Busulfan


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Palliative treatment in chronic myeloid leukaemia Remission induction: Initial: 0.06 mg/kg/day or 1.8 mg/m2/day. Max: 4 mg/day (may be given as a single dose). Dosage may be increased only if response is inadequate after 3 weeks. Usual maintenance dose: 0.5-2 mg/day. Dose adjustment, dosing interruption or discontinuation may be required according to individual haematologic values, safety, and tolerability (refer to detailed product guideline). Polycythemia vera Usual dose: 4-6 mg/day, continued for 4-6 weeks with careful blood count monitoring especially platelet count. Essential thrombocythemia; Myelofibrosis Usual dose: 2-4 mg/day. Conditioning regimens for haematopoietic stem cell transplantation In combination with cyclophosphamide: 1 mg/kg 6 hourly for 4 days, starting 7 days before transplantation. Cyclophosphamide is usually given for 2 days, initiated 24 hours after the final dose of busulfan. IV Conditioning regimens for haematopoietic stem cell transplantation In combination with cyclophosphamide: 0.8 mg/kg (ideal or actual body weight, whichever is lower) 6 hourly given via 2-hour infusion through a central venous catheter for 4 days, starting 7 days before transplantation. Cyclophosphamide is usually given for 2 days, initiated at least 24 hours after the final dose of busulfan. Antineoplastic regimens and dosing recommendations may vary among countries (refer to local treatment protocols).
Dosage Details
Intravenous
Conditioning regimens for haematopoietic stem cell transplantation
Adult: In combination with cyclophosphamide: 0.8 mg/kg (ideal or actual body weight, whichever is lower) 6 hourly given via infusion over 2 hours through a central venous catheter for 4 days, starting 7 days before transplantation. Cyclophosphamide is usually given for 2 days, initiated at least 24 hours after the final dose of busulfan. Antineoplastic regimens and dosing recommendations may vary among countries (refer to local treatment protocols).
Child: In combination with cyclophosphamide or melphalan: 0-17 years Based on actual body weight: <9 kg: 1 mg/kg; 9-<16 kg: 1.2 mg/kg; 16-23 kg: 1.1 mg/kg; >23-34 kg: 0.95 mg/kg; >34 kg: 0.8 mg/kg. All doses are given 6 hourly via infusion over 2 hours through a central venous catheter for 4 days, followed by cyclophosphamide or melphalan initiated at least 24 hours after the final dose of busulfan. Antineoplastic regimens and dosing recommendations may vary among countries (refer to local treatment protocols).

Oral
Chronic myeloid leukaemia
Adult: As palliative treatment: Remission induction: Initially, 0.06 mg/kg daily or 1.8 mg/m2 daily. Max: 4 mg daily (may be given as a single dose). Dosage may be increased only if response is inadequate after 3 weeks. Usual maintenance dose: 0.5-2 mg daily. Dose adjustment, dosing interruption or discontinuation may be required according to individual haematologic values, safety, and tolerability (refer to detailed product guideline).
Child: Same as adult dose.
Elderly: Initiate with the lowest recommended dose.

Oral
Conditioning regimens for haematopoietic stem cell transplantation
Adult: In combination with cyclophosphamide: 1 mg/kg 6 hourly for 4 days, starting 7 days before transplantation. Cyclophosphamide is usually given for 2 days, initiated 24 hours after the final dose of busulfan. Antineoplastic regimens and dosing recommendations may vary among countries (refer to local treatment protocols).
Child: In combination with cyclophosphamide: Max: 37.5 mg/m2 6 hourly for 4 days, starting 7 days before transplantation. Cyclophosphamide is usually given for 2 days, initiated 24 hours after the final dose of busulfan. Antineoplastic regimens and dosing recommendations may vary among countries (refer to local treatment protocols).

Oral
Polycythemia vera
Adult: Usual dose: 4-6 mg daily, continued for 4-6 weeks with careful blood count monitoring especially platelet count. Further courses may be given if relapse occurs; alternatively, maintenance therapy of approx half the induction dose may be given.

Oral
Essential thrombocythemia, Myelofibrosis
Adult: Usual dose: 2-4 mg daily. Dosing interruption may be required according to individual haematologic values, safety, and tolerability (refer to detailed product guideline).
Special Patient Group
Obese patients: Dosage requirements may be based on BSA or adjusted ideal body weight. Refer to product literature for the detailed treatment guideline.

Oral busulfan is indicated for the palliative treatment of chronic myeloid leukaemia. According to the FDA-approved label for oral busulfan, it is less effective in patients with chronic myeloid leukaemia who lack the Philadelphia (Ph1) chromosome. Moreover, the juvenile type of chronic myeloid leukaemia, which usually occurs in children and associated with the absence of Philadelphia chromosome, responds poorly to oral busulfan.
Administration
May be taken with or without food. Take w/ chilled liqd, ensure adequate fluid intake.
Reconstitution
IV infusion: Dilute vial labelled as 60 mg with 0.9% NaCl inj or 5% dextrose in water prior to use. Quantity of diluent must be 10 times the volume of busulfan to ensure a final concentration of approx 0.5 mg/mL. Add busulfan to the diluent; not the diluent to busulfan. Mix by inversion.
Contraindications
Oral: Disease that demonstrated resistance to busulfan; patients without definitive diagnosis of chronic myeloid leukaemia. Lactation.
Special Precautions
Patient with compromised bone marrow reserve due to previous radiation therapy, prior chemotherapy of ≥3 cycles, prior stem cell transplantation; history of seizures, predisposition to seizures, head trauma, receiving epileptogenic drugs; hyperuricaemia or hyperuricosuria, acute porphyria, thalassaemia, Fanconi’s anaemia. Obese patient. Considered ineffective once in blast crisis phase. Premedicate with prophylactic anticonvulsants (e.g. benzodiazepines, levetiracetam) and antiemetics if high-dose treatment for haematopoietic stem cell transplantation (HSCT) is prescribed. Patient with chronic myeloid leukaemia who lacks Philadelphia (Ph1) chromosome. Renal and hepatic impairment. Children and elderly. Pregnancy. Concomitant immunisation using live vaccines during therapy is not recommended.
Adverse Reactions
Significant: Secondary malignancies (e.g. malignant tumours, acute leukaemia, chromosomal alterations); cellular dysplasia in some organs (e.g. giant hyperchromatic nuclei in lymph nodes, adrenal glands, thyroid gland, liver, pancreas, bone marrow); infertility (temporary or permanent), ovarian suppression and amenorrhoea with menopausal symptoms in premenopausal patient; ovarian failure, including failure to achieve puberty in young females; impotence, sterility, azoospermia, and testicular atrophy in males; gastrointestinal toxicity (e.g. nausea, vomiting), seizures (high dose), hyperpigmentation.
Cardiac disorders: Tachycardia, atrial fibrillation, pericarditis, cardiomegaly, arrhythmia, pericardial effusion, chest pain.
Eye disorders: Rarely, cataract, lens disorder, corneal thinning.
Gastrointestinal disorders: Diarrhoea, stomatitis, haematemesis, oesophagitis, dyspepsia, hiccup, constipation, ileus, anorectal discomfort, abdominal pain.
General disorders and administration site conditions: Chills, pyrexia, asthenia, pain or inflammation at inj site, mucositis.
Hepatobiliary disorders: Biliary fibrosis with hepatic atrophy and necrosis; jaundice, ascites, hepatomegaly.
Immune system disorders: Hypersensitivity.
Investigations: Increased transaminases, bilirubin, blood creatinine, BUN and weight; decreased ejection fraction, abnormal breath sounds.
Metabolism and nutrition disorders: Anorexia, hypocalcaemia, hyperglycaemia, hypokalaemia, hypophosphataemia, hyponatraemia, hypomagnesaemia, oedema.
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia, back pain.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Depression, anxiety, insomnia, confusional state.
Renal and urinary disorders: Haemorrhagic cystitis, dysuria, oliguria, haematuria, moderate renal insufficiency.
Respiratory, thoracic and mediastinal disorders: Idiopathic pneumonia syndrome, dyspnoea, cough, epistaxis, rhinitis, pharyngitis, hyperventilation, asthma, atelectasis, pleural effusion.
Skin and subcutaneous tissue disorders: Alopecia, rash, pruritus, desquamation.
Vascular disorders: Hypertension, hypotension, vasodilatation, thrombosis.
Potentially Fatal: Severe and prolonged bone marrow suppression (e.g. leucopenia, thrombocytopenia, neutropenia, anaemia, bone marrow failure, pancytopenia); hyperbilirubinaemia, hepatic sinusoidal obstruction syndrome (formerly hepatic veno-occlusive disease), cardiac tamponade in patient with thalassaemia (high oral dose); thrombotic microangiopathy (high IV dose). Rarely, bronchopulmonary dysplasia with pulmonary fibrosis or “busulfan lung” (prolonged use).
IV/Parenteral/PO: D
MonitoringParameters
Determine pregnancy status before treatment initiation. Monitor CBC with differential and platelet count daily until engraftment for HSCT or weekly for palliative therapy; LFTs (transaminases, alkaline phosphatase, bilirubin) daily for at least 28 days after transplant; cardiac and renal function regularly. Assess for signs and symptoms of sinusoidal obstruction syndrome, cardiac tamponade, adverse haematologic and pulmonary effects during and for several months after treatment. Monitoring of drug levels during conditioning treatment prior to haematopoietic progenitor cell transplantation is recommended.
Overdosage
Symptoms: Myelosuppression and pancytopenia. Management: Supportive treatment. Closely monitor haematologic status. May induce vomiting or perform gastric lavage, then administer charcoal for recent ingestion. May consider haemodialysis and administration of glutathione.
Drug Interactions
Concomitant immunisation with live vaccines may cause infections in immunocompromised patients. Reduced clearance resulting in increased plasma levels and risk of toxicity with itraconazole and metronidazole. Clearance may be decreased by paracetamol and cyclophosphamide. Additive myelosuppression and pulmonary toxicity with other myelosuppressive and cytotoxic agents, respectively. Increased clearance resulting in decreased serum levels with phenytoin. May cause oesophageal varices with tioguanine.
Action
Description: Busulfan is a potent cytotoxic and bifunctional alkylating agent. It reacts with the N-7 position of guanosine and interferes with the replication of deoxyribonucleic acid (DNA) and transcription of ribonucleic acid (RNA) by alkylating and cross-linking the DNA strands.
Synonym: busulphan.
Pharmacokinetics:
Absorption: Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability: Oral: 80% (range: 47-103%). Time to peak plasma concentration: Approx 1 hour (oral); within 5 minutes (IV).
Distribution: Crosses the blood-brain barrier; distributes into CSF with concentrations equal to those in plasma. Volume of distribution: 0.64 ± 0.12 L/kg. Plasma protein binding: Approx 32%, mainly to albumin (irreversible); approx 7% (reversible).
Metabolism: Extensively metabolised in the liver primarily via conjugation with glutathione (either spontaneously or mediated by glutathione-S-transferase); glutathione conjugate undergoes further metabolism via oxidation.
Excretion: Via urine (25-60% mainly as metabolites; <2% as unchanged drug). Elimination half-life: Approx 2-3 hours.
Chemical Structure

Chemical Structure Image
Busulfan

Source: National Center for Biotechnology Information. PubChem Database. Busulfan, CID=2478, https://pubchem.ncbi.nlm.nih.gov/compound/Busulfan (accessed on Jan. 22, 2020)

Storage
Tab: Store between 15-30°C. Vial: Store between 2-8°C. Diluted solution: Store at 25°C for up to 8 hours (diluted in 0.9% NaCl or 5% dextrose in water) or between 2-8°C for up to 12 hours (diluted in 0.9% NaCl); infusion must be completed within the respective stability time. Do not freeze. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
ATC Classification
L01AB01 - busulfan ; Belongs to the class of alkylating agents, alkyl sulfonates. Used in the treatment of cancer.
References
Anon. Busulfan. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 21/01/2016.

Buckingham R (ed). Busulfan. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 21/01/2016.

McEvoy GK, Snow EK, Miller J et al (eds). Busulfan. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 21/01/2016.

Disclaimer: This information is independently developed by MIMS based on Busulfan from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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