriage, stillborns, intrauterine growth restriction, transient leukopaenia.

It has been shown to be genotoxic, embryotoxic and carcinogenic in rats.

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

Epirubicin is contraindicated in breastfeeding.

The molecular weight is low enough that excretion into human breast milk should be expected, a risk to neonates cannot be excluded.

Schaefer recommends suspending breast feeding for at least 7 days following treatment with epirubicin.

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

Allergic reaction
Alopecia
Amenorrhoea
Anaemia
Anaphylaxis
Anorexia
Arrhythmias
Ascites
Asthenia
Atrioventricular block
Azoospermia
Bradycardia
Bundle branch block
Burning sensation
Cardiomyopathy
Cardiotoxicity
Cellulitis
Chills
Congestive cardiac failure
Conjunctivitis
Cystitis - chemical (transient)
Decreased ejection fraction
Dehydration
Diarrhoea
Dizziness
Dyspnoea
ECG changes
Erythema at injection site
Erythematous rash
Extravasation necrosis
Febrile neutropenia
Fever
Flushing
Granulocytopenia
Haemorrhage
Haemorrhagic cystitis
Headache
Hepatomegaly
Hot flushes
Hyperpigmentation
Hyperpyrexia
Hyperuricaemia
Hypoxia
Increase of liver transaminases
Increased susceptibility to infection
Infertility
Keratitis
Leucopenia
Leukaemia
Local pain (injection site)
Malaise
Mucositis
Myelosuppression
Nausea
Neutropenia
Oedema
Oesophagitis
Peripheral neuropathy
Phlebitis
Phlebosclerosis
Photosensitivity
Pleural effusion
Pneumonia
Pollakiuria
Proteinuria
Pruritus
Pulmonary embolism
Pulmonary oedema
Radiation recall dermatitis
Rash
Red urine
Sepsis
Septic shock
Shock
Skin reddening
Stomatitis
Tachycardia
Thrombocytopenia
Thromboembolic disorders
Thrombophlebitis
Tumour lysis syndrome
Urticaria
Ventricular tachycardia
Vomiting
Weakness

Presentation

Injections containing epirubicin hydrochloride

Drugs List

Therapeutic Indications

Uses

Carcinoma of breast
Carcinoma-in-situ of the bladder
Leukaemia
Lymphoma
Myeloma - multiple
Prophylaxis of bladder cancer recurrences after transurethral resection
Treatment of carcinoma of the ovary
Treatment of colorectal carcinoma
Treatment of gastric carcinoma
Treatment of lung carcinoma
Treatment of papillary transitional cell carcinoma of the bladder

Unlicensed Uses

Acute lymphoblastic leukaemia in relapsed or refractory paediatric patients
Childhood rhabdomyosarcoma
Soft tissue tumours of childhood

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 network protocols and Trust chemotherapy protocols should be consulted.

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For intravenous infusion or injection via tubing of fast running infusion.

Alternatively, it may be given intravesically for superficial bladder carcinoma and carcinoma-in-situ. This route is not suitable for tumours that have penetrated the bladder wall.

Contraindications

Acute infection
Breastfeeding
Cardiac impairment
Cystitis - if for intravesical use
Haematuria - if for intravesical use
History of myocardial infarction
Large residual volume of urine - if for intravesical use
Long QT syndrome
Myelosuppression
Myocardial infarction
Pregnancy
Severe hepatic impairment
Torsade de pointes
Urethral stenosis preventing urethral catheterisation-If intravesical use
Urinary tract infection - if for intravesical use

Precautions and Warnings

Children under 18 years
Family history of long QT syndrome
History of cardiotoxic drug
History of mediastinal radiotherapy
History of treatment with anthracyclines
Within 7 months of discontinuing trastuzumab
Dehydration
Electrolyte imbalance
Hepatic impairment
History of torsade de pointes
Renal impairment - glomerular filtration rate below 10ml/minute

Administration of live vaccines is not recommended
Correct electrolyte disorders before treatment
Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Cardiotoxic -Avoid anthracyclines for up to 7 months after last trastuzumab
Consider premedication with hypouricaemic agent
Exclude invasive tumours penetrating the bladder wall before treatment
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of anti-cancer drugs
Do not use intravesical route if bladder is contracted
Do not use intravesical route if catheterisation problems occur
If extravasation occurs follow local policy & seek expert help immediately
Staff: Not to be handled by pregnant staff
Baseline & follow-up ECGs during & immediately after administration advised
Measurement of LV ejection fraction recommended before and during treatment
Monitor full blood count and differential WBC before and during therapy
Perform echocardiography before commencing therapy
Perform liver function tests before commencing therapy and during therapy
Consider monitoring ECG in patients at risk of QT prolongation
Monitor cardiac function
Monitor patients for signs of tumour lysis syndrome
Monitor serum creatinine
Monitor serum electrolytes
Monitor uric acid levels
Advise patient to report symptoms of infection immediately
Risk of cardiomyopathy increases with high cumulative dosage
May colour urine red
Not licensed for use in children under 18 years
Lifetime cumulative dose should be limited to 1000mg/m squared
May cause impaired fertility
Female: Ensure adequate contraception during treatment
Male: Contraception required during and for 6 months after treatment
Breastfeeding: Do not breastfeed & discard milk for 1 week after therapy

Cardiotoxicity
Treatment in the presence of pre-existing heart disease or reduced cardiac function should be carefully considered. Cardiac function should be assessed before patients undergo treatment and must be monitored throughout therapy to minimise the risk of incurring severe cardiac impairment (e.g. by LVEF, ECG, ECHO, MUGA as appropriate). The risk of cardiotoxicity may be decreased through regular monitoring and prompt discontinuation of epirubicin at the first sign of impaired function.

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.

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 cardiomyopathy is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF). Subacute effects such as pericarditis/myocarditis have also been reported. 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 (e.g. doxorubicin). The maximum cumulative lifetime doses of epirubicin is 900 mg/square. Above this dosage, the risk of irreversible congestive cardiac failure increases greatly, however cardiotoxicity may occur at doses lower than the recommended cumulative limit. Epirubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines and anthracenediones (e.g. mitoxantrone).

Myelosuppression
White blood cell count reaches a nadir between days 10 to 14 after administration, and usually recovers by about 21 days.

Malignancy
Secondary leukaemia is more common when anthracyclines are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pre-treated with cytotoxic drugs or when doses of the anthracyclines have been escalated. These leukaemias can have a 1 to 3 year latency period.

Pregnancy and Lactation

Pregnancy

Epirubicin is contraindicated in pregnancy.

Reports of epirubicin in combination with other cytotoxic agents in human pregnancy has resulted in miscarriage, stillborns, intrauterine growth restriction, transient leukopaenia.

It has been shown to be genotoxic, embryotoxic and carcinogenic in rats.

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

Epirubicin is contraindicated in breastfeeding.

The molecular weight is low enough that excretion into human breast milk should be expected, a risk to neonates cannot be excluded.

Schaefer recommends suspending breast feeding for at least 7 days following treatment with epirubicin.

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

Allergic reaction
Alopecia
Amenorrhoea
Anaemia
Anaphylaxis
Anorexia
Arrhythmias
Ascites
Asthenia
Atrioventricular block
Azoospermia
Bradycardia
Bundle branch block
Burning sensation
Cardiomyopathy
Cardiotoxicity
Cellulitis
Chills
Congestive cardiac failure
Conjunctivitis
Cystitis - chemical (transient)
Decreased ejection fraction
Dehydration
Diarrhoea
Dizziness
Dyspnoea
ECG changes
Erythema at injection site
Erythematous rash
Extravasation necrosis
Febrile neutropenia
Fever
Flushing
Granulocytopenia
Haemorrhage
Haemorrhagic cystitis
Headache
Hepatomegaly
Hot flushes
Hyperpigmentation
Hyperpyrexia
Hyperuricaemia
Hypoxia
Increase of liver transaminases
Increased susceptibility to infection
Infertility
Keratitis
Leucopenia
Leukaemia
Local pain (injection site)
Malaise
Mucositis
Myelosuppression
Nausea
Neutropenia
Oedema
Oesophagitis
Peripheral neuropathy
Phlebitis
Phlebosclerosis
Photosensitivity
Pleural effusion
Pneumonia
Pollakiuria
Proteinuria
Pruritus
Pulmonary embolism
Pulmonary oedema
Radiation recall dermatitis
Rash
Red urine
Sepsis
Septic shock
Shock
Skin reddening
Stomatitis
Tachycardia
Thrombocytopenia
Thromboembolic disorders
Thrombophlebitis
Tumour lysis syndrome
Urticaria
Ventricular tachycardia
Vomiting
Weakness

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 2015

Reference Sources

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.

Joint Formulary Committee. British National Formulary(online) London: BMJ Group and Pharmaceutical Press. Accessed on 14 August 2015.

Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.

Paediatric Formulary Committee. BNF for Children (online) London: BMJ Group, Pharmaceutical Press, and RCPCH Publications. Accessed on 14 August 2015.

Summary of Product Characteristics: Epirubicin 2mg/ml Injection. Teva UK Ltd. Revised January 2013.
Summary of Product Characteristics: Epirubicin 2mg/ml Injection. Hospira UK Ltd. Revised June 2015.
Summary of Product Characteristics: Epirubicin 2mg/ml Solution for Injection. Medac GmbH. Revised April 2014.
Summary of Product Characteristics: Epirubicin Hydrochloride 2mg/ml Solution for Injection or infusion. Accord healthcare limited. Revised September 2012.
Summary of Product Characteristics: Pharmorubicin 2mg/ml Solution for Injection. Pfizer Ltd. Revised October 2012.

The Cytotoxics Handbook Fourth Edition (2002), ed. Allwood, Stanley, Wright. Radcliffe Medical Press, Abingdon.

The Renal Drug Handbook. Fourth Edition (2014) ed. Ashley, C and Dunleavy, A, Radcliffe Publishing Ltd, London.