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    Alkyl Sulfonates

    BOXED WARNING

    Bleeding, bone marrow suppression, infection, leukopenia, neutropenia, radiation therapy, thrombocytopenia

    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.

    New primary malignancy

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    A bifunctional alkylating agent
    IV formulation used in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic stem-cell transplantation in patients with chronic myelogenous leukemia (CML); oral tablet formulation used for palliative treatment of CML
    Black box warning for myelosuppression

    COMMON BRAND NAMES

    Busulfex, Myleran

    HOW SUPPLIED

    Busulfan/Busulfex Intravenous Inj Sol: 1mL, 6mg
    Myleran Oral Tab: 2mg

    DOSAGE & INDICATIONS

    For the palliative treatment of chronic myelogenous leukemia (CML).
    Oral dosage
    Adults, Adolescents, and Children

    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.

    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).

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    ADMINISTRATION

    Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    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 polycarbonate syringes or polycarbonate filter needles for busulfan preparation or administration.
    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.

    STORAGE

    Busulfex:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store diluted product in accordance with package insert instructions
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Myleran:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Bleeding, bone marrow suppression, infection, leukopenia, neutropenia, radiation therapy, thrombocytopenia

    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.

    Hepatic disease, hepatotoxicity, sinusoidal obstruction syndrome (SOS), veno-occlusive disease (VOD)

    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.

    Head trauma, seizures

    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.

    New primary malignancy

    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, tumor lysis syndrome (TLS)

    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.

    Children, infants, neonates

    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.

    Pregnancy

    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.

    Contraception requirements, infertility, male-mediated teratogenicity, reproductive risk

    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. Additionally, sterility, azoospermia, and testicular atrophy have been reported in male patients who received busulfan.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    graft-versus-host disease (GVHD) / Delayed / 0-45.0
    thrombosis / Delayed / 33.0-33.0
    hyperbilirubinemia / Delayed / 0-30.0
    pulmonary fibrosis / Delayed / 0-16.9
    veno-occlusive disease (VOD) / Delayed / 7.7-12.0
    sinusoidal obstruction syndrome (SOS) / Delayed / 7.7-12.0
    seizures / Delayed / 0-6.0
    cardiac tamponade / Delayed / 2.0-2.0
    new primary malignancy / Delayed / 0-1.6
    porphyria / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    aplastic anemia / Delayed / Incidence not known
    esophagitis / Delayed / Incidence not known
    anorexia / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    ileus / Delayed / Incidence not known
    pleural effusion / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    pericardial effusion / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    coma / Early / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    hemorrhagic cystitis / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 0-100.0
    thrombocytopenia / Delayed / 0-100.0
    lymphopenia / Delayed / 0-79.0
    hypomagnesemia / Delayed / 77.0-77.0
    anemia / Delayed / 0-69.0
    hyperglycemia / Delayed / 66.0-66.0
    hypokalemia / Delayed / 64.0-64.0
    hypocalcemia / Delayed / 49.0-49.0
    sinus tachycardia / Rapid / 44.0-44.0
    constipation / Delayed / 38.0-38.0
    edema / Delayed / 36.0-36.0
    chest pain (unspecified) / Early / 26.0-26.0
    depression / Delayed / 23.0-23.0
    anhidrosis / Delayed / 0-1.0
    cataracts / Delayed / 0-1.0
    myasthenia / Delayed / 0-1.0
    leukopenia / Delayed / 10.0
    prolonged bleeding time / Delayed / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    hypoxia / Early / Incidence not known
    hemoptysis / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    hot flashes / Early / Incidence not known
    delirium / Early / Incidence not known
    confusion / Early / Incidence not known
    encephalopathy / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    anovulation / Delayed / Incidence not known
    testicular atrophy / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    enamel hypoplasia / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hypervolemia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    dysuria / Early / Incidence not known

    Mild

    vomiting / Early / 0-100.0
    fever / Early / 80.0-80.0
    anxiety / Delayed / 72.0-72.0
    rash / Early / 0-57.0
    chills / Rapid / 46.0-46.0
    dyspepsia / Early / 44.0-44.0
    rhinitis / Early / 44.0-44.0
    dizziness / Early / 30.0-30.0
    cough / Delayed / 0-28.0
    pruritus / Rapid / 28.0-28.0
    xerostomia / Early / 0-26.0
    epistaxis / Delayed / 25.0-25.0
    infection / Delayed / 0-25.0
    back pain / Delayed / 23.0-23.0
    alopecia / Delayed / 0-17.0
    skin hyperpigmentation / Delayed / 5.0-10.0
    xerosis / Delayed / 0-1.0
    urticaria / Rapid / 0-1.0
    gynecomastia / Delayed / 0-1.0
    cheilitis / Delayed / Incidence not known
    sinusitis / Delayed / Incidence not known
    hiccups / Early / Incidence not known
    pharyngitis / Delayed / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    vesicular rash / Delayed / Incidence not known
    maculopapular rash / Early / Incidence not known
    skin discoloration / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    agitation / Early / Incidence not known
    lethargy / Early / Incidence not known
    drowsiness / Early / Incidence not known
    amenorrhea / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    weakness / Early / Incidence not known
    weight loss / Delayed / Incidence not known
    weight gain / Delayed / Incidence not known

    DRUG INTERACTIONS

    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; Butalbital: (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; Butalbital; 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; Butalbital; 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.
    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; Magnesium Salicylate; Phenyltoloxamine: (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; Phenyltoloxamine; Salicylamide: (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; Phenyltoloxamine: (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; 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; Dichloralphenazone; Isometheptene: (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; 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; Pentazocine: (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; Propoxyphene: (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.
    Acetaminophen; Tramadol: (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.
    Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL 2 in combination with any antineoplastic agents have not been established. Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose aldesleukin, IL 2 and dacarbazine. Aldesleukin, IL 2 can decrease dacarbazine serum concentrations by increasing the volume of distribution of dacarbazine by 36 percent via an unknown mechanism.
    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.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely. Carbamazepine may potentially accelerate the hepatic metabolism of dacarbazine, DTIC.
    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.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Cyclophosphamide: (Minor) Use busulfan and cyclophosphamide together with caution. Concomitant use may result in increased busulfan levels and increased busulfan toxicity; additionally, myelosuppressive toxicity may be additive. An increased incidence of hepatic sinusoidal obstruction syndrome (SOS), previously referred to as veno-occlusive disease, and mucositis has been reported; additionally, there may be an increased risk of pulmonary toxicity. Busulfan and cyclophosphamide are both metabolized in the liver through conjugation with glutathione; so these drugs may compete for elimination which may reduce the clearance of busulfan.
    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.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Esomeprazole; 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.
    Famotidine; 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.
    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.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    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; 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.
    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.
    Lansoprazole; 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.
    Live Vaccines: (Severe) 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; 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.
    Naproxen; Sumatriptan: (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.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    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.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Rofecoxib: (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.
    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.
    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.
    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.
    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.
    Valdecoxib: (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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.