Busulfan - Drug Monograph

Introduction

Busulfan is an alkylating antineoplastic agent belonging to the class of nitrogen mustard derivatives. First approved by the FDA in 1954, it remains a cornerstone chemotherapeutic agent primarily used in conditioning regimens prior to hematopoietic stem cell transplantation. Busulfan is classified as a bifunctional alkylating agent that exerts its cytotoxic effects through DNA cross-linking, ultimately leading to cell death.

Mechanism of Action

Busulfan functions as a bifunctional alkylating agent that forms covalent bonds with DNA through its methanesulfonate groups. The drug cross-links DNA strands primarily at guanine N-7 positions, creating intrastrand and interstrand cross-links that disrupt DNA replication and transcription. This DNA damage triggers apoptosis in rapidly dividing cells, particularly hematopoietic stem cells and progenitor cells. Busulfan demonstrates non-cell cycle specific cytotoxicity, meaning it can damage DNA during any phase of the cell cycle.

Indications

• Primary Indication: Myeloablative conditioning prior to allogeneic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia (CML)
• Other Approved Uses:

- Conditioning regimen for patients with other hematologic malignancies undergoing bone marrow transplantation - Palliative treatment of chronic myelogenous leukemia (less common with availability of tyrosine kinase inhibitors)

• Off-label Uses:

- Conditioning for autologous stem cell transplantation - Treatment of other myeloproliferative disorders

Dosage and Administration

• Chronic myelogenous leukemia: 4-8 mg daily (0.06-0.12 mg/kg) until WBC falls to 15,000/mm³
• Transplant conditioning: Weight-based dosing (1 mg/kg every 6 hours for 16 doses)

• Transplant conditioning: 0.8 mg/kg every 6 hours for 16 doses over 4 days
• Based on ideal body weight or actual body weight (whichever is lower)
• Dosing adjustment required for pediatric patients and those with hepatic impairment

• Renal impairment: No specific dose adjustment recommended
• Hepatic impairment: Dose reduction required (25-50% reduction for severe impairment)
• Geriatric patients: Consider reduced dosing due to increased susceptibility to toxicity
• Pediatric patients: Weight-based dosing with careful monitoring

Pharmacokinetics

• Absorption: Oral bioavailability approximately 80-90% with variable absorption
• Distribution: Volume of distribution ~0.8 L/kg; crosses blood-brain barrier and placenta
• Metabolism: Primarily hepatic via glutathione S-transferase-mediated conjugation
• Elimination: Half-life ~2.5 hours; primarily excreted in urine as metabolites
• Non-linear Kinetics: Exhibits dose-dependent clearance, particularly at higher doses

Contraindications

• Hypersensitivity to busulfan or any component of the formulation
• Failure to establish venous access (for IV formulation)
• Pregnancy (unless benefits outweigh risks)
• Lack of adequate contraceptive measures in patients of reproductive potential
• Active uncontrolled infection

Warnings and Precautions

• Myelosuppression (severe and prolonged)
• Hepatic veno-occlusive disease (incidence 8-12%)
• Seizures (prophylactic anticonvulsants required)

• Pulmonary toxicity (busulfan lung)
• Cardiac tamponade
• Ovarian failure and infertility
• Secondary malignancies
• Embryo-fetal toxicity
• Hypersensitivity reactions

Drug Interactions

• Itraconazole: Decreases busulfan clearance by 25%
• Metronidazole: Increases busulfan exposure
• Phenytoin: Increases busulfan clearance by 15% or more
• Acetaminophen: Depletes glutathione, potentially increasing toxicity
• Other myelosuppressive agents: Additive bone marrow suppression

Adverse Effects

• Myelosuppression (100%)
• Nausea/vomiting (70-90%)
• Stomatitis/mucositis (60-80%)
• Anorexia (50-70%)
• Diarrhea (40-60%)
• Hyperpigmentation (30-50%)

• Hepatic veno-occlusive disease (8-12%)
• Seizures (2-4%)
• Pulmonary fibrosis (2-4%)
• Cardiac complications (1-2%)
• Hemorrhagic cystitis (1-2%)
• Secondary malignancies (long-term risk)

Monitoring Parameters

• Complete blood counts (daily during therapy)
• Liver function tests (pre, during, and post-therapy)
• Therapeutic drug monitoring (AUC targeting 900-1500 μM·min)
• Renal function
• Neurological status (seizure monitoring)
• Pulmonary function tests (baseline and as needed)
• Cardiac monitoring in high-risk patients

• Secondary malignancy screening
• Endocrine function (particularly gonadal function)
• Growth and development in pediatric patients
• Ophthalmologic exams (cataract monitoring)

Patient Education

• Importance of strict adherence to dosing schedule
• Need for adequate hydration during treatment
• Recognition of signs of infection (fever, chills)
• Understanding of fertility preservation options
• Awareness of potential long-term effects
• Importance of follow-up care and monitoring
• Contraception requirements during and after treatment
• Management of common side effects (nausea, mucositis)
• When to seek immediate medical attention

References

1. FDA Prescribing Information: Busulfex® (busulfan) Injection 2. Nath CE, Shaw PJ. Busulfan in blood and marrow transplantation: dose, concentration, and outcome. Clin Pharmacokinet. 2016;55(4):439-456. 3. DeLeve LD, et al. Drug-induced liver injury: a clinical and translational research update. Hepatology. 2019;69(2):760-773. 4. McCune JS, et al. Therapeutic drug monitoring of busulfan in hematopoietic stem cell transplantation: systematic review and consensus guidelines. Biol Blood Marrow Transplant. 2018;24(10):2006-2019. 5. National Comprehensive Cancer Network (NCCN) Guidelines: Hematopoietic Cell Transplantation (2023) 6. European Society for Blood and Marrow Transplantation (EBMT) guidelines on conditioning regimens for hematopoietic cell transplantation (2022)