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Busulfan


Pronunciation

 (byoo SUL fan)


U.S. Brand Names

 Busulfex®; Myleran®


Generic Available

 No


Canadian Brand Names

 Busulfex®; Myleran®


Use

Oral: Chronic myelogenous leukemia; 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


Use - Unlabeled/Investigational

 Oral: Bone marrow disorders, such as polycythemia vera and myeloid metaplasia; thrombocytosis


Pregnancy Risk Factor

 D


Lactation

 Contraindicated


Contraindications

 Hypersensitivity to busulfan or any component of the formulation; failure to respond to previous courses; pregnancy


Warnings/Precautions

 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. High busulfan area under the concentration versus time curve (AUC) values (>1500 M/minute) are associated with increased risk of hepatic veno-occlusive disease during conditioning for allogenic BMT.


Adverse Reactions

Fertility/carcinogenesis: Sterility, ovarian suppression, amenorrhea, azoospermia, and testicular atrophy; malignant tumors have been reported in patients on busulfan therapy.

>10%: 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: 7-10 days

Nadir: 14-21 days

Recovery: 28 days

1% to 10%:

Dermatologic: Hyperpigmentation skin (busulfan tan), urticaria, erythema, alopecia

Endocrine & metabolic: Amenorrhea

Gastrointestinal: Nausea, vomiting, diarrhea; drug has little effect on the GI mucosal lining

Neuromuscular & skeletal: Weakness

<1%:

Cardiovascular: Endocardial fibrosis

Endocrine & metabolic: Adrenal suppression, gynecomastia, hyperuricemia

Genitourinary: Isolated cases of hemorrhagic cystitis have been reported

Hepatic: Hepatic dysfunction

Ocular: Blurred vision, cataracts

Respiratory: After long-term or high-dose therapy, a syndrome known as "busulfan lung" may occur. This syndrome is manifested by a diffuse interstitial pulmonary fibrosis and persistent cough, fever, rales, and dyspnea. May be relieved by corticosteroids.


Overdosage/Toxicology

 Symptoms of overdose include leukopenia and thrombocytopenia. Induction of vomiting or gastric lavage with charcoal is indicated for recent ingestion; the effects of dialysis are unknown.


Drug Interactions

 Substrate of CYP3A4 (major)

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of busulfan. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of busulfan. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Itraconazole: May increase risk of pulmonary toxicity; monitor.

Metronidazole: May increase busulfan plasma levels.

Other cytotoxic agents: Pulmonary toxicity may be additive.


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol due to GI irritation.

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

Herb/Nutraceutical: St John's wort may decrease busulfan levels.


Stability

 Store unopened ampuls under refrigeration at 2°C to 8°C (36°F to 46°F).

Filter busulfan using the 5 micron syringe filter provided, using one filter per ampul. If using the enclosed syringe filter in the forward flow direction, allow for ~0.16 mL of residual busulfan to remain in the filter. Dilute busulfan injection in 0.9% sodium chloride injection or dextrose 5% in water. The dilution volume should be ten times the volume of busulfan injection, ensuring that the final concentration of busulfan is 0.5 mg/mL. This solution is stable for up to 8 hours at room temperature (25°C) but the infusion must also be completed within that 8-hour time frame. Dilution of busulfan injection in 0.9% sodium chloride is stable for up to 12 hours at refrigeration (2°C to 8°C) but the infusion must also be completed within that 12-hour time frame. Do not use polycarbonate syringes.


Compatibility

 Variable stability (consult detailed reference) in D5W, NS


Mechanism of Action

 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.


Pharmacodynamics/Kinetics

Duration: 28 days

Absorption: Rapid and complete

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

Protein binding: ~14%

Metabolism: Extensively hepatic (may increase with multiple doses)

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

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

Excretion: Urine (10% to 50% as metabolites) within 24 hours (<2% as unchanged drug)


Dosage

 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; refer to individual protocols

Children:

For remission induction of CML: Oral: 0.06-0.12 mg/kg/day OR 1.8-4.6 mg/m 2 /day; titrate dosage to maintain leukocyte count above 40,000/mm 3 ; reduce dosage by 50% if the leukocyte count reaches 30,000-40,000/mm 3 ; discontinue drug if counts fall to 20,000/mm 3

BMT marrow-ablative conditioning regimen:

Oral: 1 mg/kg/dose (ideal body weight) every 6 hours for 16 doses

I.V.:

12 kg: 1.1 mg/kg/dose (ideal body weight) every 6 hours for 16 doses

>12 kg: 0.8 mg/kg/dose (ideal body weight) every 6 hours for 16 doses

Adjust dose to desired AUC [1125 mol(min)] using the following formula:

Adjusted dose (mg) = Actual dose (mg) x [target AUC mol(min) / actual AUC mol(min)]

Adults:

For remission induction of CML: Oral: 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/mm 3 at which time drug is discontinued; when WBC reaches 50,000/mm 3 , maintenance dose is resumed

BMT marrow-ablative conditioning regimen:

Oral: 1 mg/kg/dose (ideal body weight) every 6 hours for 16 doses

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)

Polycythemia vera (unlabeled use): Oral: 2-6 mg/day

Thrombocytosis (unlabeled use): Oral: 4-6 mg/day


Administration

 Intravenous busulfan should be administered via a central venous catheter as a 2-hour infusion, every 6 hours for 4 consecutive days for a total of 16 doses; do not use polycarbonate syringes.

BMT only: Phenytoin or clonazepam should be administered prophylactically during and for at least 48 hours following completion of busulfan. Risk of seizures is increased in patients with sickle cell disease. Increased risk of VOD when busulfan AUC >3000 mol(min)/L (mean AUC, 2012 mol(min)/L). To facilitate ingestion of high doses, insert multiple tablets into clear gel capsules.


Monitoring Parameters

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


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take oral medication as directed with chilled liquids. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Avoid alcohol and acidic or spicy foods. You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations unless approved by prescriber). May cause mouth sores (brush teeth with soft toothbrush or cotton swab); loss of hair or darkening of skin color (reversible when medication is discontinued); nausea, vomiting, or anorexia (small, frequent meals, chewing gum, or sucking hard candy may help); constipation (increased exercise, fruit, fluids, or fiber may help); amenorrhea; sterility; or skin rash. 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. Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 None reported


Mental Health: Effects on Psychiatric Treatment

 May cause severe pancytopenia; use caution with clozapine and carbamazepine


Oncology: Emetic Potential

 Low (<10%)


Oncology: Bone Marrow Comments

 Phenytoin or clonazepam should be administered prophylactically during and for at least 48 hours following completion of busulfan. Risk of seizures is increased in patients with sickle cell disease. Increased risk of VOD when busulfan AUC >3000 mol(min)/L (mean AUC, 2012 mol(min)/L). Increased risk of failure to engraft for allogeneic BMT patients when AUC is <900 mol (min)/L. To facilitate ingestion of high doses, insert multiple tablets into clear gel capsules. Ursodiol 9-12 mg/kg/day may reduce the risk of hepatotoxicity.


Oncology: Bone Marrow - High Dose

 Note: Generally combined with other high-dose chemotherapeutic drugs or total body irradiation.

Oral:

0.875-1 mg/kg/dose every 6 hours for 16 doses; total dose: 12-16 mg/kg

37.5 mg/m 2 every 6 hours for 16 doses; total dose: 600 mg/m 2 (studied primarily in pediatric patients)

150 mg/m 2 daily for 4 days; total dose: 600 mg/m 2 (studied primarily in pediatric patients)

I.V.: 0.8 mg/kg every 6 hours for 16 doses (4 days)


Oncology: Bone Marrow - Unique Toxicity

Central nervous system: Generalized or myoclonic seizures and loss of consciousness, abnormal electroencephalographic findings

Gastrointestinal: Mucositis, anorexia, moderately emetogenic

Hepatic: Veno-occulsive disease (VOD), hyperbilirubinemia

Respiratory: Idiopathic pneumonia syndrome

Miscellaneous: Transient pain at tumor sites, transient autoimmune disorders


Dosage Forms

Injection, solution (Busulfex®): 6 mg/mL (10 mL)

Tablet (Myleran®): 2 mg


References

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.

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.

Shaw PJ, Nath C, Berry A, et al, "Busulphan Given as Four Single Daily Doses of 150 mg/m 2 is Safe and Effective in Children of All Ages," Bone Marrow Transplant , 2004, 34(3):197-205.

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


International Brand Names

 Busilvex® (CH, DE, DK, GB, SE); Busulfan® (ES); Busulfex® (CA, IL); Myleran® (AR, AT, AU, BD, BE, BG, BR, CA, CL, CZ, DE, DK); Myléran® (FR); Myleran® (GB, HK, HR, IL, IN, IT, KW, LU, MX, NL, NZ, PL, RO, RU, SE, SG, SI, TH, TR, YU)


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