Busulfan

Dosage Forms

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

Pharmacology

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. It interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA.

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid and complete

Distribution

V_d: Pediatric (IV): ~0.64 L/kg; crosses blood brain barrier and distributes into CSF with levels equal to plasma

Metabolism

Extensively hepatic (may increase with multiple doses); glutathione conjugation followed by oxidation

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)

Time to Peak

Serum: Oral: ~1 hour; IV: Within 5 minutes

Half-Life Elimination

2 to 3 hours

Protein Binding

~32% to plasma proteins and 47% to red blood cells

Use in Specific Populations

Special Populations: 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%.

Use: Labeled Indications

Chronic myeloid leukemia: Injection: Conditioning regimen (in combination with cyclophosphamide) prior to allogeneic hematopoietic progenitor cell transplantation for chronic myeloid leukemia (CML)

Use: Off Label

Essential thrombocythemia (resistant)cyes

Clinical experience suggests that cytoreductive therapy with oral busulfan may be utilized as second-line treatment of essential thrombocythemia in patients >60 years of age and with high-risk features Rumi 2016. Other experience suggests oral busulfan may be useful for the treatment of essential thrombocythemia in patients >70 years of age Fabris 2009.

Based on European Society for Medical Oncology (ESMO) practice guidelines for Philadelphia chromosome-negative (Ph-) chronic myeloproliferative neoplasms, oral busulfan may be used as second-line therapy for the treatment of essential thrombocythemia in patients (particularly older patients) who have failed or are intolerant to hydroxyurea ESMO [Vannucchi 2015].

Hematopoietic stem cell transplant (HSCT) (oral) (conditioning regimen)a

Data from a study in adults with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or chronic myeloid leukemia (CML) receiving allogeneic transplant, a study in patients with AML receiving an autologous transplant (not eligible for allogeneic transplant), and a large study in patients with AML receiving autologous or allogeneic transplant, support the use of oral busulfan (in combination with cyclophosphamide) as a conditioning regimen prior to transplant Cassileth 1993, Cassileth 1998, Tutschka 1987. Additionally, in a long-term follow-up study of 4 randomized studies in patients with myeloid leukemias, the use of oral busulfan (in combination with cyclophosphamide) was an effective conditioning regimen in patients undergoing HSCT Socié 2001. Data from a randomized study in patients with symptomatic multiple myeloma receiving autologous transplant support the use of oral busulfan (in combination with melphalan) Fermand 2005. Data from a study in patients with malignant and nonmalignant hematologic disorders receiving allogeneic transplant and from a phase III study in patients with AML and myelodysplastic syndrome (MDS) receiving allogeneic transplant support the use of oral busulfan (in combination with fludarabine) as a conditioning regimen prior to transplant Scott 2017, Slavin 1998. Results from a small study evaluating busulfan (in combination with melphalan and thiotepa) in patients with aggressive lymphomas receiving autologous transplant also support the use of busulfan as a component of the conditioning regimen Schiffman 1997. Additionally, clinical experience supports the use of oral busulfan (in combination with cyclophosphamide or fludarabine) as a conditioning regimen prior to transplant Ciurea 2009.

Polycythemia vera (refractory/resistant)cyes

Clinical experience suggests the utility of oral busulfan as second-line therapy for the treatment of refractory polycythemia vera in patients who have failed or are intolerant to hydroxyurea, particularly in patients ≥65 years of age Tefferi 2011, Tefferi 2017, Vannucchi 2014. Busulfan use may result in an increased risk for progression to acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) Finazzi 2005.

Based on European Society for Medical Oncology (ESMO) practice guidelines for Philadelphia chromosome-negative (Ph-) chronic myeloproliferative neoplasms, oral busulfan may be used as second-line therapy for the treatment of polycythemia vera in patients (particularly older patients) who have failed or are intolerant to hydroxyurea ESMO [Vannucchi 2015].

Contraindications

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

Dosage and Administration

Dosing: Adult

Note: Premedicate with prophylactic anticonvulsant 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 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 (HSCT) 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).

IV:

Bu4/Cy regimen: 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: 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: 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)

Oral:

Bu/Cy regimens: 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: 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: 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: 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: 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; withhold when platelets <200,000/mm³ or WBC <3,000/mm³, and resume with the dose reduced to 2 mg once daily (Tefferi 2017; Vannucchi 2014). Lower maintenance doses may be used in some patients (Vannucchi 2014).

Dosing: Geriatric

Oral: Start with lowest recommended doses for adults.

Dosing: Pediatric

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 anticonvulsant 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).

Dosing: Obesity

American Society for Blood and Marrow Transplantation (ASBMT) practice guideline committee position statement on chemotherapy dosing in obesity (Bubalo 2014):

Busulfan (oral): Note: For total doses over 12 mg/kg (per cycle), utilize pharmacokinetically targeted dosage (as appropriate for disease state). When busulfan and cyclophosphamide are used in combination for HSCT conditioning, the maximum tolerated busulfan dose is 4 mg/kg/day for 4 days. The maximum tolerated busulfan dose has not been determined when used in combination with other agents.

Body surface area (BSA) dosing: Adults: Utilize actual body weight (ABW) to calculate BSA

Weight based dosing (mg/kg): Adults: Utilize ABW25 for obese and nonobese patients

ABW25: Adjusted wt (kg) = Ideal body weight (kg) + 0.25 [actual wt (kg) - ideal body weight (kg)]

Reconstitution

Injection: Dilute in NS or D₅W. The dilution volume should be 10 times the volume of busulfan injection, ensuring that the final concentration of busulfan is 0.5 mg/mL. Always add busulfan to the diluent, and not the diluent to the busulfan. Mix with several inversions. Busulfan IV is incompatible with polycarbonate; do not use syringes, filters, or IV tubing containing polycarbonate for preparation or administration.

Busulfan for 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.

Extemporaneously Prepared

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).

Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31(2):164-92. doi: 10.1592/phco.31.2.164.21275495

Administration

Antiemetics may be recommended to prevent nausea and vomiting; depending on dose and/or administration route, busulfan is associated with a moderate 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.

Storage

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).

Drug Interactions

Acetaminophen: May increase the serum concentration of Busulfan. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May increase the serum concentration of Busulfan. Isavuconazonium considerations are addressed in separate monographs. Exceptions: Isavuconazonium Sulfate. Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Blinatumomab: May increase the serum concentration of Busulfan. Monitor therapy

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. 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. 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. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Busulfan. Monitor therapy

Ifosfamide: Busulfan may enhance the adverse/toxic effect of Ifosfamide. Specifically, the risk of hemorrhagic cystitis may be increased. 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. 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. 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. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

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. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. 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. Consider therapy modification

Phenytoin: May decrease the serum concentration of Busulfan. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Propacetamol: May increase the serum concentration of Busulfan. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

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

Warnings/Precautions

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 (Paw Cho Sing 2019) and a moderate emetic potential 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).
• 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 anticonvulsant 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:

• Anticonvulsants: Phenytoin increases busulfan clearance by ≥15%; busulfan kinetics and dosing recommendations for high-dose HSCT conditioning were studied with concomitant phenytoin. If alternate anticonvulsants are used, busulfan clearance may be decreased and dosing should be monitored accordingly.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

Monitoring Parameters

CBC with differential and platelet count (weekly for palliative treatment; daily until engraftment for HSCT); liver function tests (evaluate transaminases, alkaline phosphatase, and bilirubin daily for at least 28 days post transplant) and signs/symptoms of sinusoidal obstruction syndrome. Monitor for signs/symptoms of cardiac tamponade.

If conducting therapeutic drug monitoring for AUC calculations in HSCT, monitor blood samples at appropriate collections times (record collection times). Do not collect blood sample during busulfan 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.

Pregnancy

Pregnancy Risk Factor

D

Pregnancy Considerations

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.

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.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.
• It is used before bone marrow or stem cell transplant.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Dry mouth
• Skin discoloration
• Anxiety
• Back pain
• Fatigue
• Constipation
• Flushing
• Injection site irritation or swelling
• Runny nose
• Trouble sleeping
• Mouth sores
• Mouth irritation
• Lack of appetite
• Heartburn
• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in the amount of urine passed, dry mouth, dry eyes, or nausea or vomiting
• DVT like swelling, warmth, numbness, change in color, or pain in the extremities
• Severe abdominal pain
• Severe nausea
• Severe vomiting
• Cataracts
• Severe loss of strength and energy
• Chest pain
• Seizures
• Vision changes
• No menstrual periods
• Depression
• Severe dizziness
• Passing out
• Fast heartbeat
• Severe headache
• Swelling
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.