BUSULFAN IS AN ACTIVE CYTOTOXIC AGENT FOR USE ONLY UNDER THE DIRECTION OF PHYSICIANS EXPERIENCED IN THE ADMINISTRATION OF SUCH AGENTS.
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Busulfan should be discontinued if lung toxicity develops (see Adverse Reactions).
Busulfan should not generally be given in conjunction with or soon after radiotherapy.
Busulfan is ineffective once blast transformation has occurred.
If anaesthesia is required in patients with possible pulmonary toxicity, the concentration of inspired oxygen should be kept as low as safely possible and careful attention given to post-operative respiratory care.
Hyperuricaemia and/or hyperuricosuria are not uncommon in patients with chronic myeloid leukaemia and should be corrected before starting treatment with busulfan. During treatment, hyperuricaemia and the risk of uric acid nephropathy should be prevented by adequate prophylaxis, including adequate hydration and the use of allopurinol.
Studies in renally impaired patients have not been conducted, however, as busulfan is moderately excreted in the urine, dose modification is not recommended in these patients. However, caution is recommended.
Busulfan has not been studied in patients with hepatic impairment. Since busulfan is mainly metabolised through the liver, caution should be observed when busulfan is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment.
Conventional dose Treatment: Patients co-administered itraconazole or metronidazole with conventional dose busulfan should be monitored closely for signs of busulfan toxicity. Weekly measurements of blood counts are recommended when co-administering these drugs (see Interactions).
High-Dose Treatment: If high-dose busulfan is prescribed, patients should be given prophylactic anticonvulsant therapy with preferably a benzodiazepine rather than phenytoin (see Adverse Reactions and Interactions).
Concomitant administration of itraconazole or metronidazole with high-dose busulfan has been reported to be associated with an increased risk of busulfan toxicity (see Interactions). Co-administration of metronidazole and high-dose busulfan is not recommended. Co-administration of itraconazole with high-dose busulfan should be at the discretion of the prescribing physician and should be based on a risk/benefit assessment.
Hepatic veno-occlusive disease is a major complication that can occur during treatment with busulfan. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk. (see Adverse Reactions).
A reduced incidence of hepatic veno-occlusive disease and other regimen-related toxicities have been observed in patients treated with busulfan and cyclophosphamide when the first dose of cyclophosphamide has been delayed for more than 24 h after the last dose of busulfan.
Monitoring: Careful attention must be paid in monitoring the blood counts throughout treatment to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia (see Adverse Reactions).
Safe handling of Busulfan Tablets: See Instructions for Use/Handling under Cautions for Usage.
Oogenesis and spermatogenesis: Busulfan interacts with oogenesis and spermatogenesis. It may cause sterility in both sexes. Men treated with busulfan should be informed about sperm preservation prior to treatment (see Fertility under Use in Pregnancy & Lactation and Adverse Reactions).
Ability to perform tasks that require judgement, motor or cognitive skills: There are no data on the effect of busulfan on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.
Mutagenicity: Various chromosome aberrations have been noted in cells from patients receiving busulfan.
Carcinogenicity: On the basis of short-term tests, busulfan has been classified as potentially carcinogenic by the IARC. The World Health Association has concluded that there is a causal relationship between busulfan exposure and cancer.
Widespread epithelial dysplasia has been observed in patients treated with long-term busulfan, with some of the changes resembling pre-cancerous lesions.
A number of malignant tumours have been reported in patients who have received busulfan treatment.
The evidence is growing that busulfan, in common with other alkylating agents, is leukaemogenic. In a controlled prospective study in which two years' busulfan treatment was given as an adjuvant to surgery for lung cancer, long-term follow-up showed an increased incidence of acute leukaemia compared with the placebo-treated group. The incidence of solid tumours was not increased.
Although acute leukaemia is probably part of the natural history of polycythaemia vera, prolonged alkylating agent therapy may increase the incidence.
Very careful consideration should be given to the use of busulfan for the treatment of polycythaemia vera and essential thrombocythaemia in view of the drug's carcinogenic potential. The use of busulfan for these indications should be avoided in younger or asymptomatic patients. If the drug is considered necessary, treatment courses should be kept as short as possible.