Busulfan

Leukemia is a cancer that forms in the blood cells. Some patients who have chronic myelogenous leukemia have Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML). The Philadelphia chromosome contains a gene that codes for a protein called Bcr-Abl. Bcr-Abl makes leukemia cells divide more rapidly. This gene can also make leukemia cells resistant to certain types of treatment.

Testing for the Philadelphia chromosome is done to see whether treatment with busulfan is likely to be effective in treating acute myelogenous leukemia. Busulfan is less effective in patients without the Philadelphia chromosome. If testing is not done, treatment with busulfan may not be effective.

Before taking busulfan, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to busulfan or to any of its ingredients
• have previously received radiation therapy or treatment with other chemotherapy medications or if you have or have ever had seizures or a head injury
• have taken busulfan before, but your cancer did not respond to the medication
• are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Antineoplastic agent; bifunctional alkylating agent.129 131

Chronic Myelogenous Leukemia

Used IV in combination with cyclophosphamide: as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia (CML) (designated an orphan drug by US FDA for this use).130 131

Also administered orally† as a component of a conditioning regimen prior to allogeneic transplantation.131 132 133 134 135

Rarely, used as an alternative agent for palliative treatment of CML.103 129 129 Not curative, but approximately 90% of patients in the chronic phase of CML treated with the drug obtain remissions.109 111 129

Pretransplant Regimens

Component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases (e.g., sickle cell disease)†.102 138 139

(byoo SUL fan)

• Busulfex
• Myleran

• Antineoplastic Agent, Alkylating Agent

Hypersensitivity to busulfan or any component of the formulation; oral busulfan is contraindicated in patients without a definitive diagnosis of CML

Canadian labeling: Additional contraindications (not in US labeling): Oral busulfan: Neutropenia or thrombocytopenia; disease that has demonstrated resistance to busulfan

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. Busulfan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011). Antiemetics are recommended when used for transplantation.

Chronic myelogenous leukemia (CML), palliation (manufacturer’s labeling): Oral:

Remission induction: 60 mcg/kg/day or 1.8 mg/m2/day; titrate dose (or withhold) to maintain leukocyte counts ≥15,000/mm3 (doses >4 mg/day should be reserved for patients with the most compelling symptoms)

Maintenance: When leukocyte count ≥50,000/mm3: Resume induction dose or (if remission <3 months) 1 to 3 mg/day (to control hematologic status and prevent relapse)

Hematopoietic stem cell transplant (HSCT) conditioning regimens:

IV:

≤12 kg: 1.1 mg/kg/dose (actual body weight) every 6 hours for 16 doses (over 4 days) (followed by cyclophosphamide)

>12 kg: 0.8 mg/kg/dose (actual body weight) every 6 hours for 16 doses (over 4 days) (followed by cyclophosphamide)

Adjust dose to desired AUC (900 to 1,350 micromolar•minute) at the completion of dose 1 using the following formula:

Adjusted dose (mg) = Actual dose (mg) x [target AUC (micromolar•minute) / actual AUC (micromolar•minute)]

Reduced intensity conditioning regimen (off-label dosing): 0.8 mg/kg/dose for 1 dose 7 to 10 days prior to transplant, followed by ~0.8 mg/kg/dose (busulfan kinetics calculated after initial dose) every 6 hours for 7 doses beginning 3 to 6 days prior to transplant (in combination with fludarabine and antithymocyte globulin) (Pulsipher 2009)

Oral (off-label use): 1 mg/kg/dose every 6 hours for 16 doses beginning 9 days prior to transplant (in combination with cyclophosphamide) (Cassileth 1998)

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).

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. Do not use polycarbonate syringes or filters for preparation or administration. Busulfan for injection contains N,N-dimethylacetamide, which is incompatible with many closed-system transfer devices (CSTDs); the plastic components of CSTDs may dissolve and result in subsequent leakage and potential infusion of dissolved plastic into the patient (ISMP [Smetzer 2015]).

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).

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 G-CSF 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.

• Gastrointestinal toxicity: Busulfan is associated with a moderate emetic potential (depending on dose and/or administration route); antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011).

• 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).

• Ovarian failure: Chronic low-dose busulfan has been associated with ovarian failure (including failure to achieve puberty) and amenorrhea.

• 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:

• Dimethylacetamide (DMA): The solvent in IV busulfan, DMA, may impair fertility. DMA may also be associated with hepatotoxicity, hallucinations, somnolence, lethargy, and confusion. N,N-dimethylacetamide is incompatible with many closed-system transfer devices (CSTDs) used for preparing injectable antineoplastics (ISMP [Smetzer 2015]).

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.

Adverse events were observed in animal reproduction studies. May cause fetal harm if administered during pregnancy. The solvent in IV busulfan, DMA, is also associated with teratogenic effects and may impair fertility. Women and men of childbearing potential should use effective contraception to avoid pregnancy during and after busulfan treatment.

There are no data on the excretion of busulfan into human milk. Because of the potential for tumorigenicity shown in animal and human studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

LactMed Record Number

37

Last Revision Date

20170411

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