busulfan (Rx)

>10%

Neutropenia (nearly 100%)

Myelosuppression (nearly 100%)

Thrombocytopenia (98%)

Nausea (97%)

Stomatitis (96%)

Anorexia (80%)

Diarrhea (80%)

Fever (80%)

Insomnia (80%)

Lymphopenia (79%)

Hypomagnesemia (77%)

Headache (69%)

Hyperglycemia (66%)

Hypokalemia (64%)

Abdominal pain (62%)

Anemia (62%)

Asthenia (52%)

Hypocalcemia (49%)

Chills (47%)

Dyspepsia (44%)

Tachycardia (44%)

Pain (41%)

Constipation (38%)

Hypertension (36%)

Hypersensitivity (32%)

Edema (27%)

Thrombosis (27%)

Dry mouth (26%)

Vasodilation (25%)

Mild epistaxis (25%)

Inflammation at injection site (25%)

Rectal disorder (25%)

Abdominal enlargement (23%)

Back pain (23%)

Chest pain (22%)

1-10%

Grade 3/4 Hypertension (7%, IV)

Hypotension (3%, IV)

Cardiac tamponade (2%, oral)

Third degree AV block (2%, IV)

Left heart failure (2%, IV)

Frequency Not Defined

Dizziness

Anxiety

Depression

Seizure

Cough

Dyspnea

Rhinitis

Bronchopulmonary dysplasia with pulmonary fibrosis (rare)

Aplastic anemia (rare)

Leukemia (rare)

Graft versus host disease

Adrenal gland disorder

Pruritis

Rash

Cataract

Hemorrhagic cystitis

Amenorrhea

Male infertility

Ovarian dysfunction

Postmarketing Reports

Febrile neutropenia

Tumor lysis syndrome

Thrombotic micro-angiopathy (TMA)

Severe bacterial, viral (eg, cytomegalovirus viremia), fungal infections, and sepsis

Tooth hypoplasia

Contraindications

Hypersensitivity, resistance to busulfan

Patients without definitive diagnosis of CML

Cautions

Bone marrow depression may occur

Seizures reported with use; initiate anticonvulsant prophylactic therapy prior to treatment with busulfan; monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs

Cardiac temponade reported in children with thalassemia in combination with cyclophosphamide

Ovarian failure may occur

Secondary malignancies reported

Antiemetics may be recommended to prevent nausea and vomiting

Increased risk of developing hepatic veno-occlusive disease (HVOD) at AUC greater than 1,500 μM•min; monitor serum transaminases, alkaline phosphatase and bilirubin daily

Bronchopulmonary dysplasia with pulmonary fibrosis reported and can be fatal; toxicity may be additive if used with other agents that cause pulmonary toxicity; discontinue therapy if busulfan toxicity develops

Avoid pregnancy; can cause fetal harm; advise of potential risk to a fetus and use of effective contraception

Pregnancy

Can cause fetal harm when administered to a pregnant woman based on animal data; drug shown to be teratogenic in mice, rats, and rabbits following administration during organogenesis; the solvent, DMA, may also cause fetal harm when administered to a pregnant woman; in rats, DMA doses of approximately 40% of daily dose of DMA in dose on a mg/m² basis given during organogenesis caused significant developmental anomalies; there are no available human data informing drug-associated risk; advise pregnant women of potential risk to a fetus

Advise females of reproductive potential to use effective contraception during treatment and for 6 months following cessation of therapy

May damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities; males with female sexual partners of reproductive potential should use effective contraception during treatment and for 3 months after cessation of therapy

Infertility

• Females: Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia; therapy may also cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose busulfan in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation
• Males: Sterility, azoospermia, and testicular atrophy reported in male patients

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Alkylating agent; interferes with DNA replication and RNA transcription; cross-links DNA strands; has little immunosuppressive activity; affects myeloid cells more than lymphoid cells; very toxic to hematopoietic stem cells

Absorption

Onset: 1-2 weeks

Duration: 24 hr

Time to peak serum: 1hr (PO); 5 min (IV)

Bioavailability: 68-80% depending on age

Distribution

Protein bound: 32%

Vd: 0.6-1.0 L/kg (adults); 1.4-1.6 L/kg (children)

Metabolism

Liver

Metabolites: Methanesulfonic acid & 3-hydroxytetrahydrothiophene-1,1-dioxide

Elimination

Half-life elimination: 2.5 hr

Clearance: 2.52 mL/min/kg

Excretion: Urine (25-60%)

Dialyzable: Yes

IV Preparation

Dilute and administer as intravenous infusion; do not administer as intravenous push or bolus

Do not infuse other medications simultaneously

Dilute busulfan injection in NS or D5W; do not use other diluents

Dilution volume should be 10x volume of busulfan concentrate, insuring final concentration is equal to or >0.5 mg/mL

IV Administration

Administer via a central venous catheter as a 2 hr infusion, q6hr for 4 consecutive days for a total of 16 doses

Do not use polycarbonate syringes

Storage

Store unopened ampules (injection) under refrigeration at 2-8°C

Prolonged storage (>8 hr) in D5W or NS at room temp causes 10%+ loss of potency