No

Antineoplastic Agent, Alkylating Agent

Oral: Chronic myelogenous leukemia and bone marrow disorders, such as polycythemia vera and myeloid metaplasia, conditioning regimens for bone marrow transplantation

I.V.: Combination therapy with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia

D

Failure to respond to previous courses; should not be used in pregnancy or lactation; hypersensitivity to busulfan or any component

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. May induce severe bone marrow hypoplasia; reduce or discontinue dosage at first sign, as reflected by an abnormal decrease in any of the formed elements of the blood; use with caution in patients recently given other myelosuppressive drugs or radiation treatment. If white blood count is high, hydration and allopurinol should be employed to prevent hyperuricemia. Use caution in patients predisposed to seizures. Discontinue if lung toxicity develops. Busulfan has been causally related to the development of secondary malignancies (tumors and acute leukemias). Busulfan has been associated with ovarian failure (including failure to achieve puberty) in females.

>10%:

Dermatologic: Urticaria, erythema, alopecia

Endocrine & metabolic: Ovarian suppression, amenorrhea, sterility

Genitourinary: Azoospermia, testicular atrophy; malignant tumors have been reported in patients on busulfan therapy

Hematologic: Severe pancytopenia, leukopenia, thrombocytopenia, anemia, and bone marrow suppression are common and patients should be monitored closely while on therapy; since this is a delayed effect (busulfan affects the stem cells), the drug should be discontinued temporarily at the first sign of a large or rapid fall in any blood element; some patients may develop bone marrow fibrosis or chronic aplasia which is probably due to the busulfan toxicity; in large doses, busulfan is myeloablative and is used for this reason in BMT

Myelosuppressive:

WBC: Moderate

Platelets: Moderate

Onset (days): 7-10

Nadir (days): 14-21

Recovery (days): 28

1% to 10%:

Dermatologic: Skin hyperpigmentation (busulfan tan)

Gastrointestinal: Nausea, vomiting, diarrhea; drug has little effect on the GI mucosal lining; however, mucosal toxicity (mucositis) has been observed in high-dose therapy associated with bone marrow transplant

Emetic potential: Low (<10%)

Hepatic: Elevated LFTs

Neuromuscular & skeletal: Weakness

Ocular: Cataracts

<1%: Generalized or myoclonic seizures and loss of consciousness have been associated with busulfan, endocardial fibrosis, adrenal suppression, gynecomastia, hyperuricemia, isolated cases of hemorrhagic cystitis have been reported, hepatic dysfunction, hepatic veno-occlusive disease (usually reported in patients receiving other chemotherapy), hepatocellular necrosis, centrilobular fibrosis, hyperbilirubinemia, cataracts, corneal thinning, lens changes, blurred vision, aplastic anemia, mucositis, sepsis, rash, radiosensitization; after long-term or high-dose therapy, a syndrome known as busulfan lung may occur; busulfan lung syndrome is manifested by a diffuse interstitial pulmonary fibrosis and persistent cough, fever, rales, and dyspnea. Busulfan should be discontinued if this toxicity develops. May be relieved by corticosteroids.

Symptoms of overdose include leukopenia, thrombocytopenia

Induction of vomiting or gastric lavage with charcoal is indicated for recent ingestions; the effects of dialysis are unknown

CYP3A3/4 enzyme substrate

Other cytotoxic agents: Pulmonary toxicity may be additive.

Store unopened ampuls under refrigeration at 2°C to 8°C/36°F to 46°F

Reacts with N-7 position of guanosine and interferes with DNA replication and transcription of RNA. Busulfan has a more marked effect on myeloid cells (and is, therefore, useful in the treatment of CML) than on lymphoid cells. The drug is also very toxic to hematopoietic stem cells (thus its usefulness in high doses in BMT preparative regimens). Busulfan exhibits little immunosuppressive activity. Interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA.

Duration: 28 days

Absorption: Rapidly and completely from the GI tract

Distribution: V_d: ~1 L/kg; distributed into the CSF and saliva with levels similar to plasma

Protein binding: ~14%

Metabolism: Extensive in the liver (may increase with multiple dosing)

Half-life: After first dose: 3.4 hours; After last dose: 2.3 hours

Time to peak serum concentration: Oral: Within 4 hours; I.V.: Within 5 minutes

Elimination: 10% to 50% excreted in the urine as metabolites within 24 hours; <2% seen as unchanged drug

Busulfan should be based on adjusted ideal body weight because actual body weight, ideal body weight, or other factors can produce significant differences in busulfan clearance among lean, normal, and obese patients

Children:

For remission induction of CML: 0.06-0.12 mg/kg/day OR 1.8-4.6 mg/m²/day; titrate dosage to maintain leukocyte count above 40,000/mm³; reduce dosage by 50% if the leukocyte count reaches 30,000-40,000/mm³; discontinue drug if counts fall to less than or equal to 20,000/mm³

BMT marrow-ablative conditioning regimen: 1 mg/kg/dose (ideal body weight) every 6 hours for 16 doses

Adults:

BMT marrow-ablative conditioning regimen: 1 mg/kg/dose (ideal body weight) every 6 hours for 16 doses

Remission: Induction of CML: 4-8 mg/day (may be as high as 12 mg/day); Maintenance doses: Controversial, range from 1-4 mg/day to 2 mg/week; treatment is continued until WBC reaches 10,000-20,000 cells/mm³ at which time drug is discontinued; when WBC reaches 50,000/mm³, maintenance dose is resumed

Unapproved uses:

Polycythemia vera: 2-6 mg/day

Thrombocytosis: 4-6 mg/day

I.V.: 0.8 mg/kg (ideal body weight or actual body weight, whichever is lower) every 6 hours for 4 days (a total of 16 doses)

I.V. dosing in morbidly obese patients: Dosing should be based on adjusted ideal body weight (AIBW) which should be calculated as ideal body weight (IBW) + 0.25 times (actual weight minus ideal body weight)

AIBW = IBW + 0.25 x (AW - IBW)

Cyclophosphamide, in combination with busulfan, is given on each of two days as a 1-hour infusion at a dose of 160 mg/m² beginning on day 3, 6 hours following the 16th dose of busulfan

No clear or firm data on the effect of food on busulfan bioavailability

CBC with differential and platelet count, hemoglobin, liver function tests

None reported

May cause severe pancytopenia; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Take oral medication as directed with chilled liquids. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) to help prevent kidney complications. Avoid alcohol, acidic or spicy foods, aspirin or OTC medications unless approved by prescriber. Brush teeth with soft toothbrush or cotton swab. You may lose head hair or experience darkening of skin color (reversible when medication is discontinued), amenorrhea, sterility, or skin rash. You may experience nausea, vomiting, anorexia, or constipation (small frequent meals, increased exercise, and increased dietary fruit or fiber may help). You will be more susceptible to infection (avoid crowds or contagious persons, and do not receive any vaccinations unless approved by prescriber). Report palpitations or chest pain, excessive dizziness, confusion, respiratory difficulty, numbness or tingling of extremities, unusual bruising or bleeding, pain or changes in urination, or other adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a female to become pregnant. Male/female: Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.

Avoid I.M. injection if platelet count falls <100,000/mm³

Monitor CBC with differential and platelet count, hemoglobin, liver function tests

Injection: 60 mg/10 mL ampuls

Tablet: 2 mg

Buggia I, Locatelli F, Regazzi MB, et al, "Busulfan," Ann Pharmacother, 1994, 28(9):1055-62.

Heard BE and Cooke RA, "Busulphan Lung," Thorax, 1968, 23(2):187-93.

Hutchins LF and Lipschitz DA, "Cancer, Clinical Pharmacology, and Aging," Clin Geriatr Med, 1987, 3(3):483-503.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Kaplan HG, "Use of Cancer Chemotherapy in the Elderly," Drug Treatment in the Elderly, Vestal RE, ed, Boston, MA: ADIS Health Science Press, 1984, 338-49.

Ljungman P, Hassan M, Bekassy AN, et al, "Busulfan Concentration in Relation to Permanent Alopecia in Recipients of Bone Marrow Transplants," Bone Marrow Transplant, 1995, 15(6):869-71.

Marcus RE and Goldman JM, "Convulsions Due to High-Dose Busulphan," Lancet, 1984, 2(8417-18):1463.

Morris LE and Guthrie TH Jr, "Busulfan-Induced Hepatitis," Am J Gastroenterol, 1988, 83(6):682-3.

Ozkaynak MF, Weinberg K, Kohn D, et al, "Hepatic Veno-Occlusive Disease Postbone Marrow Transplantation in Children Conditioned With Busulfan and Cyclophosphamide: Incidence, Risk Factors, and Clinical Outcome," Bone Marrow Transplant, 1991, 7(6):467-74.

Regazzi MB, Locatelli F, Buggia I, et al, "Disposition of High-Dose Busulfan in Pediatric Patients Undergoing Bone Marrow Transplantation," Clin Pharmacol Ther, 1993, 54(1):45-52.

Vassal G, Gouyette A, Hartmann O, et al, "Pharmacokinetics of High-Dose Busulfan in Children," Cancer Chemother Pharmacol, 1989, 24(6):386-90.