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Busulfan

Pronunciation

(byoo SUL fan)

Index Terms

  • Bussulfam
  • Busulfanum
  • Busulphan

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Busulfex: 6 mg/mL (10 mL)

Tablet, Oral:

Myleran: 2 mg

Brand Names: U.S.

  • Busulfex
  • Myleran

Pharmacologic Category

  • Antineoplastic Agent, Alkylating Agent

Pharmacology

Busulfan is an alkylating agent which reacts with the N-7 position of guanosine and interferes with DNA replication and transcription of RNA. Busulfan has a more marked effect on myeloid cells than on lymphoid cells and is also very toxic to hematopoietic stem cells. Busulfan exhibits little immunosuppressive activity. Interferes with the normal function of DNA by alkylation and cross-linking the strands of DNA.

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

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: Labeled Indications

Chronic myeloid leukemia (CML):

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

Tablets: Palliative treatment of CML

Use: Unlabeled

Conditioning regimen prior to hematopoietic stem cell transplant (HSCT) (oral); treatment of polycythemia vera and essential thrombocytosis

Contraindications

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

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. 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; usual range: 4 to 8 mg/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 (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).

Reduced intensity conditioning regimen (off-label dosing): 0.8 mg/kg/day for 4 days starting 5 days prior to transplant (in combinations with fludarabine) (Ho 2009)

Oral (off-label use): 1 mg/kg/dose every 6 hours for 16 doses (in combination with cyclophosphamide) (Socié 2001) or 1 mg/kg/dose every 6 hours for 16 doses beginning 9 days prior to transplant (in combination with cyclophosphamide) (Cassileth 1993) or 0.44 mg/kg/dose every 6 hours for 16 doses (in combination with cyclophosphamide) (Anderson 1996) or 1 mg/kg/dose every 6 hours for 16 doses beginning 6 days prior to transplant (in combination with melphalan) (Fermand 2005)

Essential thrombocythemia (off-label use): Oral: 2 to 4 mg daily (Fabris 2009; Tefferi 2011)

Polycythemia vera, refractory (off-label use): Oral: 2 to 4 mg daily (Tefferi 2011)

Dosing: Geriatric

Oral (refer to individual protocols): Start with lowest recommended doses for adults.

Dosing: Pediatric

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)

Dosing: Renal Impairment

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).

Dosing: Hepatic Impairment

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.

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 doses over 12 mg/kg, 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 and pediatrics: Utilize actual body weight (ABW) to calculate BSA

Weight based dosing (mg/kg): Adults: Utilize ABW25 for obese and nonobese patients; Pediatric: Utilize actual body weight (ABW)

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

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). 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]).

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). When manipulating tablets, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection as well as ventilated engineering controls are recommended (NIOSH 2014).

A 2 mg/mL oral suspension can be prepared in a vertical flow hood with tablets and simple syrup. Crush one-hundred-twenty 2 mg tablets in a mortar and reduce to a fine powder. Add small portions of simple syrup and mix to a uniform paste; mix while adding the simple syrup in incremental proportions to almost 120 mL; transfer to a graduated cylinder, rinse mortar and pestle with simple syrup, and add quantity of vehicle sufficient to make 120 mL. Transfer contents of the graduated cylinder into an amber prescription bottle. Label “shake well”, “refrigerate”, and “caution chemotherapy”. Stable for 30 days.

Allen LV, "Busulfan Oral Suspension," US Pharm, 1990, 15:94-5.

Administration

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.

Intravenous busulfan should be infused over 2 hours via central line. Use an administration set with a minimal residual priming volume (2 to 5 mL for adults and 1 to 3 mL for pediatrics). Flush line before and after each infusion with 5 mL D5W or NS. Do not use polycarbonate syringes or filters for preparation or administration. Busulfan 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]).

HSCT only: To facilitate ingestion of high oral doses, may insert multiple tablets into gelatin capsules.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Avoid exposure to crushed or broken tablets ; if it is necessary to manipulate the tablets (eg, to prepare an oral solution), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

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

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

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

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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. 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. 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

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

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

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

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

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

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

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. Avoid combination

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

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. Avoid combination

Adverse Reactions

Intravenous: Frequency not always defined.

>10%:

Cardiovascular: Edema (28% to 79%), tachycardia (44%), hypertension (36%; grades 3/4: 7%), thrombosis (33%), chest pain (26%), vasodilatation (25%), hepatic veno-occlusive disease (hepatic sinusoidal obstruction syndrome; children: 21%; adults: 8% to 12%), hypotension (11%; grades 3/4: 3%)

Central nervous system: Insomnia (84%), anxiety (72% to 75%), headache (69%), chills (46%), pain (44%), dizziness (30%), depression (23%), confusion (11%)

Dermatologic: Skin rash (57%), pruritus (28%), alopecia (17%)

Endocrine & metabolic: Hypomagnesemia (77%), hyperglycemia (66% to 67%; grades 3/4: 15%), hypokalemia (64%), hypocalcemia (49%), hypophosphatemia (17%)

Gastrointestinal: Vomiting (43% to 100%), nausea (83% to 98%), mucositis (≤79% to 97%; grades 3/4: ≤26%), stomatitis (≤79% to 97%; grades 3/4: ≤26%), anorexia (85%), diarrhea (84%; grades 3/4: 5%), abdominal pain (72%), dyspepsia (44%), constipation (38%), xerostomia (26%), rectal disease (25%), gastrointestinal fullness (23%), hiccups (18%)

Genitourinary: Oliguria (15%)

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%; grades 3/4: 30%), increased serum ALT (31%; grades 3/4: 7%), increased serum alkaline phosphatase (15%), jaundice (12%)

Hypersensitivity: Hypersensitivity reaction (26%)

Infection: Infection (51%; includes severe bacterial infection, viral [cytomegalovirus disease], and fungal infection)

Local: Inflammation at injection site (25%), pain at injection site (15%)

Neuromuscular & skeletal: Weakness (51%), back pain (23%), myalgia (16%), arthralgia (13%)

Renal: Increased serum creatinine (21%)

Respiratory: Rhinitis (44%), pulmonary disease (34%), cough (28%), dyspnea (25%), epistaxis (25%), pneumonia (children: 21%), pharyngitis (18%)

Miscellaneous: Fever (80%)

1% to 10%:

Cardiovascular: Cardiac arrhythmia (5%), cardiomegaly (5%), atrial fibrillation (2%), cardiac failure (grades 3/4: 2%), cardiac tamponade (children with thalassemia: 2%), ECG abnormality (2%), heart block (2%), pericardial effusion (2%), ventricular premature contractions (2%)

Central nervous system: Lethargy (7%), hallucination (5%), agitation (2%), brain disease (2%), delirium (2%), drowsiness (2%), seizure (2%), cerebral hemorrhage (1%)

Dermatologic: Vesicular eruption (10%), vesiculobullous dermatitis (10%), maculopapular rash (8%), skin discoloration (8%), acne vulgaris (7%), exfoliative dermatitis (5%), erythema nodosum (2%)

Endocrine & metabolic: Weight gain (8%), hyponatremia (2%), hypervolemia

Gastrointestinal: Intestinal obstruction (8%), esophagitis (grade 3: 2%), hematemesis (2%), pancreatitis (2%)

Genitourinary: Hematuria (8%), dysuria (7%), hemorrhagic cystitis (grade 3/4: 7%)

Hematologic & oncologic: Prolonged prothrombin time (2%)

Hepatic: Hepatomegaly (6%)

Renal: Increased blood urea nitrogen (3%; grades 3/4: 2%)

Respiratory: Asthma (8%), hyperventilation (5%), pulmonary alveolar hemorrhage (5%), hemoptysis (3%), pleural effusion (3%), sinusitis (3%), atelectasis (2%), hypoxia (2%)

Oral: Frequency not always defined.

Dermatologic: Skin hyperpigmentation (5% to 10%), skin rash

Endocrine & metabolic: Amenorrhea, ovarian function suppression

Gastrointestinal: Xerostomia

Hematologic & oncologic: Bone marrow depression (including anemia, leukopenia, thrombocytopenia)

IV and/or Oral: <1% (Limited to important or life-threatening): Acute leukemia, adrenocortical insufficiency, alopecia (permanent), aplastic anemia (may be irreversible), azoospermia, bronchopulmonary dysplasia, capillary leak syndrome, cataract (rare), cheilosis, cholestatic jaundice, corneal thinning, endocardial fibrosis, erythema multiforme, esophageal varices, febrile neutropenia, gynecomastia, hepatic insufficiency, hepatocellular atrophy, hyperuricemia, lens changes, malignant neoplasm, myasthenia gravis, myelopathy (radiation-induced), ovarian failure, pancytopenia, porphyria cutanea tarda, pulmonary fibrosis, pulmonary interstitial fibrosis, recall skin sensitization (skin rash), sepsis, sterility, testicular atrophy, thrombotic thrombocytopenic purpura, tumor lysis syndrome, uricosuria, urticaria, xeroderma

ALERT: U.S. Boxed Warning

Experienced physician:

Do not use oral busulfan 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.

Bone marrow suppression:

Busulfan is a potent cytotoxic drug that causes severe and prolonged myelosuppression at the recommended dosage. 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. Perform a bone marrow examination if the bone marrow status is uncertain. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications from prolonged myelosuppression due to IV busulfan.

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 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]).

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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 Risk Factor

D

Pregnancy Considerations

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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dry mouth, skin discoloration, anxiety, back pain, constipation, flushing, injection site irritation or edema, rhinorrhea, insomnia, mouth sores, lack of appetite, heartburn, or diarrhea. Have patient report immediately to prescriber signs of infection, signs of bleeding (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 bleeding that is very bad or that will not stop), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, nausea or vomiting), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), severe abdominal pain, severe nausea, severe vomiting, cataracts, severe loss of strength and energy, angina, seizures, vision changes, amenorrhea, depression, severe dizziness, passing out, tachycardia, severe headache, or edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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