Busulfan is a potent drug. Busulfan oral tablets should not be used unless a diagnosis of chronic myelogenous leukemia (CML) has been adequately established and the responsible health care provider is knowledgeable in assessing response to chemotherapy.
Busulfan tablets can induce severe bone marrow hypoplasia. Reduce or discontinue the dosage of oral busulfan immediately at the first sign of any unusual depression of bone marrow function as reflected by an abnormal decrease in any of the formed elements of the blood. A bone marrow examination should be performed if the bone marrow status is uncertain.
Busulfan injection causes severe and prolonged myelosuppression at the recommended dosage. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression.
Note: Dose, frequency, number of doses, and/or start date may vary by protocol and treatment phase. Refer to individual protocols and/or therapeutic drug monitoring. Premedicate with prophylactic antiseizure therapy (eg, phenytoin, levetiracetam, benzodiazepines, or valproic acid) beginning 12 hours prior to high-dose busulfan treatment and continuing for 24 hours after last busulfan dose.
Dosing presented as mg/kg and mg/m2; use extra precaution. Busulfan is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013; Paw Cho Sing 2019). Antiemetics are recommended when used for transplantation.
Hematopoietic stem cell transplant (HSCT) conditioning regimen:
IV: Infants, Children, and Adolescents: Note: Dosing based on actual body weight, including obese individuals (Bubalo 2014):
Initial: Therapeutic drug monitoring should be considered early in regimen (eg, after first dose) and doses adjusted accordingly.
≤12 kg: IV: 1.1 mg/kg/dose every 6 hours for 16 doses (over 4 days followed by cyclophosphamide).
>12 kg: IV: 0.8 mg/kg/dose every 6 hours for 16 doses (over 4 days followed by cyclophosphamide).
Dosing adjustment: Doses adjusted based upon AUC or steady state concentration (CSS) depending upon protocol. The desired AUCs or CSSs are variable and may be dependent upon multiple factors, including indication for transplant, type of transplant, and donor source; specific protocols should be consulted. A desired AUC of 900 to 1,350 micromolar/minute has been suggested per the manufacturer, and CSS of 600 to 900 ng/mL ± 10% has also been reported (Bolinger 2001; Horn 2006; Law 2012). Adjusted dose may be determined from the following formulas:
Adjusted dose (mg) = Actual dose (mg) x [target AUC (micromolar•minute) / actual AUC (micromolar•minute)].
Adjusted dose (mg) = Actual dose (mg) x [target CSS (ng/mL) / actual CSS (ng/mL)].
Reduced intensity conditioning regimens: Limited data available:
12-dose regimen: Children ≥2 and Adolescents: IV: 0.8 mg/kg/dose every 6 hours for 12 doses starting on Day -6; used in combination with fludarabine and melphalan for patients receiving haploidentical, peripheral blood HSCT for acute leukemia (Jaiswal 2016).
8-dose regimen: Infants, Children, and Adolescents: 0.8 mg/kg/dose for one dose on either day -7 (related donor) or day -10 (unrelated donor or cord recipient) prior to transplant, followed by 7 additional doses of ~0.8 mg/kg/dose every 6 hours (actual dose based on pharmacokinetic analysis after initial dose) beginning days -3 and -2 (related donor) or days -6 and -5 (unrelated donor or cord recipient) prior to transplant; used in combination with fludarabine and antithymocyte globulin (rabbit). In clinical trials, there was no minimum age for inclusion; the youngest patient treated was 2 years (Pulsipher 2009).
Once-Daily Dosing: Limited data available: Note: Dosing based on actual body weight up to 120% of IBW, then dose based on adjusted dosing weight (ideal body weight plus 50% of the difference between ideal and actual weight) based on experience from adult patients (De Lima 2004).
Infants <1 year: IV: 80 mg/m2/dose over 3 hours once daily for 4 days prior to HSCT, starting on Day -8 (combined with cyclophosphamide or fludarabine and etoposide); dose adjustment (Days -7 to -5) to target AUC 4,384 to 4,628 micromolar•minute/liter/day has been reported (Lee 2012; Lee 2015).
Children ≥1 year and Adolescents: IV: 120 mg/m2/dose over 3 hours once daily for 4 days prior to HSCT, starting on Day -8 (combined with cyclophosphamide or fludarabine and etoposide); dose adjustment (Days -7 to -5) to target AUC 4,384 to 4,628 micromolar•minute/liter/day has been reported (Lee 2012; Lee 2015).
Oral: Note: Dosing based on actual body weight, including obese individuals (Bubalo 2014): Note: Not routinely used for HSCT conditioning regimens, IV formulation is the preferred dosage form. Dosing variable dependent upon indication for HSCT.
Acute Myeloid Leukemia: Limited data available: Adolescents ≥16 years: Oral: 1 mg/kg/dose every 6 hours for 16 doses on days -9 to -6 in combination with cyclophosphamide (Cassileth 1998).
Thalassemia major: Limited data available:
Class 1 or Class 2 (ie, low-risk for GVHD or transplant mortality):
Infants and Children <3 years: Oral: 1.25 mg/kg every 6 hours for 16 doses on day -9 to day -6 prior to transplant in combination with cyclophosphamide and antithymocyte globulin (horse) (Hussein 2013).
Children ≥3 years and Adolescents: Oral: 1 mg/kg/dose every 6 hours for 16 doses prior to transplant; on days -9 to -6 in combination with cyclophosphamide and antithymocyte globulin (horse) (Hussein 2013).
Class 3 (ie, high-risk disease): Children ≥10 years and Adolescents: Oral: 2 mg/kg/dose every 12 hours for 4 doses on days -8 and -7 in combination with fludarabine and antithymocyte globulin (horse) (Hussein 2013).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Oral: There are no dosage adjustments provided in the manufacturer's labeling; elimination appears to be independent of renal function; some clinicians suggest adjustment is not necessary (Aronoff 2007).
IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Oral: There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Busulfan: Drug information")
Note: Premedicate with prophylactic antiseizure therapy (eg, phenytoin, levetiracetam, benzodiazepines, or valproic acid) beginning 12 hours prior to high-dose busulfan treatment and continuing for 24 hours after the last busulfan dose. Antiemetics may be recommended to prevent nausea and vomiting; depending on dose and/or administration route, busulfan is associated with a moderate or high emetic potential in adults. Antiemetics are recommended when used for transplantation.
Essential thrombocythemia, resistant (off-label use): Adults >60 years of age: Oral: 2 to 4 mg once daily (Fabris 2009; Tefferi 2011; Tefferi 2017); withhold when platelets <200,000/mm3 or WBC <3,000/mm3, and resume with the dose reduced to 2 mg once daily (Tefferi 2017).
Hematopoietic stem cell conditioning regimen:
IV: 0.8 mg/kg/dose (ideal or actual body weight, whichever is lower) every 6 hours for 4 days (a total of 16 doses) beginning 7 days prior to transplant (followed by cyclophosphamide).
Obesity: For obese or severely-obese patients, use of an adjusted body weight [IBW + 0.25 x (actual – IBW)] is recommended (by the manufacturer).
Conditioning regimens; regimen specific dosing (off-label): Note: Myeloablative conditioning regimens generally include total busulfan doses >8 mg/kg (per course) and reduced intensity conditioning regimens typically include total busulfan doses ≤8 mg/kg (per course).
Bu4/Cy regimen: IV: 0.8 mg/kg every 6 hours for 16 doses (total busulfan dose of 12.8 mg/kg over 4 days; followed by 2 days of cyclophosphamide, then allogeneic HSCT after 1 day of rest) (Andersson 2002).
Flu/Bu4 regimen: IV: 0.8 mg/kg every 6 hours for 16 doses beginning 6 days before allogeneic transplant (total busulfan dose 12.8 mg/kg over 4 days; in combination with 4 days of fludarabine) (Rambaldi 2015) or (reduced intensity conditioning regimen): 0.8 mg/kg once daily for 4 days beginning 5 days before allogeneic transplant (total busulfan dose 3.2 mg/kg over 4 days; in combination with 4 days of fludarabine) (Ho 2009).
Flu/Bu4 (once daily) regimen: IV: 130 mg/m2 over 3 hours once daily for 4 days (in combination with 4 days of fludarabine ± thymoglobulin [administer busulfan after fludarabine each day], followed by allogeneic transplant) (De Lima 2004; Madden 2007).
Bu/Cy regimens: Oral: 1 mg/kg every 6 hours for 16 doses (total busulfan dose of 16 mg/kg over 4 days; followed by 2 days of cyclophosphamide, then allogeneic HSCT 2 days later on day 8) (Tutschka 1987) or 1 mg/kg every 6 hours for 16 doses (total busulfan dose of 16 mg/kg over 4 days; followed by 2 days of cyclophosphamide, followed by allogeneic marrow transplant) (Socié 2001) or 1 mg/kg every 6 hours for 16 doses beginning 9 days prior to transplant (total busulfan dose of 16 mg/kg over 4 days; followed by 4 days of cyclophosphamide, followed by allogeneic or autologous marrow transplant) (Cassileth 1993; Cassileth 1998).
Bu/Mel regimen: Oral: 1 mg/kg every 6 hours for 16 doses beginning 6 days prior to transplant (total busulfan dose of 16 mg/kg over 4 days; followed by IV melphalan, followed by autologous transplant) (Fermand 2005).
Bu/Mel/TT regimen: Oral: 1 mg/kg every 6 hours for 12 doses beginning 8 days prior to transplant (total busulfan dose of 12 mg/kg over 3 days; followed by 2 days of IV melphalan and then 2 days of thiotepa (Schiffman 1997).
Flu/Bu2 regimen: Oral: 1 mg/kg every 6 hours for 8 doses beginning 6 days prior to transplant (total busulfan dose of 8 mg/kg over 2 days; in combination with 6 days of fludarabine and 4 days of ATG) (Slavin 1998).
Flu/Bu4: Oral: 1 mg/kg every 6 hours for 16 doses (total busulfan dose of 16 mg/kg over 4 days; in combination with 4 days of fludarabine) (Scott 2017).
Polycythemia vera, refractory/resistant (off-label use): Oral: Initial: 2 to 4 mg once daily (BSH [McMullin 2018]; Tefferi 2017; Vannucchi 2014). Withhold when platelets <200,000/mm3 or WBC <3,000/mm3, and resume with the dose reduced to 2 mg once daily (Tefferi 2017). Lower maintenance doses may be used in some patients (Vannucchi 2014).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Oral: There are no dosage adjustments provided in the manufacturer's labeling (elimination appears to be independent of renal function); however, it has been suggested that adjustment is not necessary (Aronoff 2007).
IV: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Oral: There are no dosage adjustments provided in the manufacturer's labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 6 mg/mL (10 mL)
Solution, Intravenous [preservative free]:
Busulfex: 6 mg/mL (10 mL) [contains polyethylene glycol]
Generic: 6 mg/mL (10 mL)
Tablet, Oral:
Myleran: 2 mg
May be product dependent
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous:
Busulfex: 6 mg/mL ([DSC]) [contains polyethylene glycol]
Generic: 6 mg/mL (10 mL)
Tablet, Oral:
Myleran: 2 mg
Busulfan is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013). Antiemetics are recommended when used for transplantation.
Oral: May be administered without regard to meals. To facilitate ingestion of high doses (for HSCT), may insert multiple tablets into clear gelatin capsules for administration.
Parenteral: Infuse over 2 hours or as defined in specific protocols or institutional policy; administer through a central venous catheter; use an administration set with a minimal residual priming volume (1 to 3 mL for pediatric patients); flush line before and after each infusion with 5 mL of D5W or NS. Do not use polycarbonate syringes, filter needles, or IV tubing for preparation or administration.
Antiemetics may be recommended to prevent nausea and vomiting; depending on dose and/or administration route, busulfan is associated with a moderate or high emetic potential in adults. Antiemetics are recommended when used for transplantation.
IV: Intravenous busulfan should be infused over 2 hours via central line. Once daily IV busulfan (off-label dose) has been infused over 3 hours (De Lima 2004; Madden 2007). Use an administration set with a minimal residual priming volume (2 to 5 mL). Flush line before and after each infusion with 5 mL D5W or NS. Busulfan IV is incompatible with polycarbonate; do not use syringes, filters, or IV tubing containing polycarbonate for preparation or administration.
Busulfan injection contains N,N-dimethylacetamide, which may be incompatible with some closed-system transfer devices (CSTDs); the plastic components of some CSTDs may dissolve and result in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]). Refer to the specific CSTD device manufacturer for compatibility data.
Oral (HSCT only): To facilitate ingestion of high oral doses, may place multiple tablets into an empty gelatin capsule.
Hazardous agent (NIOSH 2016 [group 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Injection: Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Solutions diluted in sodium chloride (NS) injection or dextrose 5% in water (D5W) for infusion are stable for up to 8 hours at room temperature (25°C [77°F]); the infusion must also be completed within that 8-hour timeframe. Dilution of busulfan injection in NS is stable for up to 12 hours refrigerated (2°C to 8°C); the infusion must be completed within that 12-hour timeframe.
Tablet: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Oral: Palliative treatment of chronic myelogenous leukemia (CML) (FDA approved in pediatric patients [age not specified] and adults); has also been used as a conditioning regimen prior to hematopoietic stem cell transplant. Note: Although an FDA-labeled indication, the use of busulfan for palliative treatment of CML in pediatric patients is no longer considered a treatment option by experts; according to the European LeukemiaNet Recommendations for Management of CML, oral busulfan (unless part of a transplant conditioning regimen) is not recommended (Baccarani 2013).
Parenteral: Conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for CML in combination with cyclophosphamide (FDA approved in pediatric patients [age not specified] and adults)
Myleran may be confused with Alkeran, Leukeran, melphalan, Mylicon
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
A solvent in IV busulfan, N,N-dimethylacetamide, may be incompatible with some closed system transfer devices (CSTDs) used for preparing injectable antineoplastics. The plastic components of some CSTDs may dissolve and result in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]). Refer to the specific CSTD device manufacturer for compatibility data.
Busulfan IV is incompatible with polycarbonate; do not use syringes, filters, or IV tubing containing polycarbonate.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Intravenous:
>10%:
Cardiovascular: Edema (28% to 36%), tachycardia (44%), hypertension (36%), thrombosis (33%), chest pain (26%), vasodilation (25%)
Central nervous system: Insomnia (84%), anxiety (72%), headache (69%), chills (46%), pain (44%), dizziness (30%), depression (23%)
Dermatologic: Skin rash (57%), pruritus (28%)
Endocrine & metabolic: Hypomagnesemia (77%), hyperglycemia (66%), hypokalemia (64%), hypocalcemia (49%)
Gastrointestinal: Vomiting (95% to 100%), nausea (adults 98%; children 83%), mucositis (≤97%), stomatitis (adults ≤97%; children 79%), anorexia (85%), diarrhea (84%; grades 3/4: 5%), abdominal pain (72%), dyspepsia (44%), constipation (38%), xerostomia (26%), rectal disease (25%), gastrointestinal fullness (23%)
Hematologic & oncologic: Neutropenia (100%; onset: 4 days; median recovery: 13 days [with G-CSF support]), bone marrow depression (≤100%), thrombocytopenia (98%; median onset: 5 to 6 days), lymphocytopenia (children: 79%), anemia (69%)
Hepatic: Hyperbilirubinemia (49%), increased serum ALT (31%), hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease; children: 21%; adults: 8% to 12%)
Hypersensitivity: Hypersensitivity reaction (26%)
Immunologic: Graft versus host disease (children: 25%)
Local: Inflammation at injection site (25%)
Neuromuscular & skeletal: Weakness (51%), back pain (23%)
Renal: Increased serum creatinine (21%)
Respiratory: Rhinitis (44%), pulmonary disease (34%), cough (28%), dyspnea (25%), epistaxis (25%), pneumonia (children: 21%)
Miscellaneous: Fever (80%)
1% to 10%: Cardiovascular: Cardiac tamponade (children with thalassemia: 2%)
Frequency not defined:
Cardiovascular: Atrial fibrillation, cardiac arrhythmia, cardiomegaly, catheter site thrombosis (central venous catheter), complete atrioventricular block, ECG abnormality, flushing, hypotension, left heart failure, pericardial effusion, ventricular premature contractions
Central nervous system: Agitation, brain disease, cerebral hemorrhage, coma, confusion, delirium, drowsiness, hallucination, lethargy
Dermatologic: Acne vulgaris, alopecia, erythema nodosum, exfoliative dermatitis, maculopapular rash, skin discoloration, vesicular eruption, vesiculobullous dermatitis
Endocrine & metabolic: Hot flash, hypervolemia, hyponatremia, hypophosphatemia, weight gain
Gastrointestinal: Esophagitis, hematemesis, hiccups, intestinal obstruction, pancreatitis, rectal pain
Genitourinary: Dysuria, hematuria, hemorrhagic cystitis, oliguria
Hematologic & oncologic: Prolonged prothrombin time
Hepatic: Hepatomegaly, increased serum alkaline phosphatase, jaundice
Immunologic: Graft versus host disease (adults)
Infection: Infection
Local: Pain at injection site
Neuromuscular & skeletal: Arthralgia, myalgia
Otic: Ear disease
Renal: Increased blood urea nitrogen
Respiratory: Asthma, atelectasis, hemoptysis, hyperventilation, hypoxia, pharyngitis, pleural effusion, pulmonary alveolar hemorrhage, pulmonary interstitial fibrosis, sinusitis
Oral:
1% to 10%:
Central nervous system: Seizure (2%; despite prophylactic seizure therapy)
Dermatologic: Skin hyperpigmentation (5% to 10%)
Frequency not defined:
Endocrine & metabolic: Amenorrhea, ovarian failure
Hematologic & oncologic: Bone marrow depression (including anemia, leukopenia, thrombocytopenia), pancytopenia
Respiratory: Pulmonary interstitial fibrosis
IV and/or Oral: <1%, postmarketing, and/or case reports: Acute leukemia, adrenocortical insufficiency, alopecia (permanent), anhidrosis, aplastic anemia (may be irreversible), azoospermia, capillary leak syndrome, cardiomyopathy (endocardial fibrosis), cataract (rare), cheilosis, cholestatic jaundice, corneal thinning, dry mucous membranes, enamel hypoplasia, erythema multiforme, esophageal varices (with continuous busulfan and thioguanine therapy), febrile neutropenia, fragile skin, gynecomastia, hepatic fibrosis (centrilobular sinus), hepatic necrosis, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease) (oral), lens disease (including particulate matter deposition), malignant neoplasm, myasthenia gravis, porphyria cutanea tarda, pulmonary fibrosis (with bronchopulmonary dysplasia), recall skin sensitization (skin rash), sepsis, sterility, testicular atrophy, thrombotic thrombocytopenic purpura, tumor lysis syndrome, urticaria, xeroderma
Hypersensitivity to busulfan or any component of the formulation; oral busulfan is contraindicated in patients without a definitive diagnosis of chronic myeloid leukemia
Canadian labeling: Additional contraindications (not in the US labeling): Oral busulfan: Neutropenia or thrombocytopenia; disease that has demonstrated resistance to busulfan
Concerns related to adverse effects:
• Bone marrow suppression: [US Boxed Warning]: Severe and prolonged bone marrow suppression commonly occurs; reduce dose or discontinue oral busulfan for unusual suppression; may require bone marrow biopsy. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications from prolonged myelosuppression due to IV busulfan. May result in severe neutropenia, thrombocytopenia, anemia, bone marrow failure, and/or severe pancytopenia; pancytopenia may be prolonged (1 month up to 2 years) and may be reversible. When used for transplantation, monitor CBC with differential daily during treatment and until engraftment. The onset of neutropenia is a median of 4 days post-transplant; recovery is within a median of 13 days following allogeneic transplant (with prophylactic filgrastim use in most patients). Thrombocytopenia occurred at a median of 5 to 6 days. Use with caution in patients with compromised bone marrow reserve (due to prior treatment or radiation therapy). Monitor closely for signs of infection (due to neutropenia) or bleeding (due to thrombocytopenia). May require antibiotic therapy and platelet and red blood cell support.
• Cardiovascular: Cardiac tamponade has been reported in children with thalassemia treated with high dose oral busulfan in combination with cyclophosphamide. Abdominal pain and vomiting preceded tamponade in most children. Monitor for signs/symptoms and evaluate/treat promptly if cardiac tamponade is suspected.
• GI toxicity: Antiemetics may be recommended to prevent nausea and vomiting; depending on dose and/or administration route, busulfan is associated with a high emetic potential in pediatrics (POGO [Paw Cho Sing 2019]) and a moderate or high emetic potential (depending on dose or route) in adults.
• Hepatic sinusoidal obstruction syndrome: High busulfan area under the concentration versus time curve (AUC) values (>1500 micromolar•minute) are associated with increased risk of hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) due to conditioning for allogenic HSCT. Patients with a history of radiation therapy, prior chemotherapy (≥3 cycles), or prior stem cell transplantation are also at increased risk of hepatic SOS 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 SOS. Monitor liver function tests (serum transaminases, alkaline phosphatase, and bilirubin) daily until 28 days post-transplant to detect hepatotoxicity (which may preclude hepatic SOS).
• Hepatitis B virus screening: The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
• Pulmonary toxicity: Bronchopulmonary dysplasia with pulmonary fibrosis (“busulfan lung”) is associated with chronic busulfan use; onset is delayed with symptoms occurring at an average of 4 years (range: 4 months to 10 years) after treatment; may be fatal. Symptoms generally include a slow onset of cough, dyspnea and fever (low-grade), although acute symptomatic onset may also occur. Diminished diffusion capacity and decreased pulmonary compliance have been noted with pulmonary function testing. Differential diagnosis should rule out opportunistic pulmonary infection or leukemic pulmonary infiltrates; may require lung biopsy. Discontinue busulfan if toxicity develops. Pulmonary toxicity may be additive if administered with other cytotoxic agents also associated with pulmonary toxicity.
• Secondary malignancies: Tumors and acute leukemias have been reported following use. Chromosomal alterations may also occur.
• Seizures: Seizures have been reported with IV busulfan and with high-dose oral busulfan. When using as a conditioning regimen for transplant, initiate prophylactic antiseizure therapy (eg, phenytoin, levetiracetam, benzodiazepines, or valproic acid) prior to treatment. Use with caution in patients predisposed to seizures, with a history of seizures, head trauma, or with other medications associated with inducing seizures.
• Tissue dysplasia: Cellular dysplasia in many organs has been observed (in addition to lung dysplasia); giant hyperchromatic nuclei have been noted in adrenal glands, liver, lymph nodes, pancreas, thyroid, and bone marrow. May obscure routine diagnostic cytologic exams (eg, cervical smear).
Concurrent drug therapy issues:
• Antiseizure medications: Phenytoin increases busulfan clearance by ≥15%; busulfan kinetics and dosing recommendations for high-dose HSCT conditioning were studied with concomitant phenytoin. If alternate antiseizure medications are used, busulfan clearance may be decreased and dosing should be monitored accordingly.
Dosage form specific issues:
• Busulfan injection: The solvent in IV busulfan, dimethylacetamide (DMA) may be associated with hepatotoxicity, hallucinations, somnolence, lethargy, and confusion.
Other warnings/precautions:
• Experienced physician: [US Boxed Warning]: According to the manufacturer, oral busulfan should not be used until CML diagnosis has been established. The responsible health care provider should be experienced in assessing response to chemotherapy.
None known.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Acetaminophen: May increase the serum concentration of Busulfan. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Blinatumomab: May increase the serum concentration of Busulfan. Risk C: Monitor therapy
Brincidofovir: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing cytotoxic chemotherapy several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: In the US, after receipt of the single dose COVID-19 adenovirus vector vaccine (Janssen), administer an additional 2nd dose using an mRNA COVID-19 vaccine, at least 28 days after the primary vaccine dose, in patients taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider administration of a 3rd dose of COVID-19 vaccine, at least 28 days after completion of the primary 2-dose series, in patients 5 years of age and older taking immunosuppressive therapies. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
Deferasirox: May increase the serum concentration of Busulfan. Management: Discontinue deferasirox 2 to 3 days (approximately 5 half-lives) before initiation of busulfan. If combined, monitor for increased busulfan concentrations and effects. Decreased busulfan doses may be required during concomitant use. Risk D: Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and cytotoxic chemotherapy. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants, such cytotoxic chemotherapy. If combined, monitor for reduced efficacy of cytotoxic chemotherapy. Risk D: Consider therapy modification
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Fosphenytoin: May decrease the serum concentration of Busulfan. Risk C: Monitor therapy
Ifosfamide: Busulfan may enhance the adverse/toxic effect of Ifosfamide. Specifically, the risk of hemorrhagic cystitis may be increased. Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating chemotherapy if possible. If vaccination occurs less than 2 weeks prior to or during chemotherapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification
Itraconazole: May increase the serum concentration of Busulfan. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents, such as cytotoxic chemotherapy. Risk D: Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
MetroNIDAZOLE (Systemic): May increase the serum concentration of Busulfan. Management: The toxic effects of busulfan may be greatly increased with concomitant use of metronidazole. This combination should probably be avoided when possible. If these agents must be used together, increased monitoring for busulfan toxicity is recommended. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Phenytoin: May decrease the serum concentration of Busulfan. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Pneumococcal Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Propacetamol: May increase the serum concentration of Busulfan. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants, such as cytotoxic chemotherapy, prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated): Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of chemotherapy when possible. Patients vaccinated less than 14 days before initiating or during chemotherapy should be revaccinated at least 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Cytotoxic Chemotherapy) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Cytotoxic Chemotherapy) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Females of reproductive potential should use effective contraception to avoid pregnancy during treatment and for 6 months after completion of therapy. Males with female partners of reproductive potential should use effective contraception during treatment and for 3 months after completion of therapy.
Busulfan may impair fertility in females and males. Busulfan has been associated with ovarian suppression and amenorrhea. High-dose busulfan may cause temporary or permanent infertility in prepubertal females or in females of childbearing potential. Sterility, azoospermia, and testicular atrophy may occur in males.
Based on animal reproduction studies, busulfan may cause fetal harm if administered during pregnancy. The solvent in IV busulfan, DMA, is also associated with teratogenic effects in animal studies.
CBC with differential and platelet count (weekly for palliative treatment in adults; daily until engraftment for HSCT); liver function tests, bilirubin, and alkaline phosphatase daily through 28 days post transplant.
If conducting therapeutic drug monitoring for AUC calculations in HSCT, monitor busulfan plasma concentrations at appropriate collection times (record collection times); for IV infusion; collect blood sample from a different port than that used for infusion. Blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4°C [39.2°F]) within 1 hour. The plasma, harvested into appropriate cryovial storage tubes, should be frozen immediately at -20°C (-4°F). All plasma samples should be sent frozen (on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations. Specific collection times may vary, consult specific protocols; for calculating AUC, the manufacturer suggests the following:
From the end of the infusion of the first dose, collect at 2 hours, 4 hours, and 6 hours (immediately prior to the next dose).
Any other dose, collect a pre-infusion concentration, then at 2 hours (end of infusion), 4 hours, and 6 hours (immediately prior to the next dose).
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. It interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA.
Absorption: Rapid and complete
Distribution: Vd: Pediatric (IV): ~0.64 L/kg; crosses blood brain barrier and distributes into CSF with levels equal 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
Bioavailability: Oral: Children ≥13 years and adults: 80% (range: 47% to 103%); Children 1.5 to 6 years: 68% (range: 22% to 120%)
Half-life elimination: 2 to 3 hours
Time to peak, serum: Oral: ~1 hour; IV: Within 5 minutes
Excretion: Urine (25% to 60% predominantly as metabolites; <2% as unchanged drug)
Clearance: Children: 3.37 mL/minute/kg; Adults: 2.52 mL/minute/kg (range: 1.49 to 4.31 mL/minute/kg)
Renal function impairment: In a patient with chronic renal failure undergoing autologous stem cell transplantation, the apparent oral clearance of busulfan during a 4-hour hemodialysis session was increased 65%, but the 24-hour oral clearance of busulfan was increased only 11%.
A 2 mg/mL oral suspension can be prepared in a biological safety cabinet 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 (refrigerated).
Solution (Busulfan Intravenous)
6 mg/mL (per mL): $13.80 - $248.40
Solution (Busulfex Intravenous)
6 mg/mL (per mL): $60.00
Tablets (Myleran Oral)
2 mg (per each): $28.11
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