PRECAUTIONS General The most consistent, dose-related toxicity is bone marrow suppression. This may be manifest by anemia, leukopenia, thrombocytopenia, or any combination of these. It is imperative that patients be instructed to report promptly the development of fever, sore throat, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Any one of these findings may indicate busulfan toxicity; however, they may also indicate transformation of the disease to an acute “blastic” form. Since busulfan may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large or exceptionally rapid fall in any of the formed elements of the blood. Patients should never be allowed to take the drug without close medical supervision. Seizures have been reported in patients receiving busulfan. As with any potentially epileptogenic drug, caution should be exercised when administering busulfan to patients with a history of seizure disorder, head trauma, or receiving other potentially epileptogenic drugs. Some investigators have used prophylactic anticonvulsant therapy in this setting. Information for Patients Patients beginning therapy with busulfan should be informed of the importance of having periodic blood counts and to immediately report any unusual fever or bleeding. Aside from the major toxicity of myelosuppression, patients should be instructed to report any difficulty in breathing, persistent cough, or congestion. They should be told that diffuse pulmonary fibrosis is an infrequent, but serious and potentially life-threatening complication of long-term busulfan therapy. Patients should be alerted to report any signs of abrupt weakness, unusual fatigue, anorexia, weight loss, nausea and vomiting, and melanoderma that could be associated with a syndrome resembling adrenal insufficiency. Patients should never be allowed to take the drug without medical supervision and they should be informed that other encountered toxicities to busulfan include infertility, amenorrhea, skin hyperpigmentation, drug hypersensitivity, dryness of the mucous membranes, and rarely, cataract formation. Women of childbearing potential should be advised to avoid becoming pregnant. The increased risk of a second malignancy should be explained to the patient. Laboratory Tests It is recommended that evaluation of the hemoglobin or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained weekly while the patient is on busulfan therapy. In cases where the cause of fluctuation in the formed elements of the peripheral blood is obscure, bone marrow examination may be useful for evaluation of marrow status. A decision to increase, decrease, continue, or discontinue a given dose of busulfan must be based not only on the absolute hematologic values, but also on the rapidity with which changes are occurring. The dosage of busulfan may need to be reduced if this agent is combined with other drugs whose primary toxicity is myelosuppression. Occasional patients may be unusually sensitive to busulfan administered at standard dosage and suffer neutropenia or thrombocytopenia after a relatively short exposure to the drug. Busulfan should not be used where facilities for complete blood counts, including quantitative platelet counts, are not available at weekly (or more frequent) intervals. Drug Interactions Busulfan may cause additive myelosuppression when used with other myelosuppressive drugs. In one study, 12 of approximately 330 patients receiving continuous busulfan and thioguanine therapy for treatment of chronic myelogenous leukemia were found to have portal hypertension and esophageal varices associated with abnormal liver function tests. Subsequent liver biopsies were performed in 4 of these patients, all of which showed evidence of nodular regenerative hyperplasia. Duration of combination therapy prior to the appearance of esophageal varices ranged from 6 to 45 months. With the present analysis of the data, no cases of hepatotoxicity have appeared in the busulfan-alone arm of the study. Long-term continuous therapy with thioguanine and busulfan should be used with caution. Busulfan-induced pulmonary toxicity may be additive to the effects produced by other cytotoxic agents. The concomitant systemic administration of itraconazole to patients receiving high-dose MYLERAN may result in reduced busulfan clearance (see CLINICAL PHARMACOLOGY). Patients should be monitored for signs of busulfan toxicity when itraconazole is used concomitantly with MYLERAN. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section. The World Health Organization has concluded that there is a causal relationship between busulfan exposure and the development of secondary malignancies. Pregnancy Teratogenic Effects: Pregnancy Category D. See WARNINGS section. Nonteratogenic Effects: There have been reports in the literature of small infants being born after the mothers received busulfan during pregnancy, in particular, during the third trimester. One case was reported where an infant had mild anemia and neutropenia at birth after busulfan was administered to the mother from the eighth week of pregnancy to term. Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for busulfan in animal and human studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections. Geriatric Use Clinical studies of busulfan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.