Drugs List

Therapeutic Indications

Uses

Prevention of cumulative cardiotoxicity caused by anthracycline treatment
Treatment of anthracycline extravasation

Treatment of anthracycline extravasation.

Prevention of chronic cumulative cardiotoxicity caused by anthracycline use in advanced and/or metastatic breast cancer patients who have received a prior cumulative dose of 300mg/metre squared of doxorubicin or a prior cumulative dose of 540mg/metre squared of epirubicin when further treatment is required.

Administration

To be administered by intravenous infusion.

Contraindications

Children under 18 years & cumulative dose <300mg doxorubicin or equivalent
Breastfeeding
Pregnancy

Precautions and Warnings

Children under 18 years
Elderly
Restricted sodium intake
Cardiac failure
Hepatic impairment
History of myocardial infarction
Myelosuppression
Renal impairment - creatinine clearance below 40ml/minute
Unstable angina
Valvular heart disease

Administration of live vaccines is not recommended
Reduce dose in patients with creatinine clearance of below 40ml/minute
Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Not all available brands are licensed for all indications
Contains potassium; caution in low potassium diets
Cardioprotective - give 30 mins before anthracycline
Dilute and use as an infusion
Extravasation treatment should be initiated within 6 hours of accident
If extravasation occurs follow local policy & seek expert help immediately
Remove cooling procedures 15 minutes before extravasation treatment
Treatment to be administered by or under supervision of specialist
Monitor cardiac function
Monitor haematological parameters regularly throughout treatment
Monitor hepatic function in patients with hepatic impairment
Monitor patients for development of second primary malignancies
Monitor patients with renal impairment for toxic effects
Monitor plasma potassium in patients at risk of hyperkalaemia
Increased risk of venous thromboembolism
Potentially mutagenic
Not licensed for all indications in all age groups
Male & female: Contraception required during & for 6 months after treatment

When dexrazoxane is used as a preventative pre-treatment administered prior to epirubicin, the clearance of epirubicin may be increased. This has only been reported with high dose epirubicin (120mg to 135mg per square metre) and is of no relevance when dexrazoxane is administered following epirubicin as an emergency treatment of anthracycline extravasation. No dosage adjustments are recommended by the manufacturer however prescribers should refer to local protocols.

Pregnancy and Lactation

Pregnancy

Dexrazoxane is contraindicated in pregnancy.

There is limited data on the use of dexrazoxane in pregnancy. It is not known whether dexrazoxane crosses the human placenta. The molecular weight, lack of plasma protein binding and elimination half-life suggest it will cross the placenta.

Briggs (2015) concludes that as dexrazoxane is used to protect from anthracycline induced cardiomyopathy, treatment should not be withheld because of pregnancy. If an inadvertent pregnancy occurs, the woman should be advised of the possible risk for severe adverse effects on the pregnancy.

Animal studies on rats and rabbits have shown embryotoxic and teratogenic effects.

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

Dexrazoxane is contraindicated during breastfeeding.

There is limited data on the use of dexrazoxane during breastfeeding. It is unknown if dexrazoxane or its metabolites are excreted in human milk. The molecular weight, lack of plasma protein binding and elimination half-life suggest that the drug will cross into the breast milk. Due to the potential for serious adverse reaction in the nursing infant the manufacturer advises mothers should discontinue breastfeeding during therapy.

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
Altered liver enzymes values
Altered serum creatinine values
Anaemia
Anaphylactic reaction
Anorexia
Asthenia
Bone marrow aplasia
Burning sensation
Candidiasis
Cellulitis
Constipation
Cough
Decrease in plasma calcium
Decreased appetite
Decreased ejection fraction
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Ear infection
Elevated amylase levels
Elevated triglyceride levels
Embolism
Eosinophilia
Erythema
Erythema at injection site
Fatigue
Febrile neutropenia
Gingivitis
Granulocytopenia
Headache
Hyperkalaemia
Hypersensitivity reactions including anaphylaxis
Hypokalaemia
Hyponatraemia
Increase in serum ALT/AST
Increased platelet count
Induration (injection site)
Infections
Leucopenia
Local pain (injection site)
Lymphoedema
Malaise
Monocytopenia
Mucosal inflammation
Myelodysplastic syndrome
Myelosuppression
Nail disorders
Nausea
Neoplasms
Neutropenia
Oedema
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Pharyngitis
Phlebitis
Phlebitis (injection site)
Pneumonia
Pruritus
Pulmonary embolism
Pyrexia
Raised neutrophil count
Reduced lymphocyte count
Sensory disturbances
Sepsis
Somnolence
Stomatitis
Superficial vein thrombophlebitis
Surgical wound complication
Swelling (injection site)
Syncope
Tachycardia
Thirst
Thrombocytopenia
Tremor
Vaginal haemorrhage
Venous thrombosis
Vertigo
Vomiting
Weight loss
White blood cell count decreased
White blood cell count raised

Presentation

Parenteral formulations containing dexrazoxane (as hydrochloride).

Drugs List

Therapeutic Indications

Uses

Prevention of cumulative cardiotoxicity caused by anthracycline treatment
Treatment of anthracycline extravasation

Treatment of anthracycline extravasation.

Prevention of chronic cumulative cardiotoxicity caused by anthracycline use in advanced and/or metastatic breast cancer patients who have received a prior cumulative dose of 300mg/metre squared of doxorubicin or a prior cumulative dose of 540mg/metre squared of epirubicin when further treatment is required.

Dosage

Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.

Adults

Children

Patients with Renal Impairment

Patients with Hepatic Impairment

Administration

To be administered by intravenous infusion.

Contraindications

Children under 18 years & cumulative dose <300mg doxorubicin or equivalent
Breastfeeding
Pregnancy

Precautions and Warnings

Children under 18 years
Elderly
Restricted sodium intake
Cardiac failure
Hepatic impairment
History of myocardial infarction
Myelosuppression
Renal impairment - creatinine clearance below 40ml/minute
Unstable angina
Valvular heart disease

Administration of live vaccines is not recommended
Reduce dose in patients with creatinine clearance of below 40ml/minute
Sodium content of formulation may be significant
Advise ability to drive/operate machinery may be affected by side effects
Not all available brands are licensed for all indications
Contains potassium; caution in low potassium diets
Cardioprotective - give 30 mins before anthracycline
Dilute and use as an infusion
Extravasation treatment should be initiated within 6 hours of accident
If extravasation occurs follow local policy & seek expert help immediately
Remove cooling procedures 15 minutes before extravasation treatment
Treatment to be administered by or under supervision of specialist
Monitor cardiac function
Monitor haematological parameters regularly throughout treatment
Monitor hepatic function in patients with hepatic impairment
Monitor patients for development of second primary malignancies
Monitor patients with renal impairment for toxic effects
Monitor plasma potassium in patients at risk of hyperkalaemia
Increased risk of venous thromboembolism
Potentially mutagenic
Not licensed for all indications in all age groups
Male & female: Contraception required during & for 6 months after treatment

When dexrazoxane is used as a preventative pre-treatment administered prior to epirubicin, the clearance of epirubicin may be increased. This has only been reported with high dose epirubicin (120mg to 135mg per square metre) and is of no relevance when dexrazoxane is administered following epirubicin as an emergency treatment of anthracycline extravasation. No dosage adjustments are recommended by the manufacturer however prescribers should refer to local protocols.

Pregnancy and Lactation

Pregnancy

Dexrazoxane is contraindicated in pregnancy.

There is limited data on the use of dexrazoxane in pregnancy. It is not known whether dexrazoxane crosses the human placenta. The molecular weight, lack of plasma protein binding and elimination half-life suggest it will cross the placenta.

Briggs (2015) concludes that as dexrazoxane is used to protect from anthracycline induced cardiomyopathy, treatment should not be withheld because of pregnancy. If an inadvertent pregnancy occurs, the woman should be advised of the possible risk for severe adverse effects on the pregnancy.

Animal studies on rats and rabbits have shown embryotoxic and teratogenic effects.

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

Dexrazoxane is contraindicated during breastfeeding.

There is limited data on the use of dexrazoxane during breastfeeding. It is unknown if dexrazoxane or its metabolites are excreted in human milk. The molecular weight, lack of plasma protein binding and elimination half-life suggest that the drug will cross into the breast milk. Due to the potential for serious adverse reaction in the nursing infant the manufacturer advises mothers should discontinue breastfeeding during therapy.

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
Altered liver enzymes values
Altered serum creatinine values
Anaemia
Anaphylactic reaction
Anorexia
Asthenia
Bone marrow aplasia
Burning sensation
Candidiasis
Cellulitis
Constipation
Cough
Decrease in plasma calcium
Decreased appetite
Decreased ejection fraction
Diarrhoea
Dizziness
Dry mouth
Dyspepsia
Dyspnoea
Ear infection
Elevated amylase levels
Elevated triglyceride levels
Embolism
Eosinophilia
Erythema
Erythema at injection site
Fatigue
Febrile neutropenia
Gingivitis
Granulocytopenia
Headache
Hyperkalaemia
Hypersensitivity reactions including anaphylaxis
Hypokalaemia
Hyponatraemia
Increase in serum ALT/AST
Increased platelet count
Induration (injection site)
Infections
Leucopenia
Local pain (injection site)
Lymphoedema
Malaise
Monocytopenia
Mucosal inflammation
Myelodysplastic syndrome
Myelosuppression
Nail disorders
Nausea
Neoplasms
Neutropenia
Oedema
Paraesthesia
Peripheral neuropathy
Peripheral oedema
Pharyngitis
Phlebitis
Phlebitis (injection site)
Pneumonia
Pruritus
Pulmonary embolism
Pyrexia
Raised neutrophil count
Reduced lymphocyte count
Sensory disturbances
Sepsis
Somnolence
Stomatitis
Superficial vein thrombophlebitis
Surgical wound complication
Swelling (injection site)
Syncope
Tachycardia
Thirst
Thrombocytopenia
Tremor
Vaginal haemorrhage
Venous thrombosis
Vertigo
Vomiting
Weight loss
White blood cell count decreased
White blood cell count raised

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: February 2018

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

Summary of Product Characteristics: Savene 20mg/ml powder for concentrate and diluent for solution for infusion. Clinigen Healthcare Ltd. Revised July 2018.

Summary of Product Characteristics: Cardioxane 500mg powder for solution for infusion. Clinigen Healthcare Ltd. Revised January 2018.

EMA 19 July 2017: Questions and answers on Cardioxane (dexrazoxane, powder for solution for injection, 500 mg)
Available at: https://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Cardioxane_13/WC500228103.pdf
Last accessed: 21 February 2018

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 21 February 2018