VA Class:AN100
Busulfan, a bifunctional alkylating agent, is an antineoplastic agent.129, 131
Allogeneic Hematopoietic Stem Cell Transplantation
Busulfan is used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in patients with chronic myelogenous leukemia (CML) and is designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this disease.130, 131 Although a preparative regimen of high-dose chemotherapy followed by allogeneic stem cell transplantation currently is the only consistently curative treatment for CML, the selection of candidates is limited by age restrictions and the availability of ideal donors (i.e., HLA-matched siblings).103, 109 Survival rates and duration are most favorable for patients undergoing transplantation during the chronic phase of CML and progressively worse for those in the accelerated or blastic phases.103, 109
The current indication for the use of IV busulfan as a component of a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation is based on data from an uncontrolled, phase 2 trial of IV busulfan and from previously published randomized, controlled studies of high-dose oral busulfan.131, 132, 133, 134, 135 In an open-label, uncontrolled trial, 61 patients received busulfan 0.8 mg/kg as a 2-hour IV infusion every 6 hours for 4 days for a total of 16 doses, followed by cyclophosphamide 60 mg/kg once a day for 2 days; after one day of rest, allogeneic hematopoietic stem cells were infused.131 The study patients had various hematologic malignancies, including acute leukemia (relapsed, refractory, or high-risk first remission), chronic myelogenous leukemia (chronic phase, accelerated phase, or blast crisis), Hodgkin's disease or non-Hodgkin's lymphoma (primary refractory or resistant relapsed disease), and myelodysplastic syndrome.131 Approximately half (48%) of the patients were heavily pretreated, defined as one or more of the following: prior radiation therapy, 3 or more prior chemotherapy regimens, or prior hematopoietic stem cell transplantation.131
Myeloablation (defined as at least one of the following: absolute neutrophil count below 0.5 x 109/L, absolute lymphocyte count below 0.1 x 109/L, platelet count below 20,000/mm3, or a requirement for platelet transfusion) was achieved in all patients.131 Onset of neutropenia occurred at a median of 4 days; prophylactic granulocyte colony-stimulating factor was administered in the majority of patients.131 Engraftment was achieved in all 60 evaluable patients and occurred at a median of 13 days after transplant (range: 9-29 days).131 Relapse occurred in 38% of patients at a median of 183 days after transplant (range: 36-406 days).131 A total of 62% of patients were free from disease with a median follow-up of 269 days after transplant (range: 20-583 days).131 A survival rate of 70% with a median follow-up of 288 days after transplant (range: 51-583 days) was reported.131
Busulfan also has been administered orally† as a component of a conditioning regimen prior to allogeneic transplantation.131, 132, 133, 134, 135 In 4 randomized, controlled studies in patients undergoing allogeneic bone marrow transplantation for CML or other hematologic malignancies, patients randomized to the busulfan-containing regimen generally received oral busulfan 4 mg/kg daily for 4 days and cyclophosphamide 60 mg/kg daily for 2 days.131, 132, 133, 134, 135 The results of these studies indicated that the efficacy of the busulfan and cyclophosphamide regimen was similar to the comparator regimens, which included cyclophosphamide plus total body irradiation and etoposide plus total body irradiation.131, 132, 133, 134, 135 Based on the clinical trial using IV busulfan and on the available literature on oral busulfan, the FDA Oncologic Drugs Advisory Committee concluded that the 2 dosage forms are comparably safe and effective as part of a conditioning regimen prior to allogeneic stem cell transplants.136
Busulfan rarely is used as an alternative agent for the palliative treatment of chronic myelogenous leukemia (CML).103, 129 Interferon alfa, with or without cytarabine, is a first-line therapy for the palliative treatment of CML in patients who cannot undergo allogeneic hematopoietic progenitor cell transplantation, which is the only therapy known to be curative for this leukemia.103, 109, 125 In a randomized trial, median survival was longer in patients receiving interferon alfa versus busulfan for CML.111 Unlike interferon alfa, busulfan has not been associated with prolonged cytogenetic response (i.e., suppression of Philadelphia chromosome-positive cells) in patients with Philadelphia chromosome (Ph)-positive CML.127, 128 Hydroxyurea, an alternative agent for the palliative treatment of CML, is superior to busulfan;103, 109, 137 in a randomized trial, patients receiving hydroxyurea experienced prolonged median survival and less toxicity compared with those receiving busulfan.126
Busulfan is not curative, but approximately 90% of patients in the chronic phase of CML treated with the drug obtain remissions.109, 111, 129 Subjective response generally starts within 1-3 weeks, and remissions are characterized by a decrease in the leukocyte count and spleen size, disappearance of sternal tenderness, and an increase in hemoglobin. Duration of therapy required to bring the leukocyte count to normal depends mainly on the level of the leukocyte count when therapy was begun, the daily dose, and the sensitivity of the patient. Approximately 2 months of continuous therapy is required in most patients to reduce the leukocyte count to desired levels. In about half the patients with CML, busulfan induces an initial remission of 9-12 months or longer. During remissions, the patient's quality of life is reportedly improved due to increased comfort, appetite, sense of well-being, and general ability to function. Resistance to busulfan develops progressively. Subsequent remissions usually become shorter and more difficult to achieve, but may be maintained for months or even years with busulfan therapy. Busulfan is an alternative agent for the palliative treatment of the accelerated phase of CML.103 The drug does not prevent, and is ineffective during, the blastic phase of CML.129
Busulfan is less effective in the management of patients with CML who lack the Philadelphia (Ph1) chromosome.129 In addition, the juvenile type of CML responds poorly to busulfan.129
Chemotherapy typically is used to reduce leukocyte count and stabilize hematologic status prior to allogeneic bone marrow transplantation.103 Retrospective analysis indicates that probability of disease-free survival at 3 years is higher in patients receiving hydroxyurea rather than busulfan for CML in chronic phase prior to allogeneic transplant.124
Busulfan has been used as a 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
Reconstitution and Administration
Busulfan tablets are administered orally.129
Busulfan for injection concentrate is administered by IV infusion.131 The manufacturer states that rapid infusion of busulfan has not been evaluated and is not recommended.131
Commercially available busulfan for injection concentrate must be diluted prior to IV infusion. 131 The manufacturer recommends diluting busulfan for injection concentrate in 0.9% sodium chloride injection or 5% dextrose injection with approximately 10 times the volume of the calculated dose of busulfan to achieve a final busulfan concentration of approximately 0.5 mg/mL.131 A 5-µm nylon filter is provided with each ampul of busulfan and should be used to withdraw the calculated volume of busulfan for injection concentrate from the ampul.131 If using the provided syringe filter in the forward flow direction, the calculated volume of busulfan for injection concentrate should allow for approximately 0.16 mL of residual busulfan for injection concentrate that will remain in the filter.131 The use of filters other than the specific type of filter provided with the busulfan ampul is not recommended.131 A new needle should then be used to inject the drug into an IV bag (or large-volume syringe) that contains the calculated volume of diluent; according to the manufacturer, the busulfan always must be added to the diluent rather than the diluent being added to the drug.131 The manufacturer states that polycarbonate syringes or polycarbonate filter needles should not be used for the preparation or administration of busulfan solutions.131 The diluted busulfan infusion should be inverted several times to ensure thorough mixing.131
Caution should be exercised in handling and preparing solutions of busulfan.131 Busulfan solutions should be prepared under a vertical laminar-flow safety hood.131 Because dermatologic reactions may occur with accidental exposure to the drug, the manufacturer recommends the use of protective gloves and clothing during the preparation and administration of busulfan infusions.131 Skin or mucosa accidentally exposed to the drug should be washed immediately and thoroughly with water.131
Busulfan for injection concentrate and diluted solutions of the drug should be inspected visually for particulate matter whenever solution and container permit.131 If particulate matter is observed in the ampul of busulfan, it should not be used.131
According to the manufacturer, an administration set with minimal residual hold-up volume (2-5 mL) should be used to administer the drug.131 Diluted IV solutions of busulfan should be administered via a central venous catheter over 2 hours using a controlled-infusion device (e.g., pump).131 The catheter line should be flushed with about 5 mL of 0.9% sodium chloride or 5% dextrose injection before and after each busulfan infusion.131 Busulfan solutions should not be mixed or administered with other IV solutions of unknown compatibility.131
For additional administration instructions related to therapeutic drug monitoring and adjust dosage of IV busulfan in children, see Pediatric Dosage in Dosage and Administration: Dosage: Chronic Myelogenous Leukemia: Allogeneic Hematopoietic Stem Cell Transplantation.131
Allogeneic Hematopoietic Stem Cell Transplantation: Adult Dosage
When used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in adult patients with chronic myelogenous leukemia, the recommended dose of IV busulfan is 0.8 mg/kg of ideal body weight or actual body weight (whichever is lower) every 6 hours for 4 consecutive days (for a total of 16 doses).131 In obese patients, busulfan dosage should be based on adjusted ideal body weight (ideal body weight plus 0.25 times the difference between actual weight and ideal body weight).131 The manufacturer states that all patients should receive premedication with phenytoin for seizure prophylaxis;131 in addition, all patients should receive antiemetics prior to the first dose of IV busulfan and on a fixed schedule throughout busulfan therapy.131 Cyclophosphamide should be administered (at a dose of 60 mg/kg IV over 1 hour daily for 2 days) starting 6 hours after the 16th dose of IV busulfan (i.e., on bone marrow transplant day 3).131 When available, monitoring of the busulfan area under the plasma concentration-time curve (AUC) may be considered to optimize dosage adjustment for busulfan.131
When administered orally† as a component of a conditioning regimen prior to allogeneic transplantation, a busulfan dosage of 4 mg/kg per day for 4 days most commonly has been used.131
Allogeneic Hematopoietic Stem Cell Transplantation: Pediatric Dosage
When used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation in pediatric patients, the manufacturer suggests an initial IV busulfan dosage (based on actual body weight) of 1.1 mg/kg in children weighing 12 kg or less, and 0.8 mg/kg in children weighing more than 12 kg.131 Simulations based on a pharmacokinetic model of a pediatric population indicate that about 60% of children will achieve a target busulfan area under the plasma concentration-time curve (AUC) of 900-1350 µ M •minute with the first dose of IV busulfan using these recommended initial dosages.131 Therapeutic drug monitoring and dosage adjustment following the first dose of IV busulfan is recommended.131
Dosage Adjustment Based on Therapeutic Drug Monitoring
The manufacturer suggests the use of therapeutic drug monitoring to adjust the dosage of IV busulfan in children following administration of the initial dose.131
The busulfan AUC should be calculated based on blood samples collected at specified time points; actual sampling times should be recorded.131 When measuring serum busulfan concentrations with the initial dose of the drug, blood samples should be collected at 2 hours (the end of the infusion), 4 hours, and 6 hours (immediately prior to the next scheduled busulfan dose).131 For doses other than the first dose, blood samples should be collected prior to the infusion (baseline), and then at 2 hours (the end of the infusion), 4 hours, and 6 hours (immediately prior to the next scheduled busulfan dose).131 Calculations based on fewer samples than specified may result in inaccurate AUC determinations.131
Special instructions for drug administration and blood sample collection should be followed to ensure accurate therapeutic drug monitoring.131 An administration set with minimal residual hold-up (priming) volume (1-3 mL) should be used for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for the measurement of serum busulfan concentrations.131 The administration set tubing should be primed with drug solution to allow accurate documentation of the start time of the busulfan infusion.131 The blood sample should be collected from a peripheral IV line to avoid contamination with the infusing drug solution.131 If the blood sample is taken directly from the existing central venous catheter, it is important that the blood sample not be collected while the drug is infusing to ensure that the end of the infusion sample is not contaminated with any residual drug.131 At the end of the infusion (2 hours), the administration tubing should be disconnected and the central venous catheter line should be flushed with 5 mL of normal saline prior to the collection of the blood sample from the central venous catheter port.131 The blood samples should be collected from a different port than that used for the busulfan infusion.131 The time required to flush the indwelling catheter line should not be included when recording the busulfan infusion stop time.131 The administration tubing should be discarded at the end of the 2-hour infusion.131
Collection of the blood samples should be performed by collecting 1-3 mL of blood into heparinized (Na or Li heparin) Vacutainer® tubes.131 The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4°C) within 1 hour.131 The plasma should be harvested into appropriate cryovial storage tubes and frozen immediately at -20°C.131 All plasma samples should be sent in a frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations.131
Busulfan AUC following the initial dose may be calculated using the following equation where AUC0-6hr is estimated using the linear trapezoidal rule and AUCextrapolated is the ratio of the busulfan concentration at hour 6 and the terminal elimination rate constant, λz.131 The terminal elimination rate constant must be calculated from the terminal elimination phase of the busulfan concentration versus time curve.131 A pre-dose busulfan concentration of zero is assumed and should be used in calculating the AUC.131
busulfan AUC∞ for dose 1 = AUC0-6hr + AUCextrapolated
When busulfan AUC for dose 1 has been calculated, the following formula may be used for the adjustment of subsequent busulfan doses to achieve the target busulfan AUC of 1125 µ M •minute:131
adjusted dose (mg) = actual dose (mg) × target AUC (µ M •minute) / actual AUC (µ M •minute)
For the determination of AUC following subsequent doses of IV busulfan, determination of steady-state busulfan AUC (AUC0-6hr) should be estimated from the trough, 2 hour, 4 hour, and 6 hour concentrations using the linear trapezoidal rule.131
Dosage of oral busulfan must be individualized based on clinical and hematologic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects.
For remission induction in the management of chronic myelogenous leukemia, the usual adult dosage of busulfan is 4-8 mg daily,129 but dosages ranging from 1-12 mg daily have been used. The manufacturer states that dosing on a weight basis is the same for both children and adults, and recommends daily dosages of approximately 0.06 mg/kg or 1.8 mg/m2.129 Some clinicians have recommended dosages of 0.065-0.1 mg/kg daily. The manufacturer states that dosages exceeding 4 mg daily are especially likely to reduce the leukocyte count rapidly and should be used only in patients with severely symptomatic disease; higher dosages increase the risk of inducing bone marrow aplasia.129 A reduction in the leukocyte count is not usually seen during the first 10-15 days of busulfan therapy; the leukocyte count may actually increase during this period and should not be interpreted as resistance to the drug nor should the dosage be increased.129 Since the leukocyte count may continue to fall for more than 1 month after discontinuing the drug, the manufacturer states that therapy with busulfan should be discontinued before the leukocyte count falls to normal levels.129 The manufacturer states that busulfan should be discontinued when the leukocyte count has decreased to approximately 15,000/mm3.129 Some authorities believe dosage should be continued until the leukocyte count falls below 10,000/mm3, while others prefer to discontinue the drug when leukocyte count reaches 15,000 to 25,000/mm3; still others propose decreasing dosage in proportion to the decrease in leukocyte count. During remissions induced by intermittent treatment regimens, the patient should be examined at monthly intervals and busulfan therapy should be resumed when the leukocyte count reaches 50,000/mm3.129
There is little agreement on whether busulfan should be administered continually or intermittently. Although many clinicians use maintenance doses, others believe toxicities occur less frequently on intermittent therapy and maintenance dosage should be reserved for patients who cannot sustain a remission without the drug. When remission is not sustained for longer than 3 months, the manufacturer states that maintenance therapy of 1-3 mg daily may be advisable in order to prevent rapid relapses.129 Other suggested maintenance dosages range from 2 mg/week to 4 mg/day.
Pediatric busulfan dosage recommendations range from 0.06-0.12 mg/kg daily. Alternatively, 1.8-4.6 mg/m2 daily has been recommended. Dosage should be titrated to maintain a leukocyte count of about 20,000/mm3.
Information on the adverse effects of IV busulfan is based mainly on data from an uncontrolled clinical trial involving 61 patients with various hematologic malignancies who received the drug as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation.131 In this study, 2 deaths occurred during the 28 days following the allogeneic transplant, and 6 deaths occurred between day 29 and day 100 following transplant.131 Additional information on adverse effects of the drug in this setting is derived from randomized trials using high-dose oral busulfan as part of a conditioning regimen for bone marrow transplant in patients with CML or other types of leukemia.131
Dimethylacetamide, a solvent that previously was studied as a potential chemotherapy agent, is present in the daily recommended dosage of IV busulfan in an amount equivalent to 42% of the maximum tolerated dose on a mg/m2 basis.131 The dose-limiting toxicities of dimethylacetamide are hepatotoxicity, including increased serum AST concentrations, and neurotoxicity, including hallucinations, somnolence, lethargy, and confusion; the relative contribution of the solvent (and/or other concomitantly administered medications) to adverse hepatic and neurologic effects observed in patients receiving IV busulfan is not known.131
Hematologic Effects and Infectious Complications
The major adverse effect of busulfan is hematologic toxicity,129, 131 which is usually dose related and reversible after discontinuance of the drug. Myelosuppression may manifest as leukopenia, thrombocytopenia, anemia, or any combination of these.129, 131
In patients receiving oral busulfan, pancytopenia generally occurs with failure to adequately monitor hematologic status and promptly discontinue the drug in response to a large or rapid decrease in leukocyte or platelet counts.129 Although individual variation in response to the drug does not appear to be an important contributing factor, some patients may be especially sensitive to busulfan and experience abrupt onset of neutropenia or thrombocytopenia.129 Busulfan-induced pancytopenia may be more prolonged than that induced by other alkylating agents;129 although recovery may take 1 month to 2 years, the toxicity is potentially reversible and patients should be vigorously supported through any period of severe pancytopenia.76, 129 Some patients develop bone marrow fibrosis or chronic aplasia which is probably due to busulfan toxicity. Aplastic anemia, sometimes irreversible, has been reported rarely in patients receiving oral busulfan; aplastic anemia usually has occurred following high doses of the drug or long-term administration of conventional doses.129
Profound myelosuppression occurs in all patients receiving the recommended dosage of IV busulfan, with absolute neutrophil counts decreasing to below 0.5 x 109/L at a median of 4 days after allogeneic transplant.131 Recovery of the absolute neutrophil count occurred at a median of 13 days after transplantation; prophylactic granulocyte colony-stimulating factor was administered in the majority of patients.131 Thrombocytopenia (platelet count below 25,000/mm3 or requiring platelet transfusion; median onset of 5-6 days) was reported in 98% of patients receiving IV busulfan, and a median of 6 platelet transfusions and 4 red blood cell transfusions per patient were required.131 Anemia (hemoglobin less than 8 g/dL) occurred in 69% of patients.131 Prolonged prothrombin time was reported in 1 patient receiving IV busulfan.131
Infections, including sepsis and pneumonia, have been reported in patients receiving oral or IV busulfan.129, 131 Infections were reported in 51% of patients receiving IV busulfan.131 Life-threatening pneumonia occurred in 3% of patients and was fatal in at least one patient.131
Fatal pulmonary effects have occurred in patients receiving oral or intravenous busulfan.129, 131
A rare but serious syndrome which usually occurs only after long-term busulfan therapy with onset of symptoms at an average of 4 years following initiation of therapy (range: 4 months to 10 years) is “busulfan lung.”129, 131 The syndrome is manifested by bronchopulmonary dysplasia with a diffuse interstitial pulmonary fibrosis and is characterized by persistent cough, fever, rales, and dyspnea. Histologically, the syndrome mimics findings associated with pulmonary irradiation.129 Pulmonary function studies have shown diminished diffusion capacity and decreased pulmonary compliance.129 Diagnosis of “busulfan lung” may be confounded by the presence of common underlying conditions (e.g., opportunistic infections, pulmonary leukemic infiltrates).129 If diagnostic measures such as sputum cultures, virologic studies, and exfoliative cytology fail to establish the etiology of pulmonary infiltrates, lung biopsy may be necessary to establish the diagnosis.129 There is no specific therapy for “busulfan lung,” and the drug should be discontinued immediately if this toxicity develops; although corticosteroids have been used, their efficacy seems equivocal.129 In some patients, “busulfan lung” has been relieved by discontinuance of the drug and administration of corticosteroids; in most patients, however, the syndrome has progressed to respiratory insufficiency despite the discontinuance of busulfan, and deaths have usually occurred within 6 months of diagnosis of the syndrome.129
In patients receiving IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic stem cell transplantation, lung disorders were reported in 34% of patients.131 Alveolar hemorrhage requiring mechanical ventilation and resulting in death was reported in 3 patients (5%) receiving IV busulfan.131 Dyspnea occurred in 27% of patients and was severe in 2% of patients, and cough occurred in 28% of patients and was mild to moderate.131 Mild or moderate asthma was reported in 8% of patients receiving IV busulfan.131 Hyperventilation was reported in 5% of patients and was severe in one patient.131
Rhinitis, epistaxis, and pharyngitis were reported in 44, 25, and 18% of patients receiving IV busulfan.131 Additional adverse pulmonary effects reported in less than 5% of patients receiving IV busulfan were mild to moderate and included atelectasis, pleural effusion, hypoxia, sinusitis, and hemoptysis.131
Interstitial pneumonitis and pulmonary fibrosis, which rarely were fatal, also have been reported in patients receiving high oral doses of busulfan as a component of a conditioning regimen prior to allogeneic bone marrow transplantation.131 Nonspecific interstitial fibrosis was diagnosed by lung biopsy in one patient receiving IV busulfan who subsequently died from respiratory failure.131
Life-threatening hepatic veno-occlusive disease has occurred in patients receiving busulfan (usually in combination with cyclophosphamide or other antineoplastic agents as a component of marrow-ablative therapy prior to bone marrow transplantation).112, 113, 114, 115, 129 The manufacturer states that a clear causal relationship to busulfan has not been demonstrated.129 Hepatic veno-occlusive disease diagnosed by clinical examination and laboratory findings occurred in 8% (5/61) of patients receiving IV busulfan in the allogeneic transplant clinical trial and was fatal in 40% (2/5) of cases.131 Overall mortality from hepatic veno-occlusive disease was 3% for the entire study population.131 Retrospectively, 3 of the 5 patients diagnosed with hepatic veno-occlusive disease were found to meet the Jones' criteria for this condition.131 In patients receiving high-dose oral busulfan as a component of a conditioning regimen prior to bone marrow transplant in randomized, controlled studies, the incidence of hepatic veno-occlusive disease was 7.7-12%.131
Other adverse hepatic effects reported in patients receiving oral busulfan include cholestatic jaundice, centrilobular sinusoidal fibrosis, and hepatocellular atrophy or necrosis.129
Hyperbilirubinemia has been reported in patients receiving oral or IV busulfan.129, 131 In patients receiving IV busulfan prior to allogeneic hematopoietic stem cell transplant, hyperbilirubinemia occurred in 49% of patients; hyperbilirubinemia was grade 3 or 4 in severity in 30% of patients and was life-threatening in 5% of these patients.131 Hyperbilirubinemia was associated with graft-versus-host disease in 6 patients and with hepatic veno-occlusive disease in 5 patients.131 Jaundice and hepatomegaly were reported in 12 and 6% of patients, respectively, and were mild or moderate in severity.131 Increases in serum ALT occurred in 31% of patients and were grade 3 or 4 in severity in 7% of patients, and mild or moderate increases in alkaline phosphatase concentrations were reported in 15% of patients.131
Busulfan has been associated with adverse nervous system effects, including dizziness,106 blurred vision,106 loss of consciousness,106 intermittent muscle twitching,106 myoclonic seizures,107 and generalized tonic-clonic (grand mal) seizures.106, 107, 112, 117, 119, 120, 121
Seizures have been reported in patients receiving busulfan orally, including administration of the drug at high doses (resulting in plasma concentrations similar to those achieved with the recommended dose of IV busulfan) as part of a conditioning regimen prior to bone marrow transplant.129, 131 In addition, despite the use of prophylactic phenytoin therapy, a seizure was reported in a patient receiving IV busulfan.131 According to the manufacturers, prophylactic anticonvulsant therapy should be started prior to treatment with IV busulfan and also may be considered in patients receiving oral busulfan. (See Precautions and Contraindications.)129, 131
Additional adverse neurologic effects reported in patients receiving IV busulfan include insomnia, anxiety, headache, dizziness, and depression, which were reported in 84, 75, 69, 30, and 23% of patients, respectively.131 Confusion and hallucinations were observed in 11 and 5%, respectively, of patients receiving IV busulfan, and lethargy was reported in 7% of patients.131 Delirium, agitation, somnolence, and encephalopathy each occurred in 2% of patients.131
Cardiac tamponade, often fatal, has been reported in a small number of pediatric patients with thalassemia who received oral busulfan and cyclophosphamide as the preparatory regimen for bone marrow transplantation;129, 131 abdominal pain and vomiting preceded the tamponade in most cases.129, 131 Cardiac tamponade was not reported in a clinical study of patients receiving IV busulfan.131
One case of endocardial fibrosis has been reported in a patient receiving long-term therapy with oral busulfan.58, 129
In patients receiving IV busulfan, mild or moderate tachycardia was reported in 44% of patients; in 11% of patients, the tachycardia was first reported during administration of the drug.131 Mild or moderate thrombosis involving a central venous catheter was reported in 33% of patients receiving IV busulfan.131 Hypertension occurred in 36% of patients and was grade 3 or 4 in severity in 7% of patients, and hypotension occurred in 11% of patients and was grade 3 or 4 in severity in 3% of patients.131 Mild vasodilation, manifested as flushing and hot flushes (flashes), was observed in 25% of patients.131 Edema and chest pain were reported in 36 and 26% of patients, respectively.131 Other adverse cardiovascular effects reported in 5% or fewer of patients receiving IV busulfan included mild or moderate arrhythmia, mild or moderate atrial fibrillation, and mild or moderate ventricular extrasystoles.131 Mild or moderate third degree heart block also has occurred in patients receiving IV busulfan.131 Cardiomegaly, mild ECG abnormality, grade 3 or 4 left-sided heart failure, and moderate pericardial effusion were reported in 5% or fewer of patients receiving IV busulfan, but were reported principally in the post-cyclophosphamide phase.131
Some form of mild or moderate edema was reported in 79% of patients receiving IV busulfan for allogeneic progenitor cell transplant.131 Hypervolemia also was reported, and documented weight increase occurred in 8% of patients.131
Adverse GI effects occur frequently in patients receiving IV busulfan.131 Nausea was reported in 98% of patients receiving IV busulfan in clinical trials and was severe in 7% of patients, and vomiting occurred in 95% of patients.131 The incidence of vomiting during administration of IV busulfan was 43%.131 Stomatitis occurred in 97% of patients and was grade 3 or 4 in severity in 26% of patients.131 Diarrhea was mild to moderate in 75% of patients and grade 3 or 4 in 5% of patients.131 Anorexia was reported in 85% of patients and was severe in 21% of patients, and abdominal pain was reported in 72% of patients.131 Mild to moderate constipation occurred in 38% of patients, and ileus occurred in 8% of patients and was severe in 2% of patients.131 Dyspepsia and rectal discomfort were reported in 44 and 24%, respectively, of patients receiving IV busulfan and were mild or moderate.131 Dry mouth and abdominal enlargement occurred in 26 and 23% of patients, respectively.131 Pancreatitis, grade 3 esophagitis, and mild hematemesis each was reported in 2% of patients.131
GI distress, nausea, vomiting, diarrhea, anorexia, and weight loss have been reported in patients receiving oral busulfan.129 Cheilosis,129 mucositis,129 and glossitis also have been reported in patients receiving oral busulfan.
As a result of extensive purine catabolism accompanying rapid cellular destruction, hyperuricemia may occur in patients receiving busulfan, especially those with widespread disease. In some patients, uric acid nephropathy, renal stones, and acute renal failure may result. These effects may be minimized by adequate hydration, alkalinization of the urine, and/or administration of a xanthine oxidase inhibitor, such as allopurinol.129
A wasting or Addison-like syndrome has occurred in a small number of patients, usually after long-term busulfan therapy. The wasting syndrome is generally characterized by melanoderma, asthenia, hypotension, nausea, vomiting, diarrhea, anorexia, weight loss, fatigue, apathy, and confusion. Patients with this syndrome do not usually exhibit a corresponding deficit in adrenocorticoid function; however, the pituitary response to metyrapone may be decreased (i.e., decreased urinary excretion of 17-hydroxycorticosteroids).129 Symptoms of this syndrome have occasionally resolved when busulfan was discontinued.129
In a clinical trial, hyperglycemia was reported in 67% of patients receiving IV busulfan, and was of grade 3 or 4 severity in 15% of patients.131 Hypomagnesemia was reported in 77% of patients and was mild to moderate in severity.131 Mild or moderate hypokalemia was observed in 62% of patients, and severe hypokalemia occurred in 2% of patients.131 Hypocalcemia occurred in 49% of patients and was severe in 3% of patients, and mild or moderate hypophosphatemia was reported in 17% of patients.131 Hyponatremia was reported in 2% of patients.131
Graft-versus-host disease, in some cases fatal, has occurred in patients receiving busulfan as a component of a conditioning regimen prior to allogeneic transplant.131 In patients receiving IV busulfan in a clinical trial, graft-versus-host disease occurred in 18% of patients, was severe in 3% of patients, and resulted in death in 5% of patients (i.e., 3 patients).131
Adverse dermatologic effects reported in patients receiving busulfan include rash, pruritus, and alopecia.129, 131 An increased incidence of local cutaneous reactions has been reported in patients receiving radiation therapy soon after busulfan therapy.129
In a clinical trial, rash and pruritus occurred in 57 and 28%, respectively, of patients receiving IV busulfan.131 Alopecia was reported to be mild in 15% of patients and moderate in 2% of patients.131 Mild vesicular rash and vesiculobullous rash each occurred in 10% of patients, and mild to moderate maculopapular rash occurred in 8% of patients.131 Skin discoloration, acne, and exfoliative dermatitis were reported in 8, 7, and 5% of patients, respectively, and erythema nodosum occurred in 2% of patients.131
Hyperpigmentation has been reported in 5-10% of patients receiving oral busulfan and appears to occur more frequently in patients with a dark complexion.129 Erythema nodosum, erythema multiforme, urticaria, porphyria cutanea tarda, dryness of the skin and mucous membranes, and anhidrosis also have been reported in patients receiving the drug orally.129
Mild to moderate increases in serum creatinine concentrations were reported in 21% of patients receiving IV busulfan in a clinical trial.131 In addition, elevated BUN was reported in 3% of patients and was grade 3 or 4 in 2% of patients.131 Oliguria, hematuria, and dysuria occurred in 15, 8, and 7% of patients, respectively, and grade 3 or 4 hemorrhagic cystitis was reported in 7% of patients.131
Use of busulfan has been associated with hemorrhagic cystitis;104, 105, 131 grade 3 or 4 hemorrhagic cystitis was reported in 7% of patients receiving IV busulfan in a clinical trial.131
Cataracts rarely have occurred in patients receiving oral busulfan.129 Corneal thinning and lens changes also have been reported in patients receiving oral busulfan.129
Back pain, mild or moderate myalgia, and mild or moderate arthralgia was reported in 23, 16, and 13%, respectively, of patients receiving IV busulfan in a clinical trial.131 Myasthenia gravis has been reported in patients receiving oral busulfan.129
Allergic reactions occurred in 26% of patients receiving IV busulfan in a clinical trial and were severe in 2% of patients.131 Erythema nodosum occurred in 2% of patients receiving IV busulfan in a clinical trial131 and also has been reported in patients receiving oral busulfan.129
Inflammation and mild or moderate pain at the injection site occurred in 25 and 15%, respectively, of patients receiving IV busulfan in a clinical trial.131
Fever has been reported in 80% of patients receiving IV busulfan and was severe in 3%.131 Other adverse effects reported in patients receiving IV busulfan include asthenia in 51%, chills in 46%, pain in 44%, hiccup in 18%, and otic disorder in 3%.131 Gynecomastia has been reported in patients receiving oral busulfan.62, 129
Cellular dysplasia characterized by giant, hyperchromic nuclei has occurred in the cells of many organs, including lymph nodes, pancreas, thyroid, adrenal glands, liver, and bone marrow.129, 131 Cytologic dysplasia may be severe enough to make interpretation of exfoliative cytologic examinations of cells from lung, bladder, breast, and cervix difficult.129, 131
Precautions and Contraindications
Busulfan is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents. Clinicians supervising the administration of IV busulfan also should be experienced in hematopoietic stem cell transplantation and the management of patients with severe pancytopenia.131
Patients who receive myelosuppressive drugs experience an increased incidence of infections as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the physician if fever, sore throat, unusual bleeding or bruising, or symptoms suggestive of anemia occur.
Patients beginning oral busulfan therapy should be informed of the importance of having periodic blood counts.129 The patient's hematologic status must be monitored carefully, and blood counts (hemoglobin or hematocrit, leukocyte and differential counts, and quantitative platelet count) should be performed at least once a week during oral busulfan therapy.129 Since the maximum effect on bone marrow function may be delayed, therapy should be discontinued temporarily or dosage reduced at the first sign of abnormal bone marrow depression.129 In some cases, bone marrow examination may be necessary in addition to blood counts.129 The decision to adjust dosage and/or continue therapy must be based on the rapidity of hematologic changes as well as on absolute hematologic values.129 Dosage of busulfan may need to be reduced when the drug is administered concomitantly with other drugs whose principal toxicity is myelosuppression.129 Busulfan should not be used when facilities for performing complete blood counts, including quantitative platelet counts, at weekly (or more frequent) intervals are not available.129 Busulfan should be used with extreme caution and particular vigilance in patients whose bone marrow reserve may have been compromised by other myelosuppressive drugs or radiation therapy, or whose marrow function is recovering from previous cytotoxic therapy.129
Profound myelosuppression occurs universally in patients receiving IV busulfan at the recommended dose as part of a preparatory regimen prior to allogeneic hematopoietic stem cell transplant (see Cautions: Hematologic Effects and Infectious Complications).131 Daily complete blood cell counts, including leukocyte cell differentials, and platelet counts should be monitored during therapy and until recovery occurs.131 Anti-infective therapy and platelet and red blood cell transfusions should be administered when needed.131
Patients receiving busulfan should be informed that diffuse pulmonary fibrosis is an infrequent but serious and potentially life-threatening complication of long-term therapy with the drug.129 Patients should be instructed to report any difficulty in breathing or persistent cough or congestion.129 If interstitial pulmonary fibrosis occurs during busulfan therapy, the drug should be discontinued immediately.129 (See Cautions: Pulmonary Effects.)
Patients receiving busulfan must not be allowed to take the drug without close medical supervision.129 In addition to warnings about the potential hematologic and pulmonary toxicities, patients should be instructed to report any signs of abrupt weakness, unusual fatigue, anorexia, weight loss, nausea and vomiting, and melanoderma that could be associated with a wasting or Addison-like syndrome.129 Patients also should be informed that other adverse effects of busulfan may include infertility, amenorrhea, skin hyperpigmentation, hypersensitivity, dryness of the mucous membranes, and, rarely, cataract formation.129
Because life-threatening hepatic veno-occlusive disease has occurred in patients receiving busulfan (usually in combination with cyclophosphamide or other antineoplastic agents prior to bone marrow transplantation),112, 113, 114, 115, 129 the manufacturer recommends that serum alkaline phosphatase, bilirubin, and aminotransferase concentrations be determined periodically during oral busulfan therapy (and daily through bone marrow transplant day +28 in patients receiving IV busulfan) so that possible hepatotoxicity can be detected early.129, 131 Possible risk factors for the development of hepatic veno-occlusive disease include a total busulfan dose exceeding 16 mg/kg based on ideal body weight and concurrent use of multiple alkylating agents.129 The incidence of hepatic veno-occlusive disease is higher (about 33% versus 3%) in those with an average busulfan concentration at steady state exceeding 900 ng/mL and/or an area under the plasma concentration-time curve (AUC) exceeding 1500 µ M •minute than in those with lesser values for these parameters.129 A reduced incidence of hepatic veno-occlusive disease has been observed in patients receiving high-dose oral busulfan and cyclophosphamide when the first dose of cyclophosphamide was delayed for more than 24 hours following the last dose of busulfan.129 In addition, the manufacturer of busulfan for injection concentrate states that the risk of hepatic veno-occlusive disease associated with busulfan may be increased in patients who have received prior radiation therapy, 3 or more cycles of chemotherapy, or a prior progenitor cell transplant.131 A busulfan AUC of 1500 µ M •minute or greater also is thought to be associated with a greater risk of hepatic veno-occlusive disease in patients receiving IV busulfan.131 A busulfan AUC below 1500 µ M •minute measured at the time of dose 9 was reported in almost all (i.e., 93%) of evaluable patients receiving IV busulfan in clinical trials.131
Concomitant therapy with busulfan and cyclophosphamide should be administered with caution in the treatment of patients with thalassemia; cardiac tamponade, often fatal, has been reported in a small number (2% in one series) of patients with thalassemia who received busulfan and cyclophosphamide as the preparatory regimen for bone marrow transplantation.129 Abdominal pain and vomiting preceded the occurrence of cardiac tamponade in most of these patients.129, 131
Oral busulfan should be administered with caution and administration of prophylactic anticonvulsant therapy may be considered in patients with a history of seizures or head trauma or those receiving other potentially epileptogenic drugs,129 since seizures have been reported in patients receiving busulfan.106, 107, 116, 117, 118, 119, 120, 121, 129 Prophylactic administration of phenytoin is recommended in all patients receiving IV busulfan, and caution is advised when administering the recommended dose of IV busulfan to patients with a history of seizures or head trauma or those receiving other potentially epileptogenic drugs. (See Dosage: Allogeneic Hematopoietic Stem Cell Transplantation under Dosage and Administration.)131
Patients receiving busulfan should be informed of the increased risk of a secondary malignancy associated with use of the drug. (See Cautions: Mutagenicity and Carcinogenicity.)129, 131
Busulfan is contraindicated in patients with chronic myelogenous leukemia whose disease was resistant to prior therapy with the drug.129 Busulfan is contraindicated in patients in whom a definitive diagnosis of chronic myelogenous leukemia has not been firmly established.129 Busulfan also is contraindicated in patients who are hypersensitive to busulfan or any ingredient in the respective formulation.129, 131
Safety and efficacy of IV busulfan for the treatment of chronic myelogenous leukemia in children have not been studied specifically to date.131
The pharmacokinetics of IV busulfan have been evaluated in an uncontrolled study involving 24 children (age range 5 months to 16 years, median age 3 years) receiving the drug as part of a conditioning regimen prior to hematopoietic progenitor cell transplantation for various malignant hematologic or non-malignant diseases.131 Following an initial IV busulfan dose (based on actual body weight) of 1 mg/kg in patients 4 years of age or younger or 0.8 mg/kg in patients older than 4 years of age, subsequent doses were adjusted based on plasma busulfan concentration to achieve a target AUC of 900-1350 µ M •minute.131 Busulfan doses were administered as a 2-hour IV infusion every 6 hours for 4 days (for a total of 16 doses), followed by cyclophosphamide 50 mg/kg once daily for 4 days.131 After one rest day, hematopoietic progenitor cells were infused.131 Phenytoin was administered to all patients for seizure prophylaxis.131 The target busulfan AUC was achieved with the first dose in 71% of patients.131 Steady-state pharmacokinetic analysis was performed at doses 9 and 13, and serum busulfan concentrations were within the target range for 21 of 23 evaluable patients.131 Based on the results of this study, the manufacturer has developed a suggested dosing regimen for IV busulfan in children. (See Pediatric Dosage in Dosage and Administration: Dosage: Chronic Myelogenous Leukemia: Allogeneic Hematopoietic Stem Cell Transplantation.)131
Myeloablation consisting of neutropenia (absolute neutrophil count less than 500/mm3) and thrombocytopenia (platelet transfusions or platelet count below 20,000/mm3) was observed in all 24 patients, and lymphopenia (absolute lymphocyte count less than 100/mm3) occurred in 79% of patients.131 Absolute neutrophil count recovered to above 500/mm3 in 23 patients at a median of bone marrow transplant (BMT) day +13 (range, BMT day +9 to +22).131 Absolute neutrophil count had not recovered to above 500/mm3 in one patient who died on BMT day +28.131
The mortality rate in the study was 17% (4 deaths).131 Two patients died within 28 days of the transplant, one due to pneumonia and capillary leak syndrome and the other due to pneumonia and hepatic veno-occlusive disease.131 Two more patients died before day 100, one due to progressive disease and one due to multiorgan failure.131 Adverse effects reported during or after the study period (up to BMT day +100) included vomiting (100%), nausea (83%), stomatitis (79%), hepatic veno-occlusive disease (21%), graft-versus-host disease (25%), and pneumonia (21%).131
According to the manufacturer, the recommended weight-adjusted dosage of oral busulfan for remission induction in chronic myelogenous leukemia is the same for children and adults;129 however, alternative dosing regimens have been suggested because of the higher clearance of the drug observed in children.140
Poor response to oral busulfan has been reported in patients with the “juvenile” type of chronic myelogenous leukemia, which typically occurs in young children and is characterized by the absence of a Philadelphia chromosome.129
Safety and efficacy of busulfan in geriatric patients have not been studied specifically to date.129, 131 Clinical studies of busulfan did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.129 While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.129 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.129
In a phase 2 clinical trial using IV busulfan as part of a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation, the 5 patients (out of a total of 61 patients) who were older than 55 years of age (range: 57-64) all achieved myeloablation and engraftment.131
Mutagenicity and Carcinogenicity
Busulfan is potentially mutagenic in humans.129 Busulfan has caused chromosomal aberrations in patients receiving the drug and has been shown to be mutagenic in mice.129, 131
Busulfan is a presumed human carcinogen.131 Malignant tumors and acute leukemias have occurred in patients receiving the drug.129 Although the exact mechanism has not been determined, busulfan is thought to be leukemogenic. A few cases of acute leukemia, becoming clinically apparent 5-8 years after pancytopenia had developed during busulfan therapy, have been reported in patients who received the drug as adjunctive therapy following surgical resection of bronchogenic carcinoma.129, 131 The World Health Organization has determined that sufficient evidence exists to support a causal relationship between busulfan exposure and the development of secondary cancers.129 The increased risk of a secondary malignancy with busulfan therapy should be explained to patients receiving the drug.129, 131
Pregnancy, Fertility, and Lactation
Busulfan may cause fetal harm when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus. Fetal malformation early in pregnancy, bone marrow depression late in gestation, fetal growth retardation, and fetal deaths have been reported in pregnant women who received therapeutic doses of busulfan or other alkylating agents. Mild anemia and neutropenia were present in one neonate whose mother had received busulfan from the eighth week of pregnancy until parturition.
Busulfan has been shown to be teratogenic in mice, rats, and rabbits; teratogenic effects included abnormalities in the musculoskeletal system, body weight, and size.131 Sterility in male and female offspring secondary to an absence of germinal cells in the testes and ovaries also was observed in reproduction studies in rats.131
Dimethylacetamide (DMA), the solvent used in commercially available busulfan for injection concentrate, also may cause fetal harm when administered to pregnant women.131 When administered to pregnant rats at a dose of 400 mg/kg daily (about 40% of the amount present on a mg/m2 basis in the recommended daily dose of IV busulfan), dimethylacetamide caused developmental abnormalities, including anasarca, cleft palate, vertebral anomalies, rib malformation, and serious anomalies of the vessels of the heart.131
There are no adequate and well-controlled studies using busulfan or dimethylacetamide in pregnant women.129, 131 Busulfan should be used during pregnancy only in conditions such as life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective. Women of childbearing potential should be advised to avoid becoming pregnant during busulfan therapy.129, 131 If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.129, 131
Busulfan can impair fertility. Busulfan produces sterility in male and female offspring of drug-exposed pregnant rats resulting from germinal cell aplasia in testes and ovaries. Germinal cell aplasia and sterility have not been reported in human offspring of mothers who received busulfan during pregnancy. Ovarian suppression and amenorrhea with menopausal symptoms commonly occur during long-term busulfan therapy in premenopausal women;129, 131 ovarian fibrosis and atrophy have also occurred. Failure to achieve puberty due to ovarian failure also has been reported in female patients receiving busulfan.129 Busulfan interferes with spermatogenesis in animals, and there have been reports of impotence, sterility, azoospermia, and testicular atrophy in men who received the drug.62, 129, 131
Dimethylacetamide (DMA), the solvent used in commercially available busulfan for injection concentrate, also may impair fertility.131 When administered to rats at a dose of approximately 0.5 g/kg daily (about 44% of the amount present in the recommended daily dose of IV busulfan on a mg/m2 basis) for 9 days, dimethylacetamide caused decreases in spermatogenesis.131 In addition, administration of a single subcutaneous dose of 2.2 g/kg (about 27% of the amount present in the recommended daily dose of IV busulfan on a mg/m2 basis) to hamsters 4 days after insemination resulted in termination of pregnancy in all of the hamsters tested.131
It is not known whether busulfan is distributed into milk.129, 131 Because of the potential for serious adverse reactions from busulfan in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.129, 131
Additive myelosuppression may occur with concomitant administration of busulfan with other myelosuppressive agents.129 In addition, additive pulmonary toxicity may occur when busulfan is administered in combination with other cytotoxic agents.129
Concomitant use of cylcophosphamide may result in reduced clearance of busulfan, presumably due to competition for glutathione.129 A reduced incidence of hepatic veno-occlusive disease and other toxicities has been observed in patients receiving high-dose busulfan and cyclophosphamide when the first dose of cyclophosphamide was delayed for longer than 24 hours following the last dose of busulfan.129
Hepatotoxicity, esophageal varices, and portal hypertension were reported in some patients receiving long-term therapy with busulfan and thioguanine concomitantly;110, 122, 129 hepatotoxicity was manifested by elevations of hepatic enzyme concentrations and nodular regenerative hyperplasia of the liver.110, 129 Similar effects were not reported in patients receiving busulfan therapy alone.123, 129 Although further studies are needed to establish a causal relationship between these adverse effects and concomitant use of busulfan and thioguanine,110 the manufacturer of busulfan states that caution should be exercised during such long-term concomitant therapy.129
Itraconazole may reduce the clearance of busulfan by up to 25% in patients receiving oral or IV busulfan therapy.129, 131 Administration of itraconazole with IV busulfan may result in a busulfan AUC exceeding 1500 µ M •minute (which may be associated with an increased risk of hepatic veno-occlusive disease).131 Patients receiving busulfan and concomitant itraconazole therapy should be monitored carefully for busulfan toxicity.129
Concomitant use of phenytoin increases clearance of busulfan and cyclophosphamide, which may lead to decreased serum concentrations of both drugs.129
Phenytoin has been reported to increase busulfan clearance by 15% or more, possibly by induction of glutathione- S -transferase.131 Because the patients included in pharmacokinetic evaluations of IV busulfan also were receiving phenytoin (which is recommended for seizure prophylaxis), administration of the recommended dose of IV busulfan without concomitant phenytoin therapy may result in reduced busulfan clearance and greater exposure to the drug.131 The manufacturer recommends monitoring busulfan plasma concentrations in patients who must receive anticonvulsants other than phenytoin with IV busulfan.131
Use of acetaminophen in combination with or within 72 hours prior to busulfan therapy may cause a decrease in busulfan clearance by reducing glutathione concentrations in the blood and tissues.131
Limited information is available on the acute toxicity of busulfan. Without subsequent hematopoietic progenitor cell transplantation, the recommended dosage of IV busulfan used prior to transplantation would constitute an overdose of the drug.131
The single-dose LD50 of busulfan in mice is 120 mg/kg.129 At median lethal doses administered intraperitoneally in animals, two distinct types of toxic responses are observed.129 Within hours of administration, there are signs of CNS stimulation with seizures and death on the first day; mice are more sensitive to this effect than rats.129 At the LD50 dose, delayed death secondary to bone marrow damage also occurs.129 At doses 3 times the LD50, atrophy of the large intestine mucosa is evident after a week, but the mucosa of the small intestine is minimally affected.129
The principal toxic effect of busulfan is on the bone marrow, including myelosuppression and pancytopenia, but the CNS, liver, lungs, and GI tract also may be affected.129, 131 A 4-year-old child was reported to survive an acute ingestion of 140 mg (approximately 8 mg/kg).131 Accidental administration of a dose of 2.1 mg/kg of busulfan orally (total dose: 23.3 mg/kg) in a 2-year-old patient prior to bone marrow transplant resulted in no adverse sequelae.131 A fatal overdose of 2.4 g of busulfan has been reported in a 10-year-old boy.131
There is no specific antidote for busulfan intoxication (other than hematopoietic stem cell transplantation).129, 131 If acute overdosage occurs, the hematologic status of the patient should be closely monitored and vigorous supportive measures instituted if necessary.129, 131
Following recent acute ingestion of oral busulfan, the stomach should be emptied immediately by inducing emesis or by gastric lavage.129 If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Following emesis or gastric lavage, activated charcoal may be administered.129
Because at least one report has suggested that busulfan is dialyzable, dialysis should be considered in the event of busulfan overdose.129, 131 (See Pharmacokinetics: Elimination.) In addition, administration of glutathione may be considered since busulfan is metabolized by conjugation with glutathione.131
Busulfan, as an alkylating agent, interferes with DNA replication and transcription of RNA and ultimately results in the disruption of nucleic acid function. Busulfan contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain; in aqueous media, busulfan is hydrolyzed, releasing the methanesulfonate groups and producing reactive carbonium ions capable of alkylating DNA.131 Damage to DNA is considered largely responsible for the cytotoxic activity of the drug.131 Busulfan exhibits little immunosuppressive activity.
Based on currently available data, the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee concluded that similar variability in pharmacokinetics is exhibited with both IV busulfan and oral busulfan.136 The pharmacokinetics of busulfan have not been evaluated separately by gender, ethnic group, or hepatic or renal impairment.131
Busulfan is rapidly and completely absorbed from the GI tract after oral administration of the drug.129 The effect of food on the bioavailability of busulfan is not known.129
For adults receiving busulfan 2, 4, or 6 mg orally as a single dose on consecutive days, the drug exhibits linear kinetics for both the maximum plasma concentration and the area under the concentration-time curve (AUC); a mean peak plasma concentration (normalized to a dose of 2 mg) of about 30 ng/mL was observed.129 In a study of 12 patients receiving single oral busulfan doses of 4-8 mg, a mean peak plasma concentration (normalized to a dose of 4 mg) of about 68 ng/mL was reported; the time to peak plasma concentration was about 0.9 hours.129
In patients receiving busulfan (0.8 mg/kg IV every 6 hours for 4 days) in combination with cyclophosphamide prior to allogeneic hematopoietic progenitor stem cell transplantation, a mean peak plasma concentration of 1222 ng/mL (range: 496-1684 ng/mL) and a mean area under the plasma concentration-time curve (AUC) of 1167 µ M •minute (range: 556-1673 µ M •minute) were reported at steady state.131
Busulfan, a small and highly lipophilic molecule, easily crosses the blood-brain barrier.129 Busulfan concentrations in the CSF are approximately equal to concurrent busulfan plasma concentrations.131 It is not known whether the drug is distributed into milk.129, 131
Irreversible binding of the drug to plasma proteins (mainly albumin) is reported to be about 32%.129, 131
The pharmacokinetic disposition of busulfan differs in children versus adults.129, 131, 140 The mean bioavailability of busulfan is lower in children than in adults; the interindividual variation in bioavailability for oral busulfan is large, particularly in children.129, 140 In a pharmacokinetic study in children receiving IV busulfan (0.8 or 1 mg/kg based on actual body weight), an estimated volume of distribution of 0.64 L/kg (with an interpatient variability of 11%) was reported.131
The elimination half-life is about 2.6 hours in adults receiving oral busulfan.129
In patients receiving busulfan (0.8 mg/kg IV every 6 hours for 4 days) in combination with cyclophosphamide prior to allogeneic hematopoietic progenitor stem cell transplantation, a mean clearance of 2.52 mL/minute per kg (range: 1.49-4.31 mL/minute per kg) was reported.131
Busulfan is rapidly eliminated from the plasma.129 The drug is reported to be extensively metabolized by the liver; at least 12 metabolites have been isolated, including methanesulfonic acid and 3-hydroxytetrahydrothiophene-1,1-dioxide, and these metabolites do not have cytotoxic activity.129 Busulfan is metabolized in the liver mainly by glutathione conjugation (spontaneous and glutathione S -transferase-mediated).131 The glutathione conjugate is then further metabolized in the liver by oxidation.131 Busulfan is slowly excreted in urine, as metabolites.129, 131 About 30-60% of a dose of busulfan is excreted in the urine within 48 hours.129, 131 Less than 2% of a dose of busulfan is excreted in the urine unchanged within 24 hours.129 Negligible amounts of busulfan are excreted in the feces.131
Because it is poorly soluble in water and rapidly metabolized, it is expected that dialysis would remove minimal amounts of unreacted busulfan.129
The effect of hemodialysis on the oral clearance of busulfan has been reported in one patient with chronic renal failure who was undergoing autologous peripheral stem cell transplantation.129 An increase of about 65% in the apparent oral clearance of busulfan was observed following 4 hours of hemodialysis; however, the mean 24-hour oral clearance of the drug was increased by only 11%.129
Busulfan clearance is higher in children than in adults.131 In a pharmacokinetic study in children receiving IV busulfan (0.8 or 1 mg/kg based on actual body weight) in combination with cyclophosphamide, an estimated clearance of 3.37 mL/minute per kg (with an interpatient variability of 23%) was reported.131
Busulfan, an alkylsulfonate, is a bifunctional alkylating agent.129, 131 The drug occurs as a white, crystalline powder and is very slightly soluble in water131 and slightly soluble in alcohol. Because busulfan is only very slightly soluble in water, the commercially available for injection concentrate, which occurs as a sterile, colorless, clear solution, is a nonaqueous solution of the drug in N,N -dimethylacetamide (DMA) and polyethylene glycol 400.131 Solutions of busulfan containing a drug concentration of approximately 0.5 mg/mL have a pH of 3.4-3.9, depending on the diluent used (i.e., 0.9% sodium chloride injection or 5% dextrose injection).131
Commercially available busulfan tablets should be stored in well-closed containers at 25°C but may be exposed to temperatures ranging from 15-30°C.129
Commercially available busulfan for injection concentrate should be stored in unopened ampuls at 2-8°C.131 The manufacturer states that, when diluted as directed in 0.9% sodium chloride injection or 5% dextrose injection, busulfan solutions are stable for up to 8 hours when stored at room temperature (approximately 25°C), and the busulfan infusion must be completed during the 8-hour time period.131 Solutions of busulfan diluted in 0.9% sodium chloride injection also have been shown to be stable when refrigerated at 2-8°C for up to 12 hours, during which time the infusion must be completed.131
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 2 mg | ||
Parenteral | For injection concentrate, for IV infusion only | 6 mg/mL (60 mg) |
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