Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Busulfan is indicated as conditioning treatment prior to haemopoietic progenitor cell transplantation in patients when the combination of high-dose busulfan and cyclophosphamide is considered the best available option.
Busulfan is indicated for the palliative treatment of the chronic phase of chronic myeloid leukaemia.
Busulfan is effective in producing prolonged remission in polycythaemia vera, particularly in cases with marked thrombocytosis.
Busulfan may be useful in selected cases of essential thrombocythaemia and myelofibrosis.
The bioavailability of oral Busulfan shows large intra-individual variations ranging from 47% to 103% (mean 80%) in adults and from 22% to 120% (mean 68%) in children (see section 5.2).
There are other formulations available which may be more suitable for paediatric patients.
Busulfan tablets are usually given in courses or administered continuously. The dose must be adjusted for the individual patient under close clinical and haematological control. Should a patient require an average daily dose of less than the content of the available Busulfan tablets, this can be achieved by introducing one or more busulfan free days between treatment days. The tablets should not be divided (see section 6.6).
Dosing based on body surface area or adjusted ideal body weight should be considered in the obese (see section 5.2).
The relevant literature should be consulted for full details of treatment schedules.
When bulsulfan is used as a conditioning treatment prior to haemopoietic progenitor cell transplantation, drug level monitoring is recommended.
Adults: The recommended dose of busulfan in adult patients is 1 mg/kg every 6 hours for four days, starting seven days prior to transplantation. 60 mg/kg per day of cyclophosphamide is usually given for two days commencing 24 h after the final dose of Busulfan (see section 4.4 and 4.5).
Paediatric population: The conventional dosage plan for conditioning before haemopoietic stem cell transplantation is 30 to 37.5 mg/m² every 6 hours for 4 days, starting seven days prior to transplantation. The dosing of cyclophosphamide is the same as for adults.
Treatment is usually initiated as soon as the condition is diagnosed. The dose is 0.06 mg/kg/day, with an initial daily maximum of 4 mg, which may be given as a single dose.
There is individual variation in the response to Busulfan and in a small proportion of patients the bone marrow may be extremely sensitive (see section 4.4).
The blood count must be monitored at least weekly during the induction phase and it may be helpful to plot counts on semilog graph paper.
The dose should be increased only if the response is inadequate after three weeks.
Treatment should be continued until the total leucocyte count has fallen to between 15 and 25 × 109 per litre (typically 12 to 20 weeks). Treatment may then be interrupted, following which a further fall in the leucocyte count may occur over the next two weeks. Continued treatment at the induction dose after this point or following depression of the platelet count to below 100 × 109 per litre is associated with a significant risk of prolonged and possibly irreversible bone marrow aplasia.
Control of the leukaemia may be achieved for long periods without further Busulfan treatment; further courses are usually given when the leucocyte count rises to 50 × 109 per litre, or symptoms return.
Some clinicians prefer to give continuous maintenance therapy. Continuous treatment is more practical when the duration of unmaintained remissions is short.
The aim is to maintain a leucocyte count of 10 to 15 × 109 per litre and blood counts must be performed at least every 4 weeks. The usual maintenance dosage is on average 0.5 to 2 mg/day, but individual requirements may be much less. Should a patient require an average daily dose of less than the content of one tablet, the maintenance dose may be adjusted by introducing one or more Busulfan free days between treatment days.
Note: Lower doses of Busulfan should be used if it is administered in conjunction with other cytotoxic agents (see section 4.5 and 4.8).
Chronic myeloid leukaemia is very rare in the paediatric age group. Busulfan may be used to treat Philadelphia chromosome positive (Ph' positive) disease, but the Ph' negative juvenile variant responds poorly.
The usual dose is 4 to 6 mg daily, continued for 4 to 6 weeks, with careful monitoring of the blood count, particularly the platelet count.
Further courses are given when relapse occurs; alternatively, maintenance therapy may be given using approximately half the induction dose.
If the polycythaemia is controlled primarily by venesection, short courses of Busulfan may be given solely to control the platelet count.
The usual initial dose is 2 to 4 mg daily.
Very careful haematological control is required because of the extreme sensitivity of the bone marrow in this condition.
The usual dose is 2 to 4 mg per day.
Treatment should be interrupted if the total leucocyte count falls below 5 × 109 per litre or the platelet count below 500 × 109 per litre.
The acute dose-limiting toxicity of Busulfan in man is myelosuppression (see section 4.8).
The main effect of chronic overdose is bone marrow depression and pancytopenia.
There is no known antidote to Busulfan. Haemoialysis should be considered in the management of overdose as there is one report of successful haemodialysis of Busulfan.
Appropriate supportive treatment should be given during the period of haematological toxicity.
3 years.
Do not store above 25°C.
Busulfan tablets are supplied in amber glass bottles with a child resistant closure containing 25 or 100 tablets.
The tablets should not be divided and provided the outer coating is intact, there is no risk in handling Busulfan tablets.
Handlers of Busulfan tablets should follow guidelines for the handling of cytotoxic drugs.
Busulfan tablets surplus to requirements should be destroyed in a manner appropriate for the destruction of dangerous substances.
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