BUSULFAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BUSULFAN (BUSULFAN).
Busulfan is a bifunctional alkylating agent that crosslinks DNA, primarily at guanine N7 positions, leading to DNA strand breaks and inhibition of DNA replication and transcription. It is cell cycle phase-nonspecific.
| Metabolism | Hepatic glutathione conjugation (with glutathione S-transferases) and oxidation via cytochrome P450 enzymes (CYP3A4 major contributor). |
| Excretion | Renal (10-50% unchanged), hepatic metabolism (primarily via glutathione S-transferases) with metabolites excreted in bile and urine. Fecal excretion minimal (<5%). |
| Half-life | Terminal elimination half-life is 2.5 to 4 hours (mean ~2.6 hours) after oral administration; prolonged to 3-5 hours with high-dose regimens. Half-life may increase with hepatic impairment. |
| Protein binding | 32-35% reversibly bound to plasma proteins (primarily albumin). Binding is concentration-independent. |
| Volume of Distribution | Approximately 0.6-0.8 L/kg (total body water). Higher in children (0.9-1.2 L/kg). Penetrates CSF (10-50% of plasma concentrations). |
| Bioavailability | Oral: ~80% (range 60-100%) with significant interpatient variability. IV: 100%. |
| Onset of Action | Oral: 2-4 hours for myeloablation; IV: immediate for myeloablation. Antineoplastic effect may take days to weeks. |
| Duration of Action | Myelosuppression persists for 11-30 days after single dose; recovery may take weeks. Conditioning effects last for the duration of the transplant preparative regimen. |
1-4 mg/day orally for remission induction in CML; 0.8-1 mg/kg every 6 hours orally for 4 days as part of myeloablative conditioning with cyclophosphamide.
| Dosage form | INJECTABLE |
| Renal impairment | CrCl 10-50 mL/min: reduce dose by 25-50%; CrCl <10 mL/min: avoid use. |
| Liver impairment | Child-Pugh class A: no adjustment; Child-Pugh B: reduce dose by 25%; Child-Pugh C: avoid use or use extreme caution. |
| Pediatric use | IV: weight-based dosing for myeloablative conditioning: 1.1 mg/kg/dose every 6 hours for 16 doses (total dose 17.6 mg/kg) if weight <12 kg; 0.8 mg/kg/dose for weight 12-30 kg; 0.6 mg/kg/dose for weight >30 kg. Adjust to ideal body weight if obese. |
| Geriatric use | No specific age-based adjustment; reduce dose or prolong interval if renal or hepatic impairment; monitor for myelosuppression and mucositis. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for BUSULFAN (BUSULFAN).
| Breastfeeding | Busulfan is excreted into human breast milk. The M/P ratio has not been determined. Due to potential for severe adverse effects (myelosuppression, carcinogenesis) in the nursing infant, breastfeeding is contraindicated during therapy and for at least 1 week after the last dose. |
| Teratogenic Risk | FDA Pregnancy Category D. There is positive evidence of human fetal risk. First trimester exposure is associated with congenital malformations including cleft palate, eye abnormalities, and skeletal anomalies. Second and third trimester exposure may cause intrauterine growth restriction, bone marrow suppression, and pancytopenia. Use is contraindicated in pregnancy unless no safer alternative exists. |
■ FDA Black Box Warning
WARNING: MYELOSUPPRESSION, HEPATOTOXICITY, AND PULMONARY TOXICITY. Busulfan causes severe and prolonged myelosuppression at high doses. Hepatic veno-occlusive disease (VOD) is a potentially fatal complication. Pulmonary toxicity (interstitial pneumonitis/bronchopulmonary dysplasia) occurs especially with high cumulative doses. Neurotoxicity (seizures) occurs with high doses; prophylactic anticonvulsants recommended. Secondary malignancies reported.
| Serious Effects |
Hypersensitivity to busulfan or any component. Patients with a history of hypersensitivity reaction to busulfan. Not for use in chronic myelogenous leukemia (CML) in chronic phase when conventional therapy is possible (relative). Pregnancy.
| Precautions | Myelosuppression (profound neutropenia, thrombocytopenia, anemia); monitor CBCs. Hepatic VOD: monitor liver function and weight. Pulmonary fibrosis: cumulative dose-related; evaluate for dyspnea, cough. Seizures: prophylactic phenytoin or benzodiazepines recommended, especially with high-dose busulfan. Fetal harm: pregnancy category D. Cardiac arrhythmias, tamponade reported. Mucosal toxicity. Sterility. |
| Food/Dietary |
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| Fetal Monitoring | Monitor maternal complete blood counts (CBC) with differential and platelet count weekly; liver function tests (ALT, AST, bilirubin); serum creatinine; pulmonary function tests (DLCO, FEV1) baseline and periodically. Fetal monitoring includes serial ultrasound for growth, amniotic fluid volume, and anatomy; consider fetal echocardiography. Monitor for signs of fetal distress in third trimester. |
| Fertility Effects | Busulfan causes dose-dependent gonadal toxicity in both sexes. In females, it may induce ovarian failure, amenorrhea, and premature menopause; in males, it can cause azoospermia or oligospermia with permanent sterility. Prepubertal patients may experience delayed or arrested puberty. Gonadal function may not recover. |
| Avoid grapefruit and grapefruit juice during busulfan therapy as they may inhibit CYP3A4, potentially altering busulfan clearance. Avoid alcohol due to hepatotoxicity risk. No other specific food restrictions; maintain adequate hydration. |
| Clinical Pearls | Busulfan is an alkylating agent used primarily in conditioning regimens for hematopoietic stem cell transplantation (HSCT). Monitoring of busulfan plasma levels is recommended for dose adjustment to minimize toxicity, especially hepatic veno-occlusive disease (VOD). Seizure prophylaxis with benzodiazepines (e.g., clonazepam) is required due to busulfan's neurotoxicity at high doses. Administer antiemetics prior to infusion. Busulfan is extensively metabolized via glutathione conjugation; drug interactions with glutathione-modulating agents (e.g., acetaminophen) may alter toxicity. Pulmonary fibrosis is a late complication; monitor for dyspnea and cough. |
| Patient Advice | Take busulfan exactly as prescribed; do not crush or chew tablets. For IV infusion, report any burning or pain at the injection site immediately. · You will receive medications to prevent seizures (e.g., clonazepam) before and during busulfan therapy; do not skip these. · Report immediately any signs of infection (fever, chills), unusual bleeding or bruising, yellowing of skin or eyes, dark urine, or shortness of breath. · Avoid acetaminophen (Tylenol) unless approved by your doctor, as it may increase the risk of liver toxicity. · Do not receive live vaccines during and after treatment without consulting your doctor. · Women of childbearing age must use effective contraception during and for at least 6 months after treatment; busulfan can cause fetal harm. · You may experience nausea, vomiting, or diarrhea; take antiemetics as prescribed and stay hydrated. · Regular blood tests are necessary to monitor blood counts and liver function. |