Busulfex (Busulfan) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Drug Interactions

Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC > 1500 µM•min in some patients. Fluconazole, and the 5-HT3 antiemetics odansetron (Zofran®) and granisetron (Kytril®) have all been used with BUSULFEX.

Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin, the clearance of BUSULFEX at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin. Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (<72 hours) or concurrent with BUSULFEX may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.

OVERDOSAGE

There is no known antidote to BUSULFEX other than hematopoietic progenitor cell transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for BUSULFEX would constitute an overdose of busulfan. The principal toxic effect is profound bone marrow hypoplasia/aplasia and pancytopenia, but the central nervous system, liver, lungs, and gastro intestinal tract may be affected. The hematologic status should be closely monitored and vigorous supportive measures instituted as medically indicated. Survival after a single 140 mg dose of Myleran® Tablets in an 18 kg, 4-year old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan (2.1 mg/kg; total dose of 23.3 mg/kg) occurred in a 2-year old child prior to a scheduled bone marrow transplant without sequelae. An acute dose of 2.4 g was fatal in a 10-year old boy. There is one report that busulfan is dialyzable, thus dialysis should be considered in the case of overdose. Busulfan is metabolized by conjugation with glutathione, thus administration of glutathione may be considered.

CONTRAINDICATIONS

BUSULFEX is contraindicated in patients with a history of hypersensitivity to any of its components.

References

1. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety, National Institutes of Health; 1983. US Department of Health and Human Services, Public Health Service publication NIH 83-2621.
2. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA 1985; 253:1590-1591.
3. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts  College of Pharmacy and Allied Health Sciences, 179 Longhwood Avenue, Boston, MA  02115.
4. Clinical Oncology Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1983; 1:426-428.
5. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from the Mount Sinai  Medical  Center. CA-A Cancer J for Clin 1983; 33:258-263.
6. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1049.

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