|
This information has been developed and provided by an independent third-party source. Merck & Co., Inc. does not endorse and is not responsible for the accuracy of the content, or for practices or
standards of non-Merck sources.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(byoo SUL fan)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Oral: Chronic myelogenous leukemia (CML); 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
Pregnancy Considerations
Animal studies have demonstrated teratogenic effects. May cause fetal harm if administered during pregnancy. The solvent in I.V. busulfan, DMA, is associated with teratogenic effects and may impair fertility. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should avoid pregnancy while receiving treatment.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Due to the tumorigenicity potential and the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity to busulfan or any component of the formulation; oral busulfan is contraindicated in patients without a definitive diagnosis of CML
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: Severe bone marrow suppression is common, resulting in possibly prolonged pancytopenia. May result in severe neutropenia, thrombocytopenia, and/or anemia.
• Cardiovascular: Cardiac tamponade has been reported in children with thalassemia treated with high dose oral busulfan in combination with cyclophosphamide,
• Hepatic veno-occlusive disease: High busulfan area under the concentration versus time curve (AUC) values (>1500 μM/minute) are associated with increased risk of hepatic veno-occlusive disease (VOD) during conditioning for allogenic BMT. Patients with a history of radiation therapy, prior chemotherapy (≥3 cycles) and prior stem cell transplantation are also at increased risk of hepatic VOD at recommended doses regimens. Oral busulfan doses above 16 mg/kg (based on IBW) and concurrent use with alkylating agents may also increase the risk for hepatic VOD.
• Ovarian failure: Use has been associated with ovarian failure (including failure to achieve puberty) and amenorrhea.
• Pulmonary toxicity: May cause delayed pulmonary toxicity (known as “busulfan lung” - bronchopulmonary dysplasia with pulmonary fibrosis); may occur between 4 months and 10 years after treatment (the average onset is 4 years).
• Secondary malignancies: Tumors and acute leukemias have been reported following use.
• Seizures: Have been reported with use; initiate prophylactic anticonvulsant therapy (eg, phenytoin) prior to treatment.
Disease-related concerns:
• Seizures: Use with caution in patients predisposed to seizures, with a history of seizures or head trauma; initiate prophylactic anticonvulsant therapy (eg, phenytoin) prior to treatment.
Dosage form specific issues:
• Dimethylacetamide (DMA): The solvent in I.V. busulfan, DMA, may impair fertility. DMA may also be associated with hepatotoxicity, hallucinations, somnolence, lethargy, and confusion.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
I.V.:
>10%:
Cardiovascular: Tachycardia (44%), hypertension (36%; grades 3/4: 7%), edema (28% to 79%), thrombosis (33%), chest pain (26%), vasodilation (25%), hypotension (11%; grades 3/4: 3%)
Central nervous system: Insomnia (84%), fever (80%), anxiety (72% to 75%), headache (69%), chills (46%), pain (44%), dizziness (30%), depression (23%), confusion (11%)
Dermatologic: Rash (57%), pruritus (28%), alopecia (2% to 15%)
Endocrine & metabolic: Hypomagnesemia (77%), hyperglycemia (66%; grades 3/4: 15%), hypokalemia (64%), hypocalcemia (49%), hypophosphatemia (17%)
Gastrointestinal: Nausea (98%), mucositis/stomatitis (97%; grades 3/4: 26%), vomiting (43% to 95%), anorexia (85%), diarrhea (84%; grades 3/4: 5%), abdominal pain (72%), dyspepsia (44%), constipation (38%), xerostomia (26%), rectal disorder (25%), abdominal fullness (23%)
Hematologic: Myelosuppression (≤100%), neutropenia (100%; median recovery: 13 days), thrombocytopenia (98%; median onset: 5-6 days), lymphopenia (children: 79%), anemia (69%)
Hepatic: Hyperbilirubinemia (49%; grades 3/4: 30%), ALT increased (31%; grades 3/4: 7%), veno-occlusive disease (adults: 8% to 12%; children: 21%), jaundice (12%)
Local: Injection site inflammation (25%), injection site pain (15%)
Neuromuscular & skeletal: Weakness (51%), back pain (23%), myalgia (16%), arthralgia (13%)
Renal: Creatinine increased (21%), oliguria (15%)
Respiratory: Rhinitis (44%), lung disorder (34%), cough (28%), epistaxis (25%), dyspnea (25%), pneumonia (children: 21%), hiccup (18%), pharyngitis (18%)
Miscellaneous: Infection (51%), allergic reaction (26%)
1% to 10%:
Cardiovascular: Arrhythmia (5%), cardiomegaly (5%), atrial fibrillation (2%), ECG abnormal (2%), heart block (2%), heart failure (grade 3/4: 2%), pericardial effusion (2%), tamponade (children with thalassemia: 2%), ventricular extrasystoles (2%), hypervolemia
Central nervous system: Lethargy (7%), hallucination (5%), agitation (2%), delirium (2%), encephalopathy (2%), seizure (2%), somnolence (2%), cerebral hemorrhage (1%)
Dermatologic: Vesicular rash (10%), vesiculobullous rash (10%), skin discoloration (8%), maculopapular rash (8%), acne (7%), exfoliative dermatitis (5%), erythema nodosum (2%)
Endocrine & metabolic: Hyponatremia (2%)
Gastrointestinal: Ileus (8%), weight gain (8%), hematemesis (2%), pancreatitis (2%)
Hematologic: Prothrombin time increased (2%)
Hepatic: Hepatomegaly (6%)
Renal: Hematuria (8%), dysuria (7%), hemorrhagic cystitis (grade 3/4: 7%), BUN increased (3%)
Respiratory: Asthma (8%), alveolar hemorrhage (5%), hyperventilation (5%), hemoptysis (3%), pleural effusion (3%), sinusitis (3%), atelectasis (2%), hypoxia (2%)
Oral: Frequency not defined:
Central nervous system: Seizure
Dermatologic: Hyperpigmentation of skin (busulfan tan 5% to 10%), alopecia, rash, urticaria
Endocrine & metabolic: Amenorrhea, ovarian suppression
Hematologic: Myelosuppression (anemia, leukopenia, thrombocytopenia), pancytopenia
I.V. and/or Oral: Infrequent, postmarketing, and/or case reports: Acute leukemias, adrenal suppression, alopecia (permanent), aplastic anemia (may be irreversible), azoospermia, blurred vision, cataracts, cheilosis, cholestatic jaundice, corneal thinning, dry skin, endocardial fibrosis, erythema multiforme, erythema nodosum, esophageal varices, gynecomastia, hemorrhagic cystitis, hepatic dysfunction, hepatocellular atrophy, hyperuricemia, hyperuricosuria, interstitial pulmonary fibrosis (busulfan lung; manifested by a diffuse interstitial pulmonary fibrosis and persistent cough, fever, rales, and dyspnea; may be relieved by corticosteroids); malignant tumors, myasthenia gravis, ocular (lens) changes, ovarian failure, porphyria cutanea tarda, radiation myelopathy, radiation recall (skin rash), sepsis, sterility, testicular atrophy
Metabolism/Transport Effects
Substrate of CYP3A4 (major)
Drug Interactions
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Busulfan. Risk C: Monitor therapy
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
MetroNIDAZOLE: May increase the serum concentration of Busulfan. Risk D: Consider therapy modification
MetroNIDAZOLE (Systemic): May increase the serum concentration of Busulfan. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): Antineoplastic Agents may enhance the anticoagulant effect of Vitamin K Antagonists. Antineoplastic Agents may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
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: Avoid St John's wort (may decrease busulfan levels).
Storage
Injection: Store unopened ampuls and vials under refrigeration (2°C to 8°C). Final solution is stable for up to 8 hours at room temperature (25°C); the infusion must be completed within that 8-hour timeframe. Dilution of busulfan injection in 0.9% sodium chloride is stable for up to 12 hours at refrigeration (2°C to 8°C); the infusion must be completed within that 12-hour timeframe.
Tablet: Store at room temperature at 15°C to 30°C (59°F to 86°F).
Reconstitution
Injection: Dilute (using manufacturer provided 5-micron filters for ampuls) in 0.9% sodium chloride injection or dextrose 5% in water. The dilution volume of busulfan injection, ensuring that the final concentration of busulfan is 0.5 mg/mL.
Compatibility
Variable stability (consult detailed reference) in D5W, NS.
Mechanism of Action
Busulfan is an alkylating agent which reacts with the N-7 position of guanosine and interferes with DNA replication and transcription of RNA. Busulfan has a more marked effect on myeloid cells than on lymphoid cells and is also very toxic to hematopoietic stem cells. 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: 32% to plasma proteins and 47% to red blood cells
Metabolism: Extensively hepatic (may increase with multiple doses); glutathione conjugation followed by oxidation
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
Note: Premedicate with prophylactic anticonvulsant therapy (eg, phenytoin) prior to high-dose busulfan treatment.
Children:
CML, remission induction: Oral: 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 ≤20,000/mm3
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 μmol(min)] using the following formula:
Adjusted dose (mg) = Actual dose (mg) x [target AUC μmol(min) / actual AUC μmol(min)]
Adults:
CML, remission induction: Oral: 60 mcg/kg/day or 1.8 mg/m2/day; usual range: 4-8 mg/day (may be as high as 12 mg/day); Maintenance doses: 1-4 mg/day to 2 mg/week to maintain WBC 10,000-20,000 cells/mm3
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); for obese or severely-obese patients adjusted ideal body weight is recommended) every 6 hours for 4 days (a total of 16 doses)
Polycythemia vera (unlabeled use): Oral: 2-6 mg/day
Thrombocytosis (unlabeled use): Oral: 4-6 mg/day
Dosing adjustment in renal impairment: I.V.: Has not been studied in patients with renal impairment per the FDA-approved labeling. Some clinicians suggest adjustment is not necessary (Aronoff, 2007).
Dosing adjustment in hepatic impairment: I.V.: Has not been administered in clinical studies in patients with hepatic impairment per the FDA-approved labeling. Busulfan has extensive hepatic metabolism and risk of hepatic veno-occlusive disease with high doses; dosage adjustment may be needed.
Administration: Oral
BMT only: To facilitate ingestion of high oral doses, insert multiple tablets into gelatin capsules.
Administration: I.V.
Intravenous busulfan should be administered as a 2-hour via central line.
Monitoring Parameters
CBC with differential and platelet count, liver function tests (evaluate transaminases, alkaline phosphatase, and bilirubin daily for at least 28 days post transplant)
Patient Education
Maintain adequate nutrition and hydration, unless instructed to restrict fluid intake. Avoid excess alcohol and acidic or spicy foods (may increase gastrointestinal irritation). You will be more susceptible to infection. May cause dizziness, insomnia, or confusion; mouth sores; loss of hair or darkening of skin color (reversible when medication is discontinued); nausea, vomiting, or loss of appetite; constipation; diarrhea (consult prescriber if severe or persistent); amenorrhea; sterility; or skin rash. Report palpitations or chest pain, weight gain, CNS changes (anxiety, confusion, depression), unusual cough or difficulty breathing, numbness or tingling of extremities, unusual bruising or bleeding, or pain or changes in urination.
Geriatric Considerations
Toxicity to immunosuppressives is increased in the elderly. Start with lowest recommended adult doses. Signs of infection, such as fever and rise in WBCs, may not occur. Lethargy and confusion may be more prominent signs of infection.
Additional Information
Oncology Comment: Low-dose monotherapy with oral busulfan for the palliative treatment of CML is no longer common. Treatment with imatinib or hematopoietic stem cell transplant (HSCT) are considered the primary treatments for CML (NCCN v1.2008).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation), mucositis/stomatitis.
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
Nursing: Physical Assessment/Monitoring
Identify any history of seizures, recent myelosuppressive therapy or radiation treatment, and pregnancy status prior to therapy. Dosing for obese patients should be based on adjusted ideal body weight. BMT: Phenytoin or clonazepam may be ordered prophylactically during and for at least 48 hours following completion of busulfan to reduce risk of seizures if patient is predisposed to seizures. Assess CBC with differential, platelet count, and LFTs. Monitor for adverse pulmonary effects (pulmonary fibrosis or toxicity; may be delayed 4 months to 10 years) or hematologic effects (pancytopenia, leukopenia, thrombocytopenia, anemia, and bone marrow suppression) during therapy and for several months following therapy.
Oncology: Emetic Potential
≥4 mg/day: Moderate (30% to 90%)
<4 mg/day: Very low (<10%)
Oncology: Vesicant
May be an irritant
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 μmol(min)/L (mean AUC, 2012 μmol(min)/L). Increased risk of failure to engraft for allogeneic BMT patients when AUC is <900 μmol (min)/L. To facilitate ingestion of high doses, multiple tablets may be inserted into gelatin capsules. Ursodiol 9-12 mg/kg/day may reduce the level of regimen-related hyperbilirubinemia.
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/m2 every 6 hours for 16 doses; total dose: 600 mg/m2 (studied primarily in pediatric patients)
150 mg/m2 daily for 4 days; total dose: 600 mg/m2 (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-occlusive disease (VOD), hyperbilirubinemia
Respiratory: Idiopathic pneumonia syndrome
Miscellaneous: Transient pain at tumor sites, transient autoimmune disorders
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution:
Busulfex®: 6 mg/mL (10 mL) [contains N,N-dimethylacetamide (DMA)]
Tablet, oral:
Myleran®: 2 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Myleran)
2 mg (60): $229.98
Extemporaneously Prepared
Hazardous agent: Use appropriate precautions for handling and disposal.
A 2 mg/mL oral suspension can be prepared in a vertical flow hood with tablets and simple syrup. Crush one-hundred-twenty 2 mg tablets in a mortar and reduce to a fine powder. Add small portions of simple syrup and mix to a uniform paste; mix while adding the simple syrup in incremental proportions to almost 120 mL; transfer to a graduated cylinder, rinse mortar and pestle with simple syrup, and add quantity of vehicle sufficient to make 120 mL. Transfer contents of the graduated cylinder into an amber prescription bottle. Label “shake well”, “refrigerate”, and “caution chemotherapy”. Stable for 30 days.
Allen LV, "Busulfan Oral Suspension," US Pharm, 1990, 15:94-5.
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 97.
Booth BP, Rahman A, Dagher R, et al, “Population Pharmacokinetic-Based Dosing of Intravenous Busulfan in Pediatric Patients,” J Clin Pharmacol, 2007, 47(1):101-11.
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.
National Comprehensive Cancer Network® (NCCN) “Practice Guidelines in Oncology: Antiemesis Version 3.2008.” Available at http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf
National Comprehensive Cancer Network® (NCCN) “Practice Guidelines in Oncology: Chronic Myelogenous Leukemia Version 1.2008.” Available at http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf
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.
Seddon BM, Cassoni AM, Galloway MJ, et al, “Fatal Radiation Myelopathy After High-Dose Busulfan and Melphalan Chemotherapy and Radiotherapy for Ewing's Sarcoma: A Review of the Literature and Implications for Practice,” Clin Oncol (R Coll Radiol), 2005, 17(5):385-90.
Shaw PJ, Nath C, Berry A, et al, “Busulphan Given as Four Single Daily Doses of 150 mg/m2 Is Safe and Effective in Children of All Ages,” Bone Marrow Transplant, 2004, 34(3):197-205.
Tosti A, Piraccini BM, Vincenzi C, et al, “Permanent Alopecia After Busulfan Chemotherapy,” Br J Dermatol, 2005, 152(5):1056-8.
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
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
| 
