Drugs List

Therapeutic Indications

Uses

Conditioning prior to haematopoietic progenitor cell transplantation
Leukaemia - chronic granulocytic
Management of thrombocythemia
Myelofibrosis
Treatment of polycythemia vera

Conditioning treatment prior to haematopoietic progenitor cell transplantation
Palliative treatment of the chronic phase of chronic granulocytic leukaemia
Treatment of polycythemia vera, particularly in cases with marked thrombocytosis
Treatment of selected cases of essential thrombocythaemia
Treatment of selected cases of myelofibrosis

Administration

As the tablets should not be halved or otherwise divided, should the patient require a daily dose of less than the content of 1 tablet, the dose should be adjusted by introducing one or more busulfan free days.

Contraindications

Breastfeeding
Porphyria
Pregnancy

Precautions and Warnings

Concurrent radiotherapy
History of progenitor cell transplantation
History of radiotherapy
Fanconi's anaemia
Hepatic impairment
History of seizures
Hyperuricaemia
Renal impairment

Administration of live vaccines is not recommended
Consider use of anti-infective prophylaxis during neutropenic phase
Correct hyperuricaemia before treatment
Correct hyperuricosuria before treatment
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor haematological parameters regularly throughout treatment
Monitor hepatic function
Consider hepatic veno-occlusive disease if hepatic impairment occurs
Consider treatment with blood growth factors if severe cytopenias develop
Consider treatments to prevent hyperuricaemia
Monitor for signs of hepatotoxicity post transplant
Potentially leukaemogenic
Potentially mutagenic and carcinogenic
Discontinue if pulmonary toxicity occurs
Consider prophylactic anti-convulsant with high dose therapy
In obese patients dosing should be based on ideal weight
Advise patient not to take paracetamol during treatment
Male & female: May cause infertility
Male & female: Contraception required during & for 6 months after treatment

Hepatic veno-occlusive disease can occur during busulfan therapy. Patients who have received prior radiation therapy (three cycles of chemotherapy or more), or prior progenitor cell transplantation may be at an increased risk. A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with high dose busulfan and cyclophosphamide, when the first dose of cyclophosphamide has been delayed for more than 24 hours after the last dose of busulfan.

Due to the carcinogenic potential of busulfan, careful consideration should be given to the use of busulfan for the treatment of polycythaemia and essential thrombocythaemia. The use of busulfan for these indications should be avoided in younger or asymptomatic patients. Where busulfan treatment is considered necessary, courses should be kept as short as possible.

Busulfan is considered to be unsafe in patients with porphyria because it has been shown to be porphyrogenic in animals.

Blood count monitoring
Regular monitoring is advised, specific recommendations vary by condition.

Chronic granulocytic leukaemia:
Induction: Monitored at least weekly.
Maintenance: Monitor at least every 4 weeks.

Polycythemia vera: Monitor carefully particularly platelet counts.

Myelofibrosis: Monitor carefully due to the extreme sensitivity of the bone marrow.

Pregnancy and Lactation

Pregnancy

Contraindicated in pregnancy.

There are no adequate studies of busulfan in pregnant women, however, in pre-clinical studies busulfan has caused malformations. A few cases of congenital abnormalities have been reported with low-dose oral busulfan, although not necessarily attributable to the active substance, and third trimester exposure may be associated with impaired intrauterine growth.

Animal studies have shown busulfan has the potential for teratogenic effects whilst exposure during the later stages of pregnancy has resulted in impairment of fertility in the offspring.

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

Busulfan is contraindicated in breastfeeding.

It is not known whether busulfan or its metabolites are excreted in human breast milk. However, due to the potential for serious toxicity in the nursing infant it is recommended that breastfeeding is discontinued during treatment.

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

Acute leukaemia
Alopecia
Amenorrhoea
Anorexia
Aplastic anaemia
Azoospermia
Cardiac tamponade
Cataracts
Cheilitis
Cholestatic jaundice
Convulsions
Corneal thinning
Cough
Diarrhoea
Dry mucous membranes
Dry skin
Dyspnoea
Dystrophic calcification
Epithelial dysplasia
Erythema multiforme
Erythema nodosum
Exacerbation of myasthenia gravis
Fatigue
Gynaecomastia
Haemorrhagic cystitis
Hepatic fibrosis
Hepatic veno-occlusive disease
Hepatocellular atrophy
Hepatocellular necrosis
Hyperbilirubinaemia
Hyperpigmentation of skin
Hypoxia
Interstitial pneumonitis
Jaundice
Lens changes
Leukopenia
Liver function disturbances
Menopausal-like symptoms
Mouth ulcers
Nausea
Ovarian failure
Pneumonia
Porphyria
Pulmonary fibrosis
Pulmonary ossification
Rash
Sjogren's syndrome
Sterility
Testicular atrophy
Thrombocytopenia
Urticaria
Vomiting
Weakness
Weight loss

Presentation

Busulfan oral formulations

Drugs List

Therapeutic Indications

Uses

Conditioning prior to haematopoietic progenitor cell transplantation
Leukaemia - chronic granulocytic
Management of thrombocythemia
Myelofibrosis
Treatment of polycythemia vera

Conditioning treatment prior to haematopoietic progenitor cell transplantation
Palliative treatment of the chronic phase of chronic granulocytic leukaemia
Treatment of polycythemia vera, particularly in cases with marked thrombocytosis
Treatment of selected cases of essential thrombocythaemia
Treatment of selected cases of myelofibrosis

Dosage

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

Patients treated with high dose busulfan should be given prophylactic anticonvulsant therapy, preferably with a benzodiazepine rather than phenytoin.

Busulfan is ineffective once blast transformation has occurred.

Adults

Elderly

Children

Administration

As the tablets should not be halved or otherwise divided, should the patient require a daily dose of less than the content of 1 tablet, the dose should be adjusted by introducing one or more busulfan free days.

Contraindications

Breastfeeding
Porphyria
Pregnancy

Precautions and Warnings

Concurrent radiotherapy
History of progenitor cell transplantation
History of radiotherapy
Fanconi's anaemia
Hepatic impairment
History of seizures
Hyperuricaemia
Renal impairment

Administration of live vaccines is not recommended
Consider use of anti-infective prophylaxis during neutropenic phase
Correct hyperuricaemia before treatment
Correct hyperuricosuria before treatment
Give pre-treatment counselling and consideration of sperm cryopreservation
Maintain adequate hydration of patient prior / during treatment
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor haematological parameters regularly throughout treatment
Monitor hepatic function
Consider hepatic veno-occlusive disease if hepatic impairment occurs
Consider treatment with blood growth factors if severe cytopenias develop
Consider treatments to prevent hyperuricaemia
Monitor for signs of hepatotoxicity post transplant
Potentially leukaemogenic
Potentially mutagenic and carcinogenic
Discontinue if pulmonary toxicity occurs
Consider prophylactic anti-convulsant with high dose therapy
In obese patients dosing should be based on ideal weight
Advise patient not to take paracetamol during treatment
Male & female: May cause infertility
Male & female: Contraception required during & for 6 months after treatment

Hepatic veno-occlusive disease can occur during busulfan therapy. Patients who have received prior radiation therapy (three cycles of chemotherapy or more), or prior progenitor cell transplantation may be at an increased risk. A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with high dose busulfan and cyclophosphamide, when the first dose of cyclophosphamide has been delayed for more than 24 hours after the last dose of busulfan.

Due to the carcinogenic potential of busulfan, careful consideration should be given to the use of busulfan for the treatment of polycythaemia and essential thrombocythaemia. The use of busulfan for these indications should be avoided in younger or asymptomatic patients. Where busulfan treatment is considered necessary, courses should be kept as short as possible.

Busulfan is considered to be unsafe in patients with porphyria because it has been shown to be porphyrogenic in animals.

Blood count monitoring
Regular monitoring is advised, specific recommendations vary by condition.

Chronic granulocytic leukaemia:
Induction: Monitored at least weekly.
Maintenance: Monitor at least every 4 weeks.

Polycythemia vera: Monitor carefully particularly platelet counts.

Myelofibrosis: Monitor carefully due to the extreme sensitivity of the bone marrow.

Pregnancy and Lactation

Pregnancy

Contraindicated in pregnancy.

There are no adequate studies of busulfan in pregnant women, however, in pre-clinical studies busulfan has caused malformations. A few cases of congenital abnormalities have been reported with low-dose oral busulfan, although not necessarily attributable to the active substance, and third trimester exposure may be associated with impaired intrauterine growth.

Animal studies have shown busulfan has the potential for teratogenic effects whilst exposure during the later stages of pregnancy has resulted in impairment of fertility in the offspring.

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

Busulfan is contraindicated in breastfeeding.

It is not known whether busulfan or its metabolites are excreted in human breast milk. However, due to the potential for serious toxicity in the nursing infant it is recommended that breastfeeding is discontinued during treatment.

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

Acute leukaemia
Alopecia
Amenorrhoea
Anorexia
Aplastic anaemia
Azoospermia
Cardiac tamponade
Cataracts
Cheilitis
Cholestatic jaundice
Convulsions
Corneal thinning
Cough
Diarrhoea
Dry mucous membranes
Dry skin
Dyspnoea
Dystrophic calcification
Epithelial dysplasia
Erythema multiforme
Erythema nodosum
Exacerbation of myasthenia gravis
Fatigue
Gynaecomastia
Haemorrhagic cystitis
Hepatic fibrosis
Hepatic veno-occlusive disease
Hepatocellular atrophy
Hepatocellular necrosis
Hyperbilirubinaemia
Hyperpigmentation of skin
Hypoxia
Interstitial pneumonitis
Jaundice
Lens changes
Leukopenia
Liver function disturbances
Menopausal-like symptoms
Mouth ulcers
Nausea
Ovarian failure
Pneumonia
Porphyria
Pulmonary fibrosis
Pulmonary ossification
Rash
Sjogren's syndrome
Sterility
Testicular atrophy
Thrombocytopenia
Urticaria
Vomiting
Weakness
Weight loss

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.

BNF for Children (2013-2014) 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.

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Summary of Product Characteristics: Busulfan tablets 2mg. Aspen Pharma Trading. Revised January 2013

N.A.P.O.S. The Drug Database for Acute Porphyria
Available at: https://www.drugs-porphyria.com/languages/UnitedKingdom/s1.php?l=gbr
Last accessed: August 13, 2013