Busulfan (1,4-butanediol dimethanesulfonate) is a bifunctional alkylating agent. The IV formulation is indicated in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem-cell transplantation in patients with chronic myelogenous leukemia (CML). The oral tablet formulation is indicated for the palliative treatment of CML. It is less effective in patients with Philadelphia chromosome (Ph)-negative CML and in young children with Ph-negative disease. It is not effective for the treatment of blast-phase CML, chronic lymphocytic leukemia, or acute leukemias.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Oral Tablets: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
-Injectables: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Pediatrics:
--IV Doses 0.8 mg/kg/dose and higher: High
-Oral Doses 1 mg/kg/dose and higher: High
-Administer routine antiemetic prophylaxis prior to treatment.
-Adults:
--IV Doses: Moderate
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Oral Administration
Administer with or without food at approximately the same time every day.
Extemporaneous Compounding-Oral
Busulfan oral suspension:
-Pulverize busulfan tablets until a uniform white powder is obtained. Add simple syrup in small amounts to a final concentration of busulfan 2 mg/5 mL; mix thoroughly after each addition.
-When refrigerated, the suspension is stable for 30 days at concentrations up to 10 mg/5 mL. The stability of the suspension is temperature dependent. If the suspension is stored at room temperature, the stability is only 2 days. Shake well before using.
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Dilution is required.
-Do not use any infusion components (e.g., syringes, filter needles, IV tubing, etc.) containing polycarbonate for busulfan preparation or administration. Busulfan is incompatible with polycarbonate.
Dilution:
-Calculate the dose, withdraw the appropriate volume from busulfan 6 mg/mL solution vial(s), and dilute with 10-times the drug volume of 0.9% Sodium Chloride Injection or 5% Dextrose Injection; the final admixture concentration will be approximately 0.5 mg/mL.
-Add the busulfan injection solution to the diluent; do not add the diluent to the busulfan injection solution; invert several times to mix thoroughly.
-Storage following dilution: store at room temperature (25 degrees C; 77 degrees F) for up to 8 hours or refrigerated (2 to 8 degrees C; 36 to 46 degrees F) for up to 12 hours; storage includes infusion time.
Intravenous (IV) Infusion:
-Using an infusion pump, administer the diluted admixture through a central venous catheter over 2 hours; rapid infusion is not recommended.
-Use an administration set with minimal residual hold-up volume (2 to 5 mL).
-Prior to and after each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
-Do NOT infuse concomitantly with IV solutions of unknown compatibility.
-For blood sample collection, obtain blood from a peripheral IV line to avoid contamination with the infusing drug; do NOT obtain blood samples from the central venous catheter while the drug is infusing.
Ear disorder has been reported in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61).
Severe and prolonged bone marrow suppression/pancytopenia including anemia, granulocytopenia (e.g., leukopenia, neutropenia), and thrombocytopenia occur with IV and oral busulfan therapy. Monitor complete blood counts (CBC) including differential and platelet counts daily during IV busulfan treatment and until engraftment occurs. Administer antibiotics and blood cell and platelet support as indicated. Monitor CBC including differential and platelet counts weekly during oral busulfan treatment. Reduce or discontinue oral busulfan therapy for myelosuppression. Following IV busulfan, the absolute neutrophil count (ANC) fell to less than 0.5 x 109 cells/L at a median of 4 days posttransplant in a clinical trial. The ANC recovered at a median of 13 days posttransplant; most patients received prophylactic granulocyte colony-stimulating factors. Severe anemia defined as a hemoglobin concentration less than 8 grams/dL patients occurred in 69% of patients; 98% of patients had a platelet count of less than 25,000 cells/mm3 or required a platelet transfusion at a median of 5 to 6 days posttransplant. Prolonged bleeding time/prolonged prothrombin time occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplant in a single-arm trial (n = 61). Hematologic adverse events that occurred in pediatric patients (median age, 3 years; range, 5 months to 16 years) who received 16 doses of IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic progenitor cell transplantation in a pharmacokinetic analysis (n = 24) include neutropenia (100%), thrombocytopenia (platelet count less than 20,000 cells/mm3) (100%), and lymphopenia (absolute lymphocyte count less than 0.1 x 109 cells/L) (79%). Febrile neutropenia and thrombotic microangiopathy have been reported in postmarketing surveillance of IV busulfan. Aplastic anemia has been reported with oral busulfan use; some cases were irreversible.
Gastrointestinal adverse events have been reported with IV busulfan therapy. Administer antiemetic agents prior to the first dose of IV busulfan and scheduled throughout busulfan therapy. Nausea (98%), stomatitis/mucositis (97%), vomiting (95%), anorexia (85%), diarrhea (84%), abdominal pain (72%), dyspepsia (44%), constipation (38%), xerostomia/dry mouth (26%), rectal disorder (25%), and enlarged abdomen (23%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic SCT in a single-arm trial (n = 61); esophagitis, ileus, hematemesis, pancreatitis, and rectal discomfort were also reported. Vomiting (100%), nausea (83%), stomatitis (79%) were reported in pediatric patients (median age, 3 years; range, 5 months to 16 years) who received 16 doses of IV busulfan in combination with cyclophosphamide prior to allogeneic stem-cell transplantation in a pharmacokinetic analysis (n = 24). Dryness oral mucous membranes and cheilosis/cheilitis have been reported with oral busulfan therapy; mucositis has also been reported in postmarketing surveillance.
Interstitial pulmonary fibrosis has been reported with oral and IV busulfan therapy; discontinue busulfan in patients who develop pulmonary fibrosis. Pulmonary function tests or lung biopsy may be used to diagnose this condition. Immediately discontinue therapy in patients who develop pulmonary fibrosis; treatment with corticosteroids may be beneficial in some cases. Rhinitis (44%), lung disorder (34%), cough (28%), epistaxis (25%), and dyspnea (25%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61); hyperventilation, alveolar hemorrhage (fatal in 3%), pharyngitis, hiccups, asthma, atelectasis, pleural effusion, hypoxia, hemoptysis, sinusitis, and interstitial fibrosis (fatal in a single case) were also reported. Fatal alveolar hemorrhage (3%) and interstitial pulmonary fibrosis (1 case) were reported. In 2 randomized trials, interstitial pneumonitis was reported in 14% and 16.9% of chronic myelogenous leukemia patients who received high-dose oral busulfan-containing conditioning regimens prior to an allogeneic bone marrow transplantation. Interstitial pulmonary fibrosis/bronchopulmonary dysplasia with pulmonary fibrosis has been reported rarely with oral busulfan use. Symptoms include cough, dyspnea, and low-grade fever. Pulmonary fibrosis has occurred within 8 months to 10 years after the initiation of therapy; the average onset is within 4 years of busulfan therapy. Pulmonary function tests or lung biopsy may be used to diagnose this condition. Immediately discontinue therapy in patients who develop pulmonary fibrosis; treatment with corticosteroids may be beneficial in some cases. Cellular dysplasia of the lung has also been observed with oral busulfan therapy.
Dermatologic adverse events have been reported with IV and oral busulfan therapy. Rash (unspecified) (57%), pruritus (28%), and allergic reaction (26%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61); alopecia, vesicular rash, maculopapular rash, vesiculo-bullous rash, exfoliative dermatitis, erythema nodosum, acne vulgaris, and skin discoloration were also reported. Injection site reaction (e.g., injection site inflammation and pain) was also reported in this study. Skin hyperpigmentation has been reported with oral busulfan use in 5% to 10% of patients, particularly in patients with dark complexions. Cases of urticaria, erythema multiforme, erythema nodosum, alopecia, porphyria cutanea tarda, xerosis, and fragile skin with anhidrosis have been reported in patients who received oral busulfan as palliative therapy for chronic myelogenous leukemia. Additionally, rash has been reported in postmarketing surveillance of oral busulfan; an increased local cutaneous reaction was reported in patients who received radiation therapy soon after busulfan.
Cataracts, corneal thinning, and lens changes have been reported in postmarketing surveillance of oral busulfan.
Cardiac tamponade has occurred with high-dose oral busulfan. Monitor patients for signs and symptoms of cardiac tamponade; promptly evaluate if cardiac tamponade is suspected. Sinus tachycardia (44%), hypertension (36%), thrombosis (33%), chest pain (unspecified) (26%), vasodilation (25%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61); arrhythmia, atrial fibrillation, ventricular extrasystoles, third-degree heart block, hypotension, flushing and hot flashes, cardiomegaly, ECG abnormality, left-sided heart failure, pericardial effusion, and central venous catheter-associated thrombosis were also reported. Cases of cardiac tamponade have been reported in 8 of 400 pediatric patients (2%) with thalassemia who received high-dose oral busulfan and cyclophosphamide as conditioning for bone marrow transplantation. Death occurred in 6 of these 8 patients; 2 patients who received rapid pericardiocentesis were saved. Symptoms of abdominal pain and vomiting occurred prior to tamponade in most patients. Endocardial fibrosis was reported on autopsy in one patient who received oral busulfan (7,200 mg over 9 years) for the treatment of chronic myelogenous leukemia.
Seizures have been reported in patients receiving high-dose oral or IV busulfan. Start prophylactic therapy with anticonvulsant agents (e.g., benzodiazepines, phenytoin, valproic acid, or levetiracetam) prior to IV busulfan therapy. Headache (69%), insomnia (84%), anxiety (72%), dizziness (30%), and depression (23%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic SCT in a single-arm trial (n = 61); cerebral hemorrhage/intracranial bleeding, coma, delirium, agitation, encephalopathy, confusion, hallucinations, lethargy, and somnolence/drowsiness were also reported. Seizures were reported in one patient (2.4%) who were treated with IV busulfan plus cyclophosphamide prior to an autologous stem-cell transplant in another clinical trial (n = 42); this patient received prophylactic phenytoin and the seizure occurred during cyclophosphamide therapy (36 hours after the last busulfan dose). Seizures were reported in up to 6% of patients with hematological malignancies who received high-dose oral busulfan-containing conditioning regimens prior to an allogeneic bone marrow transplantation.
Sinusoidal obstruction syndrome (SOS), previously termed veno-occlusive disease (VOD), has been reported in 7.7% to 12% of patients who received IV busulfan therapy in randomized trials. Evaluate liver function tests including bilirubin and alkaline phosphatase (AP) levels prior to IV busulfan and daily through day +28. Hyperbilirubinemia (49%), elevated hepatic enzymes (increased ALT level, 31%), and SOS/VOD (8%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic SCT in a single-arm trial (n = 61); increased AP level, jaundice, and hepatomegaly were also reported. Two patients (3%) died from SOS/VOD. VOD was reported in 21% of pediatric patients (median age, 3 years; range, 5 months to 16 years) who received 16 doses of IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic progenitor cell transplantation in a pharmacokinetic analysis (n = 24). Centrilobular sinusoidal fibrosis, hepatic VOD, hepatocellular atrophy, hepatic necrosis, hyperbilirubinemia, and cholestatic jaundice have been reported with oral busulfan use.
Tumor lysis syndrome (TLS) has been reported in postmarketing surveillance of IV busulfan. Hyperuricemia and/or hyperuricosuria may occur with oral busulfan therapy in patients with chronic myelogenous leukemia. Initiate prophylactic measures (e.g., hydration, urine alkalinization, and uric acid lowering agents) in patients at risk for TLS.
Gonadal suppression has been reported with busulfan use in males and females. Ovarian suppression (e.g., anovulation) and amenorrhea have been commonly reported in premenopausal women who received chronic oral busulfan therapy for chronic myelogenous leukemia. Infertility (sterility), azoospermia, and testicular atrophy have occurred in male patients treated with busulfan. Additionally, ovarian failure and subsequent failure to achieve puberty has occurred in females. Cases of gynecomastia have been reported rarely in patients who received oral busulfan as palliative therapy for chronic myelogenous leukemia.
A new primary malignancy has been reported with busulfan therapy. It may also cause chromosome aberrations, cellular dysplasia in organs (e.g., lungs), and cytologic abnormalities (i.e., giant, hyperchromatic nuclei) in lymph nodes, pancreas, thyroid, adrenal glands, liver, and bone marrow. Busulfan-induced cytologic dysplasia may cause difficulty in interpreting results from cytologic examinations of the lung, bladder, breast, and uterine cervix. Acute leukemia was reported in 1.6% of patients who received adjuvant chemotherapy following surgical resection of lung cancer (n = 243); these patients had also developed pancytopenia after taking busulfan for 5 to 8 years.
Asthenia occurred in 51% of patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61).
Back pain (23%) and pain (44%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61); myalgia and arthralgia were also reported. Cases of myasthenia gravis have been reported rarely in patients who received oral busulfan.
A clinical syndrome that is similar to adrenocortical insufficiency has been reported after prolonged use of oral busulfan; monitor patients for symptoms of adrenal insufficiency including anorexia, fatigue, melanoderma, nausea and vomiting, weakness, and weight loss. The syndrome may be reversible when busulfan is discontinued. Adrenal responsiveness to exogenously administered ACTH has usually been normal. However, pituitary function testing with metyrapone revealed a blunted urinary 17-hydroxycorticosteroid excretion in 2 patients.
Enamel hypoplasia has been reported in postmarketing surveillance of IV busulfan.
Graft-versus-host disease (GVHD) has been reported in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61); 3 deaths (5%) were attributed to GVHD in this study. GVHD occurred in 25% of pediatric patients (median age, 3 years; range, 5 months to 16 years) who received 16 doses of IV busulfan in combination with cyclophosphamide prior to allogeneic hematopoietic progenitor cell transplantation in a pharmacokinetic analysis (n = 24). In randomized trials of chronic myelogenous leukemia patients who received high-dose oral busulfan-containing conditioning regimens prior to an allogeneic bone marrow transplantation, acute GVHD was reported in 22% to 41% and chronic GVHD was reported in 31% to 45%.
Hyperglycemia (66%), hypomagnesemia (77%), hypokalemia (64%), and hypocalcemia (49%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic SCT in a single-arm trial (n = 61); hypophosphatemia and hyponatremia were also reported.
Edema (36%) and general edema (28%) were reported in 36% of patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic SCT in a single-arm trial (n = 61); hypervolemia or weight gain also occurred.
Increased creatinine levels occurred in 21% of patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic SCT in a single-arm trial (n = 61); increased BUN concentrations, dysuria, oliguria, hematuria, and hemorrhagic cystitis were also reported.
Infection has been reported have been reported with oral and IV busulfan therapy; monitor patients for signs and symptoms of infection. Chills (46%) and fever (80%) occurred in patients with hematologic malignancies who received IV busulfan plus cyclophosphamide prior to an allogeneic stem-cell transplantation in a single-arm trial (n = 61); infection including pneumonia was also reported. Life-threatening (3%) and fatal (1 case) pneumonia has occurred. In postmarketing surveillance, infection including sepsis and pneumonia has been reported with oral busulfan and bacterial, viral, and fungal infection including sepsis has been reported with IV busulfan. Pneumonia was reported in 25% of pediatric patients (median age, 3 years; range, 5 months to 16 years) who received 16 doses of IV busulfan in combination with cyclophosphamide prior to allogeneic stem-cell transplantation in a pharmacokinetic analysis (n = 24).
Severe and prolonged bone marrow suppression/pancytopenia including anemia, granulocytopenia (e.g., leukopenia, neutropenia), and thrombocytopenia occurs with IV and oral busulfan therapy. Serious infection and bleeding may occur. Patients must receive a hematopoietic stem-cell transplantation after IV busulfan therapy to prevent potentially fatal complications due to severe myelosuppression. Monitor complete blood counts (CBC) including differential and platelet counts daily during IV busulfan treatment and until engraftment occurs. Administer antibiotics and blood cell and platelet support as indicated. Monitor CBC including differential and platelet counts weekly during oral busulfan treatment. Reduce or discontinue oral busulfan therapy for myelosuppression. Perform a bone marrow examination if the bone marrow status is uncertain. Use oral busulfan with caution in patients with compromised bone marrow reserve including patients who received prior radiation therapy or chemotherapy. Bone morrow recovery following oral busulfan is potentially reversible but may take from 1 month to 2 years to occur.
Severe hepatotoxicity including sinusoidal obstruction syndrome (SOS), previously termed veno-occlusive disease (VOD) has been reported with IV busulfan therapy; some cases were fatal. Evaluate liver function tests including bilirubin and alkaline phosphatase (AP) levels prior to IV busulfan and daily through day +28. IV busulfan has not been evaluated in patients with pre-existing hepatic disease; use caution in these patients. Patients with a busulfan AUC greater than 1,500 micromoles x min, prior radiation therapy, 3 or more cycles of chemotherapy, a prior stem-cell transplant, or a total dose exceeding 16 mg/kg (based on ideal body weight) or patients who are receiving multiple alkylating agents may be at increased risk of developing SOS/VOD with busulfan therapy. The incidence of SOS/VOD and other toxicities may be reduced when the first dose of cyclophosphamide is delayed for greater than 24 hours after the last dose of busulfan.
Seizures have been reported in patients receiving high-dose oral or IV busulfan. Use busulfan with caution in patients with a history of seizure disorder or head trauma or in patients who are receiving other drugs that may cause seizures; monitor these patients closely. Start prophylactic therapy with anticonvulsant agents (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) prior to IV busulfan therapy.
A new primary malignancy has been reported with busulfan therapy. It may also cause chromosome aberrations, cellular dysplasia in organs (e.g., lungs), and cytologic abnormalities (i.e., giant, hyperchromatic nuclei) in lymph nodes, pancreas, thyroid, adrenal glands, liver, and bone marrow. Busulfan-induced cytologic dysplasia may cause difficulty in interpreting results from cytologic examinations of the lung, bladder, breast, and uterine cervix.
Hyperuricemia, hyperuricosuria, and tumor lysis syndrome (TLS) have been reported in patients receiving high-dose oral or IV busulfan. Initiate prophylactic measures (e.g., hydration, urine alkalinization, and uric acid lowering agents) in patients at risk for TLS.
Intravenous busulfan has not been evaluated for the treatment of chronic myelogenous leukemia (CML) in adolescents, children, infants, or neonates. Pediatric patients with juvenile Philadelphia chromosome-negative CML typically respond poorly to busulfan therapy.
Based on its mechanism of action and data from animal studies, busulfan may cause fetal harm if it is administered during pregnancy; therefore, females of reproductive potential should be advised to avoid pregnancy. If busulfan is used during pregnancy, the patient should be informed of the potential hazard to the fetus. One case of malformation was reported following maternal busulfan exposure. In this case, the mother had received X-ray therapy early in the first trimester, mercaptopurine until the third month, and then busulfan until delivery. In animal reproduction studies, busulfan was teratogenic when administered during organogenesis. Additionally, the injectable busulfan formulation is dissolved in N,N-dimethylacetamide (DMA), a solvent. DMA may also cause fetal harm. Developmental anomalies (e.g., anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious anomalies of the vessels of the heart) were observed in rats when DMA doses approximately 40% of the daily human dose were administered during organogenesis.
Counsel patients about the reproductive risk and contraception requirements during busulfan treatment. Females should avoid pregnancy and use effective contraception during treatment with busulfan and for 6 months after the last dose. Women who become pregnant while receiving busulfan should be apprised of the potential hazard to the fetus. Busulfan therapy may damage spermatozoa and testicular tissue in male patients, leading to possible genetic fetal abnormalities. Due to a potential for male-mediated teratogenicity, men with female partners of reproductive potential should use effective contraception during treatment with busulfan and for 3 months after the last dose. Busulfan may cause infertility in female and male patients. Amenorrhea and ovarian suppression have been commonly reported in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. Busulfan may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose busulfan in the conditioning regimen prior to allogeneic stem cell transplantation. Additionally, sterility, azoospermia, and testicular atrophy have been reported in male patients who received busulfan.
Due to a potential for serious adverse reactions in breast fed infants, nursing women should discontinue breast-feeding during busulfan therapy. It is not known whether busulfan is present in human milk.
Vaccination with live vaccines should be avoided due to the risk of severe neutropenia during busulfan therapy.
For the palliative treatment of chronic myelogenous leukemia (CML):
Oral dosage:
Adults: 60 micrograms (mcg)/kg or 1.8 mg/m2 orally once daily. Typically, the daily dose does not exceed 4 mg; however, the usual dosage range for remission induction is 4 to 8 mg/day. Hold therapy when the total leukocyte count drops to approximately 15,000 cells/mcL. Discontinue therapy before the leukocyte count falls into the normal range; the leucocyte count may continue to fall for more than 1 month after stopping therapy. During remission, busulfan therapy may be resumed at the remission induction dose when the total leukocyte count is approximately 50,000 cells/mcL. If remission is less than 3 months, maintenance therapy at 1 to 3 mg daily may be started to keep hematologic disease under control and prevent rapid relapse.
Neonates, Infants, Children, and Adolescents: 60 micrograms (mcg)/kg or 1.8 mg/m2 orally once daily. Typically, the daily dose does not exceed 4 mg. Hold therapy when the total leukocyte count drops to approximately 15,000 cells/mcL. Discontinue therapy before the leukocyte count falls into the normal range; the leucocyte count may continue to fall for more than 1 month after stopping therapy. During remission, busulfan therapy may be resumed at the remission induction dose when the total leukocyte count is approximately 50,000 cells/mcL. If remission is less than 3 months, maintenance therapy may be started to keep hematologic disease under control and prevent rapid relapse.
For stem cell transplant preparation:
NOTE: The FDA has designated busulfan as an orphan drug as preparative therapy in the treatment of malignancies with bone marrow transplantation.
-prior to allogeneic hematopoietic progenitor-cell transplantation for chronic myelogenous leukemia, in combination with cyclophosphamide:
Intravenous dosage:
Adults: 0.8 mg/kg IV over 2 hours every 6 hours for 16 doses starting on day -7 of transplantation in combination with cyclophosphamide 60 mg/kg IV over 1 hour on day -3 and -2 (beginning no sooner than 6 hours after the last busulfan dose). Dose busulfan IV based on ideal body weight (IBW) or actual body weight, whichever is lower. For obese patients, dose busulfan IV on an adjusted ideal body weight (AIBW = IBW + 0.25 X (actual weight - IBW)). All patients should receive premedication with antiemetics (starting prior to the first busulfan dose and scheduled until the completion of therapy) and anticonvulsants such as benzodiazepines, phenytoin, valproic acid or levetiracetam (starting 12 hours prior to the first busulfan dose and continuing until 24 hours after the last dose).
-prior to allogeneic transplantation for acute myelogenous leukemia, in combination with cyclophosphamide*:
Oral dosage:
Adults, Adolescents, and Children 2 years or older: 1 mg/kg orally every 6 hours for 4 days (total of 16 doses) in combination with cyclophosphamide (60 mg/kg/day IV for 2 days). Treatment with oral busulfan followed by cyclophosphamide (BuCY) compared with cyclophosphamide plus total body irradiation (CY/TBI) prior to allogeneic bone marrow transplant (alloBMT) resulted in similar 3-year (61% vs. 64%) and 7-year (59% vs. 56%) leukemia-free survival rates in a subgroup of 69 patients with AML in a randomized controlled study. However, the incidence of veno-occlusive disease, hemorrhagic cystitis, chronic graft versus host disease (GVHD), and death from GVHD at 7 years was significantly higher in the BuCY arm. In another randomized study, estimated overall survival (OS) and disease-free survival (DFS) rates were significantly worse when BuCY was given as a conditioning regimen prior to alloBMT compared with CY/TBI in 101 patients with AML in first remission. In a long-term follow-up report of this study (median follow-up time, 10.8 years; range, 9.5 to 12.7 years), the 10-year OS rates were 43% and 59% (p = 0.04) and the 10-year DFS rates were 35% and 55% (p = 0.02) in the BuCY and CY/TBI arms, respectively. Patients in both studies received cyclosporine and methotrexate as posttransplant immunosuppression. In a long-term pooled analysis (mean follow-up greater than 7 years) that evaluated 172 patients with AML from these randomized studies, treatment with BuCY prior to alloBMT led to nonsignificantly worse 10-year OS (51% vs. 63%) and DFS (47% vs. 57%) rates compared with CY/TBI. In this analysis, the 5-year cumulative incidence of extensive chronic GVHD and 7-year cumulative incidence of cataracts, pulmonary complications, and avascular osteonecrosis were not significantly different in AML patients who received BuCY or CY/TBI; alopecia occurred significantly more often with BuCY.
-prior to autologous transplantation for non-Hodgkin lymphoma, in combination with cyclophosphamide or cyclophosphamide plus etoposide*:
Oral or IV dosage:
Adults: 1 mg/kg orally or 0.8 mg/kg IV every 6 hours for 14 (patients greater than 50 years of age) or 16 (patients less than 50 years of age) doses starting on day 7 prior to stem-cell infusion plus cyclophosphamide (60 mg/kg IV over 2 hours on day -3 and -2) prior to autologous stem cell transplantation (ASCT) led to 3- and 5-year progression-free survival (PFS) rates of 48% and 36%, respectively, and 3- and 5-year overall survival (OS) rates of 65% and 59%, respectively, in a retrospective analysis of 78 patients with non-Hodgkin lymphoma (NHL). The 3-year PFS rate was 46.9% in 382 NHL patients who received busulfan 1 mg/kg PO every 6 hours for 14 doses starting 8 days prior to stem cell infusion in combination with etoposide (50 or 60 mg/kg continuous IV infusion over 36 hours starting 2 hours after the last busulfan dose) and cyclophosphamide (60 mg/kg daily IV for 2 days) prior to ASCT in another study. In a retrospective analysis of 604 patients with NHL comparing IV (0.8 mg/kg over 2 hours every 6 hours for 14 doses) with oral (1 mg/kg every 6 hours for 14 doses) busulfan in combination with cyclophosphamide and etoposide prior to ASCT, treatment with IV busulfan was associated with a significantly decreased risk of relapse (hazard ratio (HR) = 0.61; 95% CI, 0.41 to 0.9; p = 0.01) and death (HR = 0.5; 95% CI, 0.32 to 0.78; p = 0.002) compared with oral busulfan. Additionally, mucositis was significantly worse with oral busulfan. Adjusted body weight was used for oral busulfan dosing and all patients received oral phenytoin for seizure prophylaxis and filgrastim after stem cell infusion.
-prior to autologous hematopoietic stem-cell transplantation in patients with high-risk neuroblastoma, in combination with melphalan*:
Intravenous dosage:
Adults less than 21 years, Adolescents, Children, and Infants: 0.8 to 1.2 mg/kg IV over 2 hours every 6 hours for 16 doses followed by melphalan 140 mg/m2 IV once (4 mg/kg IV in patients who weigh less than 12 kg) given 24 hours after the final busulfan dose was evaluated in a randomized, phase III trial (n = 598; HR-NBL1/SIOPEN trial). Busulfan doses were based on bodyweight as follows: 1 mg/kg for weight less than 9 kg; 1.2 mg/kg for 9 kg to less than 16 kg; 1.1 mg/kg for 16 to 23 kg; 0.95 mg/kg for weight greater than 23 kg to 34 kg; and 0.8 mg/kg for weight greater than 34 kg. Stem-cell rescue was administered at least 24 hours after melphalan. Prior to high dose chemotherapy with busulfan and melphalan, patients had received multi-agent induction chemotherapy and surgery. Post-transplant, all patients received radiation and maintenance therapy. Recommended supportive therapy included granulocyte-colony stimulating factors and ursodeoxycholic acid (for veno-occlusive disease prophylaxis).
-prior to autologous hematopoietic stem-cell transplantation in patients with newly diagnosed multiple myeloma, in combination with melphalan*:
Intravenous dosage:
Adults 70 years or younger: test dose, 32 mg/m2 (use actual body weight to calculate BSA) IV over 45 minutes once on either day -8 or -9 followed by either a pharmacokinetically-adjusted busulfan dose for target daily AUC of 5,000 micromolar x minute) or 130 mg/m2 (use adjusted body weight to calculate BSA in patients who are more than 20% above ideal body weight) IV over 3 hours daily on days -7, -6, -5, and -4 in combination with melphalan 70 mg/m2 (use adjusted body weight to calculate BSA in patients who are more than 20% above ideal body weight) IV over 30 minutes daily on days -2 and -1 was evaluated as conditioning therapy prior to an autologous hematopoietic stem-cell transplant in a randomized, open-label, phase 3 trial (n = 202). Patients received induction chemotherapy and supportive care per standard institutional practice including granulocyte colony-stimulating factor 5 micrograms/kg subcutaneously daily starting on day 5 and continuing until an absolute neutrophil count of 0.5 x 109 cells/L or greater. Most patients received maintenance therapy until disease progression with a lenalidomide-containing regimen.
Therapeutic Drug Monitoring:
Therapeutic drug monitoring is recommended when busulfan is used in high doses as part of preparative regimens for stem cell transplantation. Specific guidelines are available for the monitoring of IV busulfan in children.
Using at least 3 blood samples, calculate the actual AUC value. Adjust the IV busulfan dose to achieve a busulfan target AUC of 1,125 micromolar x minute using the following formula:
Adjusted dose (mg) = Actual dose (mg) x Target AUC (micromolar x minute)/Actual AUC (micromolar x minute)
Blood Sample Collection
For each sample, collect 1 to 3 mL of blood into a heparinized tube. The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4 degrees Celsius) within 1 hour. Record the actual time of the sample collection.
For sample collection with dose 1, draw blood at hours 2, 4, and 6 from the start of the busulfan infusion; draw the hour 6 sample immediately prior to the next scheduled dose.
For sample collection with doses other than dose 1, draw blood prior to the dose and then at hours 2, 4, and 6 from the start of the busulfan infusion; draw the hour 6 sample immediately prior to the next scheduled dose.
AUC Calculation
Dose 1: AUCinfinity = AUC(0-6 hr) + AUCextrapolated; AUC(0-6 hr) is estimated using the linear trapezoidal rule and AUCextrapolated is calculated by taking the ratio of the busulfan concentration at hour 6 and the terminal elimination rate constant, Lamdaz.
Dose other than dose 1: estimate the steady state AUCss (AUC(0-6 hr)) from data from trough, 2 hour, 4 hour, and 6 hour concentrations using the lineal steady state AUCss.
Maximum Dosage Limits:
-Adults
8 mg/day PO; 1 mg/kg PO every 6 hours for 16 doses has been studied as part of a conditioning regimen prior to stem-cell transplantation.
0.8 mg/kg IV every 6 hours for 16 doses; 1 mg/kg IV every 6 hours for 16 doses has been studied as part of a conditioning regimen prior to stem-cell transplantation.
-Geriatric
8 mg/day PO; 1 mg/kg PO every 6 hours for 16 doses has been studied as part of a conditioning regimen prior to stem-cell transplantation.
0.8 mg/kg IV every 6 hours for 16 doses; 1 mg/kg IV every 6 hours for 16 doses has been studied as part of a conditioning regimen prior to stem-cell transplantation.
-Adolescents
60 mcg/kg or 1.8 mg/m2 PO per day.
-Children
60 mcg/kg or 1.8 mg/m2 PO per day.
-Infants
60 mcg/kg or 1.8 mg/m2 PO per day.
-Neonates
60 mcg/kg or 1.8 mg/m2 PO per day.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no initial dosage adjustments are needed. Therapeutic drug monitoring is recommended in patients receiving high-dose therapy.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no initial dosage adjustments are needed. Therapeutic drug monitoring is recommended in patients receiving high-dose therapy.
*non-FDA-approved indication
Acetaminophen: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Aspirin: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Caffeine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Chlorpheniramine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Codeine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Dextromethorphan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Diphenhydramine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Hydrocodone: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Ibuprofen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Oxycodone: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Phenylephrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Acetaminophen; Pseudoephedrine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Amlodipine; Celecoxib: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Benzhydrocodone; Acetaminophen: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Systemic metronidazole should not be administered with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole exist, monitor busulfan concentrations and adjust the busulfan doses as necessary. Metronidazole may increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Systemic metronidazole should not be administered with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole exist, monitor busulfan concentrations and adjust the busulfan doses as necessary. Metronidazole may increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease.
Bupivacaine; Meloxicam: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Butalbital; Acetaminophen: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Butalbital; Acetaminophen; Caffeine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Celecoxib: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Celecoxib; Tramadol: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cyclophosphamide: (Moderate) Monitor hepatic function if coadministration of cyclophosphamide with busulfan is necessary as there is an increased risk of hepatic sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease (VOD). An increased incidence of mucositis has also been reported with concomitant use.
Deferasirox: (Major) Discontinue iron chelating agents (e.g., deferasirox) well in advance of busulfan administration. Decreased clearance of busulfan was observed with concomitant use with deferasirox. The mechanism of this interaction is not fully elucidated.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Diclofenac: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Diflunisal: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ethotoin: (Moderate) Ethotoin may increase the clearance of busulfan due to the induction of glutathione-S-transferase.
Etodolac: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
Fenoprofen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Flurbiprofen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Fosphenytoin: (Moderate) Phenytoin may increase the metabolism of some antineoplastic drugs, which could potentially affect chemotherapy efficacy. Increased antineoplastic clearance has been reported with busulfan when phenytoin was administered concurrently. Documentation of these interactions is limited, but could be significant.
Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibuprofen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibuprofen; Famotidine: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Indomethacin: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Itraconazole: (Moderate) Monitor for evidence of busulfan toxicity if coadminsitration of itraconazole is necessary. Itraconazole reduced busulfan clearance by up to 25% in patients receiving itraconazole compared to patients who did not receive itraconazole. Higher busulfan exposure due to concomitant itraconazole could lead to toxic plasma levels in some patients.
Ketoconazole: (Moderate) Ketoconazole may decrease the clearance of busulfan, resulting in elevated serum concentrations of busulfan. Careful monitoring, with possible dose adjustments, is recommended during coadministration.
Ketoprofen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ketorolac: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Levoketoconazole: (Moderate) Ketoconazole may decrease the clearance of busulfan, resulting in elevated serum concentrations of busulfan. Careful monitoring, with possible dose adjustments, is recommended during coadministration.
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Mefenamic Acid: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Meloxicam: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Metronidazole: (Major) Systemic metronidazole should not be administered with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole exist, monitor busulfan concentrations and adjust the busulfan doses as necessary. Metronidazole may increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease.
Nabumetone: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Naproxen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Naproxen; Esomeprazole: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Oxaprozin: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert their toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with busulfan. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Phenytoin: (Moderate) Phenytoin may increase the metabolism of some antineoplastic drugs, which could potentially affect chemotherapy efficacy. Increased antineoplastic clearance has been reported with busulfan when phenytoin was administered concurrently.
Piroxicam: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Pretomanid: (Major) Avoid coadministration of pretomanid with busulfan, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and busulfan. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as busulfan, may occur during concurrent use with rufinamide.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Sulindac: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Sumatriptan; Naproxen: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Thioguanine, 6-TG: (Moderate) Use thioguanine and busulfan together with caution; adverse effects such as hepatotoxicity, myelosuppresion, and immunosuppression may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of liver dysfunction, bleeding, and infection. Portal hypertension and esophageal varices associated with abnormal liver function tests occurred in 12 patients with chronic myelogenous leukemia (therapy duration, 6 to 45 months) who received continuous busulfan and thioguanine therapy in a comparative study (n = 330); no hepatotoxicity was observed in patients who received single-agent busulfan. Liver biopsies in 4 of these patients revealed nodular regenerative hyperplasia.
Tolmetin: (Major) Due to the thrombocytopenic effects of busulfan, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Tramadol; Acetaminophen: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Busulfan is a member of the alkyl alkane sufonates class of alkylating agents. In aqueous solutions, busulfan hydrolyzes to release the methansulfate groups. This produces reactive carbonium ions that can alkylate DNA and other proteins resulting cytotoxicity. Busulfan reacts more readily with thiol groups of amino acids and proteins than nitrogen mustards. Busulfan exhibits SN2-alkylating kinetics which means the alkylating reaction is dependent upon the concentrations of both busulfan and the target compound. Busulfan binds to DNA at the N-7 position of guanine. Small amounts DNA-DNA interstrand crosslinking have been detected with busulfan while extensive DNA-protein crosslinking occur which may lead to interference with DNA replication, transcription of RNA, and nucleic acid function. Busulfan's activity is seen mostly in myeloid cells and in hematopoietic stem cells at high doses rather than lymphoid cells. This can lead to prolonged bone marrow aplasia in some patients. The reason for this specificity is unknown.
Resistance to busulfan occurs through similar mechanisms as other alkylating agents. Possible mechanisms of resistance include decreased drug uptake by malignant cells, increased cellular inactivation, increased inactivation of alkylating intermediates and increased DNA repair mechanisms.
Busulfan is administered orally and intravenously (IV). It is 32% bound to plasma proteins and 47% bound to red blood cells. Busulfan is a small, highly lipophilic molecule that easily crosses the blood brain barrier; it achieves concentrations in the cerebrospinal fluid approximately equal to those in plasma. The terminal elimination half-life was approximately 2.6 hours in adult patients who received oral busulfan (dose range, 2 to 8 mg). Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and via glutathione S-transferase (GST) catalysis. The conjugate undergoes extensive oxidative metabolism in the liver. Busulfan is metabolized in the liver and via enzymatic degradation, forming at least 12 metabolites. Metabolites including tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3- hydroxysulfolane are inactive. The elimination of busulfan appears to be independent of renal function; less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Following the administration of oral or IV radiolabeled busulfan, 25% to 60% of the radiation was recovered in the urine within 48 hours after administration; minimal amounts were recovered in the feces.
-Route-Specific Pharmacokinetics
Oral Route
The gastrointestinal absorption of busulfan is very good. In a study that compared a single 2-mg IV and oral dose of busulfan, the mean bioavailability was 80% +/- 20% in patients aged 13 to 60 years (n = 8). Busulfan appears to have linear kinetics over the dose range of 2 to 6 mg. Following the administration of oral busulfan 2 mg on day 1, 4 mg on day 2, and 6 mg on day 3, the mean dose-normalized (to a 2-mg dose) AUC and Cmax values were approximately 130 ng x hour/mL and 30 ng/mL, respectively, in adult patients (n = 5). The mean dose-normalized (to a 4-mg dose) AUC, Cmax, and Tmax values were 269 +/- 62 ng x hour/mL, 68.2 +/- 24.4 ng/mL, and 0.9 hours, respectively, following the administration of a single dose of busulfan (range, 4 to 8 mg) in 12 patients.
Intravenous Route
The AUC, Cmax, and clearance (normalized to actual body weight) values were 1,167 micromolar x min, 1,222 ng/mL, and 2.52 mL/min/kg, respectively, in a pharmacokinetic analysis of 59 patients who received busulfan 0.8 mg/kg IV every 6 hours for 16 doses plus cyclophosphamide prior to an allogeneic stem-cell transplantation. Only 7% of patents achieved the target AUC value of 1,500 micromolar x min or greater.
-Special Populations
Renal Impairment
The impact of hemodialysis on busulfan clearance has been evaluated in one patient with chronic renal failure undergoing autologous stem cell transplantation. The apparent clearance of oral busulfan during a 4-hour hemodialysis session was increased by 65%, but the 24-hour clearance was increased by only 11%.
Pediatrics
Pediatric patients (ages 2 months to 3.6 years) were found to have lower peak busulfan concentrations, faster elimination, and lower AUC values than adults. Changes in bioavailability, either due to changes in absorption, first pass elimination, or in actual volume of distribution may account for these changes in busulfan pharmacokinetics. The lower incidence of adverse reactions and higher transplant failure rates seen in children versus adults receiving high-dose busulfan therapy may be due to these differences. The absolute bioavailability of oral busulfan is lower in pediatric patients compared with adult patients. In a study that compared a single 2-mg IV and oral dose of busulfan, the mean bioavailability was 68% +/- 31% in patients aged 1.5 to 6 years who received a single 2-mg IV and oral dose of busulfan (n = 8). The estimated clearance and volume of distribution were 3.37 mL/min/kg and 0.64 L/kg, respectively, in pediatric patients aged 5 months to 16 years with malignant hematologic (n =15) or nonmalignant (n = 9) diseases who received 16 doses of busulfan IV plus cyclophosphamide prior to a stem-cell transplantation. The target AUC value of 900 to 1,350 micromolar x min was achieved with busulfan IV therapy at dose 1 in 71% of patients; between doses 9 and 13, the target AUC value was reached in 91% of patients.