Drugs List

Therapeutic Indications

Uses

Malignant neoplasms

Doxorubicin is used to treat a wide range of neoplastic conditions including: acute leukaemias, lymphomas, advanced multiple myeloma, osteogenic sarcomas, soft tissue sarcomas, paediatric malignancies, adult solid tumours (including breast, lung, advanced ovarian, endometrial, gastric and thyroid carcinomas), neuroblastoma and Wilms tumour.

Doxorubicin can also be used intravesically for single agent treatment and prophylaxis of superficial bladder carcinomas.

Administration

For intravenous or intravesical administration.

Intravenous administration
Doxorubicin should be administered via the tubing of a freely running intravenous infusion. The injection should take place over not less than 3 to 15 minutes. A stinging or burning sensation at the site of administration signifies a small degree of extravasation and the infusion should be stopped.

Patients with an increased risk for cardiotoxicity may be considered for treatment with a short infusion over an hour or a continuous infusion for up to 96 hours. In these patients, the ejection fraction should be measured before each course.

Intravesical administration
To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation.
The patient should be rotated a quarter turn every 15 minutes while the drug is in situ.
Exposure to the drug solution for 1 to 2 hours is generally adequate.

Contraindications

Systemic infection
Acute inflammatory cardiac disorders
Breastfeeding
Cardiac failure
Cystitis - if for intravesical use
History of myocardial infarction
Myelosuppression
Pregnancy
Serious cardiac arrhythmias
Severe hepatic impairment
Severe myocardial depression
Urethral stenosis preventing urethral catheterisation-If intravesical use
Urinary tract infection - if for intravesical use

Precautions and Warnings

Children under 15 years
Elderly
Females
History of cardiotoxic drug
History of mediastinal radiotherapy
History of treatment with anthracyclines
Obesity
Within 7 months of discontinuing trastuzumab
Buccal ulceration
Dehydration
End stage renal disease
Hepatic impairment
History of cardiovascular disorder
Hypertension

Administration of live vaccines is not recommended
Advise ability to drive/operate machinery may be affected by side effects
Cardiotoxic -Avoid anthracyclines for up to 7 months after last trastuzumab
Consider reducing initial dose or prolonging dose interval in obese patient
Give pre-treatment counselling and consideration of sperm cryopreservation
Intravesicular: Advise patient not to drink fluids for 12hrs prior to admin
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Not all available brands are licensed for all routes of administration
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of anti-cancer drugs
If extravasation occurs follow local policy & seek expert help immediately
Staff: Not to be handled by pregnant staff
Measurement of LV ejection fraction recommended before and during treatment
Monitor cardiac function before and regularly during treatment
Monitor differential WBC count before and during therapy
Monitor haematological parameters before and during treatment
Perform ECG before and during treatment
Perform liver function tests before commencing therapy and during therapy
Monitor patients for signs of tumour lysis syndrome
Monitor uric acid levels
Cardiac failure may occur weeks after administration & may resist treatment
Consider suspending treatment in presence of buccal ulceration
Consider treatments to prevent hyperuricaemia
Potentially leukaemogenic
Risk of cardiomyopathy increases with high cumulative dosage
May colour urine red
Suspend or modify if drug-induced bone marrow depression is detected
Suspend treatment if LVEF below 50% & fall of more than 10% below baseline
Lifetime cumulative dose should be limited to 550mg/m squared
May cause impaired fertility
Male & female: Contraception required during & for 6 months after treatment

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. The risk of delayed cardiomyopathy rises with increasing exposure to doxorubicin. Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines and anthracenediones (e.g. mitoxantrone).

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.

Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome. Blood uric acid levels, potassium, calcium, phosphate and creatinine should be evaluated after initial treatment.

Pregnancy and Lactation

Pregnancy

Doxorubicin is contraindicated in pregnancy.

Doxorubicin is known to have harmful pharmacological effects in humans when used in pregnancy, including embryotoxicity and the development of structural abnormalities in the developing foetus. Reports have described spontaneous abortion and intrauterine death, but these have been in patients who have received other cytotoxic drugs in conjunction with doxorubicin.

Animal studies have shown doxorubicin to be embryotoxic, teratogenic, and abortifacient. The use of doxorubicin in pregnancy is contraindicated by the manufacturer.

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 14-17 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

Doxorubicin is contraindicated in breastfeeding.

Doxorubicin is known to be excreted in the breast milk. Due to the potential for serious adverse reactions in the nursing infant, it should not be given to nursing mothers.

The effect of concurrent therapies must also be considered.

Lactmed suggests that it may be possible for a woman treated with doxorubicin to breastfeed safely during intermittent therapy by using an appropriate period of breastfeeding abstinence, but did not suggest a duration for this period.

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
Alopecia
Amenorrhoea
Anaemia
Anaphylaxis
Anorexia
Arrhythmias
Asthenia
Atrioventricular block
Azoospermia
Bladder capacity reduced
Bladder irritation
Bone marrow depression
Bradycardia
Bronchospasm
Bundle branch block
Burning pain at injection site
Cardiomyopathy
Cardiotoxicity
Chills
Colitis
Congestive cardiac failure
Conjunctivitis
Decreased ejection fraction
Dehydration
Diarrhoea
Dizziness
Drowsiness
Dyspnoea
Dysuria
ECG changes
Elevation of liver enzymes (transient)
Erythema at injection site
Exanthema
Facial flushing
Fever
Gastric erosions
Gastrointestinal bleeding
Haematuria
Haemorrhage
Haemorrhagic cystitis
Hepatotoxicity
Hot flushes
Hyperuricaemia
Hypoxia
Increased normal tissue reactions to radiation
Infections
Itching
Keratitis
Lacrimation
Leucopenia
Malaise
Mucositis
Myelodysplastic syndrome
Myelosuppression
Nausea
Neutropenia
Oesophagitis
Oligospermia
Onycholysis
Palmar-plantar erythrodysaesthesia
Phlebitis
Phlebosclerosis
Pigmentation of nails, skin and oral mucosa
Pollakiuria
Radiation recall dermatitis
Rash
Red urine
Reduced beard growth
Renal damage
Secondary leukaemia
Sepsis
Septic shock
Septicaemia
Shivering
Shock
Skin reactions
Stinging
Stomatitis
Stranguria
Supraventricular tachycardia
Tachycardia
Thrombocytopenia
Thromboembolism
Thrombophlebitis (injection site)
Tissue necrosis and ulceration with extravasation
Tumour lysis syndrome
Urethral irritation
Urticaria
Vomiting
Weakness

Presentation

Doxorubicin hydrochloride injection solution and powder for solution for injection.

Drugs List

Therapeutic Indications

Uses

Malignant neoplasms

Doxorubicin is used to treat a wide range of neoplastic conditions including: acute leukaemias, lymphomas, advanced multiple myeloma, osteogenic sarcomas, soft tissue sarcomas, paediatric malignancies, adult solid tumours (including breast, lung, advanced ovarian, endometrial, gastric and thyroid carcinomas), neuroblastoma and Wilms tumour.

Doxorubicin can also be used intravesically for single agent treatment and prophylaxis of superficial bladder carcinomas.

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.

Patients with Renal Impairment

Patients with Hepatic Impairment

Additional Dosage Information

Administration

For intravenous or intravesical administration.

Intravenous administration
Doxorubicin should be administered via the tubing of a freely running intravenous infusion. The injection should take place over not less than 3 to 15 minutes. A stinging or burning sensation at the site of administration signifies a small degree of extravasation and the infusion should be stopped.

Patients with an increased risk for cardiotoxicity may be considered for treatment with a short infusion over an hour or a continuous infusion for up to 96 hours. In these patients, the ejection fraction should be measured before each course.

Intravesical administration
To avoid undue dilution with urine, the patient should be instructed not to drink any fluid in the 12 hours prior to instillation.
The patient should be rotated a quarter turn every 15 minutes while the drug is in situ.
Exposure to the drug solution for 1 to 2 hours is generally adequate.

Contraindications

Systemic infection
Acute inflammatory cardiac disorders
Breastfeeding
Cardiac failure
Cystitis - if for intravesical use
History of myocardial infarction
Myelosuppression
Pregnancy
Serious cardiac arrhythmias
Severe hepatic impairment
Severe myocardial depression
Urethral stenosis preventing urethral catheterisation-If intravesical use
Urinary tract infection - if for intravesical use

Precautions and Warnings

Children under 15 years
Elderly
Females
History of cardiotoxic drug
History of mediastinal radiotherapy
History of treatment with anthracyclines
Obesity
Within 7 months of discontinuing trastuzumab
Buccal ulceration
Dehydration
End stage renal disease
Hepatic impairment
History of cardiovascular disorder
Hypertension

Administration of live vaccines is not recommended
Advise ability to drive/operate machinery may be affected by side effects
Cardiotoxic -Avoid anthracyclines for up to 7 months after last trastuzumab
Consider reducing initial dose or prolonging dose interval in obese patient
Give pre-treatment counselling and consideration of sperm cryopreservation
Intravesicular: Advise patient not to drink fluids for 12hrs prior to admin
Maintain adequate hydration of patient prior / during treatment
Not all available brands are licensed for all indications
Not all available brands are licensed for all routes of administration
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of anti-cancer drugs
If extravasation occurs follow local policy & seek expert help immediately
Staff: Not to be handled by pregnant staff
Measurement of LV ejection fraction recommended before and during treatment
Monitor cardiac function before and regularly during treatment
Monitor differential WBC count before and during therapy
Monitor haematological parameters before and during treatment
Perform ECG before and during treatment
Perform liver function tests before commencing therapy and during therapy
Monitor patients for signs of tumour lysis syndrome
Monitor uric acid levels
Cardiac failure may occur weeks after administration & may resist treatment
Consider suspending treatment in presence of buccal ulceration
Consider treatments to prevent hyperuricaemia
Potentially leukaemogenic
Risk of cardiomyopathy increases with high cumulative dosage
May colour urine red
Suspend or modify if drug-induced bone marrow depression is detected
Suspend treatment if LVEF below 50% & fall of more than 10% below baseline
Lifetime cumulative dose should be limited to 550mg/m squared
May cause impaired fertility
Male & female: Contraception required during & for 6 months after treatment

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. The risk of delayed cardiomyopathy rises with increasing exposure to doxorubicin. Doxorubicin cardiotoxicity is enhanced by previous or concurrent use of other anthracyclines and anthracenediones (e.g. mitoxantrone).

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.

Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome. Blood uric acid levels, potassium, calcium, phosphate and creatinine should be evaluated after initial treatment.

Pregnancy and Lactation

Pregnancy

Doxorubicin is contraindicated in pregnancy.

Doxorubicin is known to have harmful pharmacological effects in humans when used in pregnancy, including embryotoxicity and the development of structural abnormalities in the developing foetus. Reports have described spontaneous abortion and intrauterine death, but these have been in patients who have received other cytotoxic drugs in conjunction with doxorubicin.

Animal studies have shown doxorubicin to be embryotoxic, teratogenic, and abortifacient. The use of doxorubicin in pregnancy is contraindicated by the manufacturer.

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 14-17 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

Doxorubicin is contraindicated in breastfeeding.

Doxorubicin is known to be excreted in the breast milk. Due to the potential for serious adverse reactions in the nursing infant, it should not be given to nursing mothers.

The effect of concurrent therapies must also be considered.

Lactmed suggests that it may be possible for a woman treated with doxorubicin to breastfeed safely during intermittent therapy by using an appropriate period of breastfeeding abstinence, but did not suggest a duration for this period.

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
Alopecia
Amenorrhoea
Anaemia
Anaphylaxis
Anorexia
Arrhythmias
Asthenia
Atrioventricular block
Azoospermia
Bladder capacity reduced
Bladder irritation
Bone marrow depression
Bradycardia
Bronchospasm
Bundle branch block
Burning pain at injection site
Cardiomyopathy
Cardiotoxicity
Chills
Colitis
Congestive cardiac failure
Conjunctivitis
Decreased ejection fraction
Dehydration
Diarrhoea
Dizziness
Drowsiness
Dyspnoea
Dysuria
ECG changes
Elevation of liver enzymes (transient)
Erythema at injection site
Exanthema
Facial flushing
Fever
Gastric erosions
Gastrointestinal bleeding
Haematuria
Haemorrhage
Haemorrhagic cystitis
Hepatotoxicity
Hot flushes
Hyperuricaemia
Hypoxia
Increased normal tissue reactions to radiation
Infections
Itching
Keratitis
Lacrimation
Leucopenia
Malaise
Mucositis
Myelodysplastic syndrome
Myelosuppression
Nausea
Neutropenia
Oesophagitis
Oligospermia
Onycholysis
Palmar-plantar erythrodysaesthesia
Phlebitis
Phlebosclerosis
Pigmentation of nails, skin and oral mucosa
Pollakiuria
Radiation recall dermatitis
Rash
Red urine
Reduced beard growth
Renal damage
Secondary leukaemia
Sepsis
Septic shock
Septicaemia
Shivering
Shock
Skin reactions
Stinging
Stomatitis
Stranguria
Supraventricular tachycardia
Tachycardia
Thrombocytopenia
Thromboembolism
Thrombophlebitis (injection site)
Tissue necrosis and ulceration with extravasation
Tumour lysis syndrome
Urethral irritation
Urticaria
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 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.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 13th August 2018

Summary of Product Characteristics: Doxorubicin 2mg/ml concentrate for solution for infusion. Seacross Pharmaceuticals Ltd, Revised February 2016.
Summary of Product Characteristics: Doxorubicin 2mg/ml concentrate for solution for infusion. Accord healthcare limited. Revised May 2016.
Summary of Product Characteristics: Doxorubicin 2mg/ml concentrate for solution for infusion. Actavis UK limited. Revised November 2015.
Summary of Product Characteristics: Doxorubicin 2mg/ml concentrate for solution for infusion. Medac GmbH. Revised September 2013.
Summary of Product Characteristics: Doxorubin 10mg, 50mg. Medac GmbH. Revised April 2005.
Summary of Product Characteristics: Doxorubicin Solution for Injection. Pfizer Limited. Revised February 2016.
Summary of Product Characteristics: Doxorubicin 2mg/ml concentrate for solution for infusion. Teva UK limited. Revised January 2001.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Doxorubicin Last revised: 11 April, 2017
Last accessed: 13 August, 2018