Drugs List

Therapeutic Indications

Uses

Conditioning for HPCT following fludarabine, in RIC suitable patients
Conditioning for HPCT in children prior to receiving melphalan
Conditioning for HPCT, prior to receiving cyclophosphamide

Busulfan followed by cyclophosphamide is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.

Busulfan following fludarabine is indicated as conditioning treatment prior to HPCT in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen.

Busulfan followed by cyclophosphamide or melphalan is indicated as conditioning treatment prior to conventional HPCT in paediatric patients.

Administration

Busulfan must be diluted prior to use and administered by intravenous infusion via central venous catheter.

Busulfan in combination with cyclophosphamide or melphalan: Busulfan should be administered as a two hour infusion.

Busulfan in combination with fludarabine: Busulfan should be administered as a three hour infusion.

Contraindications

Children under 18 years with BMI greater than 30kg/m2
Breastfeeding
Porphyria
Pregnancy

Precautions and Warnings

Children under 17 years
History of progenitor cell transplantation
History of radiotherapy
Fanconi's anaemia
Hepatic impairment
History of seizures
Renal impairment

Administration of live vaccines is not recommended
Consider use of anti-infective prophylaxis during neutropenic phase
Give pre-treatment counselling and consideration of sperm cryopreservation
Give prophylactic anti-convulsant 12hrs prior to 24hrs after last dose
Paracetamol should be avoided for 72 hours before and during administration
Pre-medicate with antiemetics & continue according to local protocol
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor cardiac function
Monitor haematological parameters regularly throughout treatment
Monitor hepatic function
Monitor patient for signs and symptoms of respiratory distress
Monitor patients with a history of mediastinal or pulmonary radiation
Monitor renal function
Advise patient to report symptoms of thrombotic microangiopathy
Advise patient to report unexplained fever, sore throat, bruising, bleeding
Consider hepatic veno-occlusive disease if hepatic impairment occurs
Consider treatment with blood growth factors if severe cytopenias develop
Immunosuppressive drugs may increase risk of malignancy
Monitor for signs of hepatotoxicity post transplant
Potentially leukaemogenic
Potentially mutagenic and carcinogenic
Risk of developing opportunistic infections
In obese patients dosing should be based on ideal weight
Not licensed for all indications in all age groups
Male & female: May cause infertility
Male & female: Contraception required during & for 6 months after treatment

Thrombotic microangiopathy and fatalities have been reported after hematopoietic cell transplantation in which high doses of busulfan was administered in combination with another conditioning treatment.

Pregnancy and Lactation

Pregnancy

Busulfan is contraindicated in pregnancy.

At the time of writing there is limited published information regarding the use of busulfan during pregnancy. Congenital abnormalities have been reported with low-dose oral busulfan, though it is unclear if this is attributable to busulfan. Briggs considers busulfan to be teratogenic.

Animal studies on busulfan have shown potential teratogenic effects and impaired fertility in the offspring.

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.

LactMed suggests that it may be possible to breastfeed safely during intermittent therapy by using an appropriate period of breastfeeding abstinence, and cautiously suggests 24 hours or more may be sufficient.

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

Abnormal breath sounds
Agitation
Allergic reaction
Alopecia
Anaemia
Anorexia
Anxiety
Arrhythmias
Arthralgia
Ascites
Asthenia
Asthma
Atelectasis
Atrial fibrillation
Bradycardia
Capillary leak syndrome
Cardiomegaly
Cellulitis
Cerebral haemorrhage
Chills
Confusion
Cough
Decreased ejection fraction
Delirium
Depression
Desquamation
Dizziness
Dyspnoea
Dysuria
Electrolyte disturbances
Enamel hypoplasia
Encephalopathy
Epistaxis
Erythema
Exacerbation of myasthenia gravis
Eye disorder
Febrile neutropenia
Fever
Gastro-intestinal haemorrhage
Gastro-intestinal symptoms
Graft versus host disease
Gynaecomastia
Haematemesis
Haematuria
Haemorrhagic cystitis
Hallucinations
Headache
Hepatic veno-occlusive disease
Hepatomegaly
Hepatotoxicity
Hiccups
Hyperbilirubinaemia
Hyperglycaemia
Hypertension
Hyperventilation
Hypogonadism
Hypotension
Hypoxia
Ileus
Increase in alkaline phosphatase
Increase in blood urea nitrogen
Increase in creatinine
Increases in hepatic enzymes
Infections
Insomnia
Interstitial lung disease
Jaundice
Leucopenia
Local pain (injection site)
Mucositis
Myalgia
Neutropenia
Oedema
Oesophagitis
Oliguria
Ovarian failure
Pain
Pancytopenia
Pericardial effusion
Pericarditis
Pleural effusion
Premature menopause
Pruritus
Pulmonary fibrosis
Pulmonary haemorrhage
Rash
Renal impairment
Respiratory distress syndrome
Respiratory failure
Seizures
Sepsis
Serum bilirubin increased
Skin pigmentation changes
Tachycardia
Thrombocytopenia
Thrombosis
Thrombotic microangiopathy
Vasodilation
Ventricular extrasystoles
Weight gain

Presentation

Parenteral formulations of busulfan.

Drugs List

Therapeutic Indications

Uses

Conditioning for HPCT following fludarabine, in RIC suitable patients
Conditioning for HPCT in children prior to receiving melphalan
Conditioning for HPCT, prior to receiving cyclophosphamide

Busulfan followed by cyclophosphamide is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option.

Busulfan following fludarabine is indicated as conditioning treatment prior to HPCT in adult patients who are candidates for a reduced-intensity conditioning (RIC) regimen.

Busulfan followed by cyclophosphamide or melphalan is indicated as conditioning treatment prior to conventional HPCT in paediatric patients.

Dosage

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

Obese patients, dosing based on adjusted ideal body weight should be considered.

Adults

Children

Administration

Busulfan must be diluted prior to use and administered by intravenous infusion via central venous catheter.

Busulfan in combination with cyclophosphamide or melphalan: Busulfan should be administered as a two hour infusion.

Busulfan in combination with fludarabine: Busulfan should be administered as a three hour infusion.

Contraindications

Children under 18 years with BMI greater than 30kg/m2
Breastfeeding
Porphyria
Pregnancy

Precautions and Warnings

Children under 17 years
History of progenitor cell transplantation
History of radiotherapy
Fanconi's anaemia
Hepatic impairment
History of seizures
Renal impairment

Administration of live vaccines is not recommended
Consider use of anti-infective prophylaxis during neutropenic phase
Give pre-treatment counselling and consideration of sperm cryopreservation
Give prophylactic anti-convulsant 12hrs prior to 24hrs after last dose
Paracetamol should be avoided for 72 hours before and during administration
Pre-medicate with antiemetics & continue according to local protocol
Treatment to be prescribed under the supervision of a specialist
Consult local policy on the safe use of anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor cardiac function
Monitor haematological parameters regularly throughout treatment
Monitor hepatic function
Monitor patient for signs and symptoms of respiratory distress
Monitor patients with a history of mediastinal or pulmonary radiation
Monitor renal function
Advise patient to report symptoms of thrombotic microangiopathy
Advise patient to report unexplained fever, sore throat, bruising, bleeding
Consider hepatic veno-occlusive disease if hepatic impairment occurs
Consider treatment with blood growth factors if severe cytopenias develop
Immunosuppressive drugs may increase risk of malignancy
Monitor for signs of hepatotoxicity post transplant
Potentially leukaemogenic
Potentially mutagenic and carcinogenic
Risk of developing opportunistic infections
In obese patients dosing should be based on ideal weight
Not licensed for all indications in all age groups
Male & female: May cause infertility
Male & female: Contraception required during & for 6 months after treatment

Thrombotic microangiopathy and fatalities have been reported after hematopoietic cell transplantation in which high doses of busulfan was administered in combination with another conditioning treatment.

Pregnancy and Lactation

Pregnancy

Busulfan is contraindicated in pregnancy.

At the time of writing there is limited published information regarding the use of busulfan during pregnancy. Congenital abnormalities have been reported with low-dose oral busulfan, though it is unclear if this is attributable to busulfan. Briggs considers busulfan to be teratogenic.

Animal studies on busulfan have shown potential teratogenic effects and impaired fertility in the offspring.

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.

LactMed suggests that it may be possible to breastfeed safely during intermittent therapy by using an appropriate period of breastfeeding abstinence, and cautiously suggests 24 hours or more may be sufficient.

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

Abnormal breath sounds
Agitation
Allergic reaction
Alopecia
Anaemia
Anorexia
Anxiety
Arrhythmias
Arthralgia
Ascites
Asthenia
Asthma
Atelectasis
Atrial fibrillation
Bradycardia
Capillary leak syndrome
Cardiomegaly
Cellulitis
Cerebral haemorrhage
Chills
Confusion
Cough
Decreased ejection fraction
Delirium
Depression
Desquamation
Dizziness
Dyspnoea
Dysuria
Electrolyte disturbances
Enamel hypoplasia
Encephalopathy
Epistaxis
Erythema
Exacerbation of myasthenia gravis
Eye disorder
Febrile neutropenia
Fever
Gastro-intestinal haemorrhage
Gastro-intestinal symptoms
Graft versus host disease
Gynaecomastia
Haematemesis
Haematuria
Haemorrhagic cystitis
Hallucinations
Headache
Hepatic veno-occlusive disease
Hepatomegaly
Hepatotoxicity
Hiccups
Hyperbilirubinaemia
Hyperglycaemia
Hypertension
Hyperventilation
Hypogonadism
Hypotension
Hypoxia
Ileus
Increase in alkaline phosphatase
Increase in blood urea nitrogen
Increase in creatinine
Increases in hepatic enzymes
Infections
Insomnia
Interstitial lung disease
Jaundice
Leucopenia
Local pain (injection site)
Mucositis
Myalgia
Neutropenia
Oedema
Oesophagitis
Oliguria
Ovarian failure
Pain
Pancytopenia
Pericardial effusion
Pericarditis
Pleural effusion
Premature menopause
Pruritus
Pulmonary fibrosis
Pulmonary haemorrhage
Rash
Renal impairment
Respiratory distress syndrome
Respiratory failure
Seizures
Sepsis
Serum bilirubin increased
Skin pigmentation changes
Tachycardia
Thrombocytopenia
Thrombosis
Thrombotic microangiopathy
Vasodilation
Ventricular extrasystoles
Weight gain

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: October 2018

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.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 17 October 2018

Summary of Product Characteristics: Busilvex 6mg per ml concentrate for solution for infusion. Pierre Fabre Limited. Revised May 2017.

Summary of Product Characteristics: Busulfan 6mg/ml concentrate for solution for infusion. Accord Healthcare Limited. Revised April 2018.

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
Busulfan. Last revised: 1 October 2018
Last accessed: 17 October 2018