Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Busulfan is a bifunctional alkylating agent in which two labile methanesulfonate groups are attached to opposite ends of a four-carbon alkyl chain. In aqueous media, busulfan hydrolyzes to release the methanesulfonate groups. This produces reactive carbonium ions that can alkylate DNA. DNA damage is thought to be responsible for much of the cytotoxicity of busulfan. Pharmacokinetics The pharmacokinetics of BUSULFEX were studied in 59 patients participating in a prospective trial of a BUSULFEX-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg BUSULFEX every six hours, for a total of 16 doses over four days. Fifty-five of fifty-nine patients (93%) administered BUSULFEX maintained AUC values below the target value (less than1500 μM•min). Table 3: Steady State Pharmacokinetic Parameters Following Busulfex® (busulfan) Infusion (0.8 mg per kg; N=59) Mean CV (%) Range Cmax (ng per mL) 1222 18 496-1684 AUC (μM•min) 1167 20 556-1673 CL (mL per min per kg)* 2.52 25 1.49-4.31 *Clearance normalized to actual body weight for all patients. BUSULFEX pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by reproducibility of steady state Cmax and a low coefficient of variation for this parameter. Distribution: Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in plasma. Busulfan primarily binds to albumin (Mean ± standard deviation=32.4 ± 2.2%). Metabolism: Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate undergoes extensive oxidative metabolism in the liver. Excretion: Following administration of 14C-labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Specific Populations Pediatric Patients: In a pharmacokinetic study of BUSULFEX in 24 pediatric patients, the population pharmacokinetic (PPK) estimates of BUSULFEX for clearance (CL) and volume of distribution (V) were determined. For actual body weight, PPK estimates of CL and V were 4.04 L/hr per 20 kg (3.37 mL per min per kg; interpatient variability 23%); and 12.8 L per 20 kg (0.64 L per kg; interpatient variability 11%). Clinical Studies Documentation of the safety and efficacy of busulfan as a component of a conditioning regimen prior to allogeneic hematopoietic progenitor cell reconstitution is derived from two sources: analysis of a prospective clinical trial of BUSULFEX that involved 61 patients diagnosed with various hematologic malignancies, and the published reports of randomized, controlled trials that employed high-dose oral busulfan as a component of a conditioning regimen for transplantation, which were identified in a literature review of five established commercial databases. Prospective Clinical Trial of BUSULFEX: The prospective trial was a single-arm, open-label study in 61 patients who received BUSULFEX as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation. The study included patients with acute leukemia past first remission (first or subsequent relapse), with high-risk first remission, or with induction failure; chronic myelogenous leukemia (CML) in chronic phase, accelerated phase, or blast crisis; primary refractory or resistant relapsed Hodgkin's disease or non-Hodgkin's lymphoma; and myelodysplastic syndrome. Forty-eight percent of patients (29/61) were heavily pretreated, defined as having at least one of the following: prior radiation, greater than or equal to 3 prior chemotherapeutic regimens, or prior hematopoietic stem cell transplant. Seventy-five percent of patients (46/61) were transplanted with active disease. Patients received 16 BUSULFEX doses of 0.8 mg per kg every 6 hours as a two-hour infusion for 4 days, followed by cyclophosphamide 60 mg per kg once per day for two days (BuCy2 regimen). All patients received 100% of their scheduled BUSULFEX regimen. No dose adjustments were made. After one rest day, allogeneic hematopoietic progenitor cells were infused. The efficacy parameters in this study were myeloablation (defined as one or more of the following: absolute neutrophil count [ANC] less than 0.5x109/L, absolute lymphocyte count [ALC] less than 0.1x109/L, thrombocytopenia defined as a platelet count less than 20,000/mm³ or a platelet transfusion requirement) and engraftment (ANC greater than or equal to 0.5x109/L). All patients (61/61) experienced myeloablation. The median time to neutropenia was 4 days. All evaluable patients (60/60) engrafted at a median of 13 days post-transplant (range 9 to 29 days); one patient was considered non-evaluable because he died of a fungal pneumonia 20 days after BMT and before engraftment occurred. All but 13 of the patients were treated with prophylactic G-CSF. Evidence of donor cell engraftment and chimerism was documented in all patients who had a chromosomal sex marker or leukemic marker (43/43), and no patient with chimeric evidence of allogeneic engraftment suffered a later loss of the allogeneic graft. There were no reports of graft failure in the overall study population. The median number of platelet transfusions per patient was 6, and the median number of red blood cell transfusions per patient was 4. Twenty-three patients (38%) relapsed at a median of 183 days post-transplant (range 36 to 406 days). Sixty-two percent of patients (38/61) were free from disease with a median follow-up of 269 days posttransplant (range 20 to 583 days). Forty-three patients (70%) were alive with a median follow up of 288 days post-transplant (range 51 to 583 days). There were two deaths before BMT Day +28 and six additional patients died by BMT Day +100. Ten patients (16%) died after BMT Day +100, at a median of 199 days post-transplant (range 113 to 275 days). Oral Busulfan Literature Review: Four publications of randomized, controlled trials that evaluated a high-dose oral busulfan-containing conditioning regimen (busulfan 4 mg/kg/d x4 days + cyclophosphamide 60 mg/kg/d x2 days) for allogeneic transplantation in the setting of CML were identified. Two of the studies (Clift and Devergie) had populations confined to CML in chronic phase that were randomized between conditioning with busulfan/cyclophosphamide (BU/CY) and cyclophosphamide/total body irradiation (CY/TBI). A total of 138 patients were treated with BU/CY in these studies. The populations of the two remaining studies (Ringden and Blume) included patients with CML, acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML). In the Nordic BMT Group study published by Ringden, et al., 57 patients had CML, and of those, 30 were treated with BU/CY. Patients with CML in chronic phase, accelerated phase, and blast crisis were eligible for this study. The participants with CML (34/122 patients) in a SWOG study published by Blume, et al., had disease beyond first chronic phase. Twenty of those CML patients were treated with BU/CY, and the TBI comparator arm utilized etoposide instead of cyclophosphamide. Table 4 summarizes the efficacy analyses reported from these 4 studies. Table 4: Summary of efficacy analyses from the randomized, controlled trials utilizing a high dose oral busulfan-containing conditioning regimen identified in a literature review. Clift, 1994 CML Chronic Phase; 3 year Overall Survival 3 year DFS (p=0.43) Relapse Time to Engraftment (ANC greater than or equal to 500) BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI 80% 80% 71% 68% 13% 13% 22.6 days 22.3 days Devergie, 1995 CML Chronic Phase; 5 year Overall Survival (p=0.5) 5 year DFS (p=0.75) Relapse (Relative Risk analysis BU/CY:CY/TBI) (p=0.04) Time to Engraftment (ANC greater than or equal to 500) BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI 60.6% ±11.7% 65.8% ±12.5% 59.1% ±11.8% 51.0% ±14% 4.10 (95%CI =1.00-20.28) None Given None Given Ringden, 1994 CML, AML, ALL; 3 year Overall Survival (p < 0.03) 3 year Relapse Free Survival (p=0.065) Relapse (p=0.9) Time to Engraftment (ANC greater than 500) BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI BU/CY CY/TBI 62% 76% 56% 67% 22% 26% 20 days 20 days Blume, 1993 * CML, AML, ALL; Relative Risk Analysis BU/CY: Etoposide/TBI RR of Mortality DFS RR of Relapse (Relative Risk analysis BU/CY:Eto/TBI) Time to Engraftment BU/CY Eto/TBI BU/CY Eto/TBI BU/CY Eto/TBI BU/CY Eto/TBI 0.97 (95% CI=0.64-1.48) Not Given 1.02 (95% CI=0.56-1.86) Not Given *Eto = etoposide. TBI was combined with etoposide in the comparator arm of this study. BU = Busulfan CY = Cyclophosphamide TBI = Total Body Irradiation DFS = Disease Free Survival ANC = Absolute Neutrophil Count REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 18, 2014 from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Find Lowest Prices on BUSULFEX (busulfan) Injection WARNING MYELOSUPPRESSION BUSULFEX® (bus ulfan) Injection caus es s evere and prolonged myelos uppres s ion at the recommended dos age. Hematopoietic progenitor cell trans plantation is required to prevent potentially fatal complications of the prolonged myelos uppres s ion [see WARNINGS AND PRECAUTIONS]. DESCRIPTION Busulfan is a bifunctional alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate. BUSULFEX® (busulfan) Injection is intended for intravenous administration. It is supplied as a clear, colorless, sterile, solution in 10 mL single use vials. Each vial of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a white crystalline powder with a molecular formula of CH3SO2O(CH2)4OSO2CH3 and a molecular weight of 246 g/mole. Busulfan has the following chemical structure: Busulfan is dissolved in N,N-dimethylacetamide (DMA), 3.3 mL and Polyethylene Glycol 400, NF 6.7 mL. The solubility of busulfan in water is 0.1 g per L and the pH of BUSULFEX diluted to approximately 0.5 mg per mL busulfan in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects the pH of the diluent used and ranges from 3.4 to 3.9.

INDICATIONS BUSULFEX is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia. DOSAGE AND ADMINISTRATION Initial Dosing Information Administer BUSULFEX in combination with cyclophosphamide as a conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement. For patients weighing more than 12 kg, the recommended doses are: BUSULFEX 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4). Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16th dose of BUSULFEX (Days -3 and - 2). Administer hematopoietic progenitor cells on Day 0. Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose BUSULFEX. Administer anticonvulsants 12 hours prior to BUSULFEX to 24 hours after the last dose of BUSULFEX [see WARNINGS AND PRECAUTIONS]. Administer antiemetics prior to the first dose of BUSULFEX and continue on a fixed schedule through BUSULFEX administration. BUSULFEX clearance is best predicted when the BUSULFEX dose is administered based on adjusted ideal body weight. Dosing BUSULFEX based on actual body weight, ideal body weight or other factors can produce significant differences in BUSULFEX clearance among lean, normal and obese patients. Calculate ideal body weight (IBW) as follows (height in cm, and weight in kg): Men: IBW (kg) = 50 + 0.91x (height in cm -152) Women: IBW (kg) = 45 + 0.91x (height in cm -152) For obese or severely obese patients, base BUSULFEX dosing on adjusted ideal body weight (AIBW): AIBW= IBW + 0.25 x (actual weight -IBW). Preparation And Administration Precautions DO NOT USE POLYCARBONATE SYRINGES OR POLYCARBONATE FILTER NEEDLES WITH BUSULFEX. Use an administration set with minimal residual hold-up volume (2-5 cc) for product administration. BUSULFEX is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing BUSULFEX. If BUSULFEX or diluted BUSULFEX solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if particulate matter is seen in the BUSULFEX vial. Preparation For Intravenous Administration BUSULFEX must be diluted prior to intravenous infusion with either 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W). The diluent quantity should be 10 times the volume of BUSULFEX, so that the final concentration of busulfan is approximately 0.5 mg per mL. Calculation of the dose for a 70 kg patient would be performed as follows: (70 kg patient) x (0.8 mg per kg) ÷ (6 mg per mL) =9.3 mL BUSULFEX (56 mg total dose). To prepare the final solution for infusion, add 9.3 mL of BUSULFEX to 93 mL of diluent (normal saline or D5W) as calculated below: (9.3 mL BUSULFEX) x (10) = 93 mL of either diluent plus the 9.3 mL of BUSULFEX to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL x 6 mg per mL ÷ 102.3 mL = 0.54 mg per mL). All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing. DO NOT put the BUSULFEX into an intravenous bag or large-volume syringe that does not contain normal saline or D5W. Always add the BUSULFEX to the diluent, not the diluent to the BUSULFEX. Mix thoroughly by inverting several times. Infusion pumps should be used to administer the diluted BUSULFEX solution. Set the flow rate of the pump to deliver the entire prescribed BUSULFEX dose over two hours. Prior to and following each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. WARNING: RAPID INFUSION OF BUSULFEX HAS NOT BEEN TESTED AND IS NOT RECOMMENDED. HOW SUPPLIED Dosage Forms And Strengths BUSULFEX Injection is supplied as a clear, colorless, sterile, solution in 10 mL single use vial containing 60 mg of busulfan at a concentration of 6 mg per mL for intravenous use only. BUSULFEX is packaged as a sterile solution in 10 mL single-use clear glass vials each containing 60 mg of busulfan at a concentration of 6 mg per mL for intravenous use, NDC 59148-047-90. BUSULFEX is distributed as a unit carton of eight vials NDC 59148-047-91. Storage And Handling Unopened vials of BUSULFEX must be stored under refrigerated conditions between 2°C to 8°C (36°F to 46°F). BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within that time. BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2°C to 8°C) for up to 12 hours but the infusion must be completed within that time. BUSULFEX is a cytotoxic drug. Follow applicable special handling and disposal procedures . Distributed and Marketed by: Otsuka America Pharmaceutical, Inc. Rockville, MD 20850. Manufactured by: Patheon Manufacturing Services LLC, Greenville, NC 27834 Or Baxter Oncology GmbH, 33790 Halle, Westfalen, Germany. Revisd: June 2017

PATIENT INFORMATION Inform patients of the possibility of developing low blood cell counts and the need for hematopoietic progenitor cell infusion. Instruct patients to immediately report to their healthcare provider if fever develops [see WARNINGS AND PRECAUTIONS]. Inform patients of the risks associated with the use of BUSULFEX as well as the plan for regular blood monitoring during therapy. Specifically inform patients of the following: The risk of venoocclusive liver disease [see WARNINGS AND PRECAUTIONS]. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use in Specific Populations]. Advise females and males of reproductive potential to use effective contraception during and after treatment with BUSULFEX [see Use in Specific Populations]. Advise females to discontinue breastfeeding during treatment with BUSULFEX [see Use in Specific Populations]. Advise females and males of reproductive potential that BUSULFEX may cause temporary or permanent infertility [see Use in Specific Populations].

OVERDOSE There is no known antidote to BUSULFEX other than hematopoietic progenitor cell transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for BUSULFEX would constitute an overdose of busulfan. The principal toxic effect is profound bone marrow hypoplasia/aplasia and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract may be affected. Monitor hematologic status closely and institute vigorous supportive measures as medically indicated. Survival after a single 140 mg dose of Myleran® Tablets in an 18 kg, 4-year old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan (2.1 mg per kg; total dose of 23.3 mg per kg) occurred in a 2-year old child prior to a scheduled bone marrow transplant without sequelae. An acute dose of 2.4 g was fatal in a 10-year old boy. There is one report that busulfan is dialyzable, thus dialysis should be considered in the case of overdose. CONTRAINDICATIONS BUSULFEX is contraindicated in patients with a history of hypersensitivity to any of its components.

SIDE EFFECTS The following adverse reactions are discussed in more detail in other sections of the labeling: Myelosuppression [see WARNINGS AND PRECAUTIONS] Seizures [see WARNINGS AND PRECAUTIONS] HVOD [see WARNINGS AND PRECAUTIONS] Embryo-fetal Toxicity [see WARNINGS AND PRECAUTIONS] Cardiac Tamponade [see WARNINGS AND PRECAUTIONS] Bronchopulmonary Dysplasia [see WARNINGS AND PRECAUTIONS] Cellular Dysplasia [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reaction information is primarily derived from the clinical study (N=61) of BUSULFEX and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review. In the BUSULFEX (busulfan) Injection allogeneic stem cell transplantation clinical trial, all patients were treated with BUSULFEX 0.8 mg per kg as a two-hour infusion every six hours for 16 doses over four days, combined with cyclophosphamide 60 mg per kg x2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of BUSULFEX maintained an AUC less than 1,500 μM•min for dose 9, which has generally been considered the level that minimizes the risk of HVOD. Table 1 lists the non-hematologic adverse reactions events through BMT Day +28 at a rate greater than or equal to 20% in patients treated with BUSULFEX prior to allogeneic hematopoietic cell transplantation. Table 1: Summary of the Incidence (greater than or equal to 20%) of Non-Hematologic Advers e Reactions through BMT Day +28 in Patients who Received BUSULFEX Prior to Allogeneic Hematopoietic Progenitor Cell Trans plantation Non-Hematological Adverse Reactions* Percent Incidence BODY AS A WHOLE Fever 80 Headache 69 Asthenia 51 Chills 46 Pain 44 Edema General 28 Allergic Reaction 26 Chest Pain 26 Inflammation at Injection Site 25 Back Pain 23 CARDIOVASCULAR SYSTEM Tachycardia 44 Hypertension 36 Thrombosis 33 Vasodilation 25 DIGESTIVE SYSTEM Nausea 98 Stomatitis (Mucositis) 97 Vomiting 95 Anorexia 85 Diarrhea 84 Abdominal Pain 72 Dyspepsia 44 Constipation 38 Dry Mouth 26 Rectal Disorder 25 Abdominal Enlargement 23 METABOLIC AND NUTRITIONAL SYSTEM Hypomagnesemia 77 Hyperglycemia 66 Hypokalemia 64 Hypocalcemia 49 Hyperbilirubinemia 49 Edema 36 SGPT Elevation 31 Creatinine Increased 21 NERVOUS SYSTEM Insomnia 84 Anxiety 72 Dizziness 30 Depression 23 RESPIRATORY SYSTEM Rhinitis 44 Lung Disorder 34 Cough 28 Epistaxis 25 Dyspnea 25 SKIN AND APPENDAGES Rash 57 Pruritus 28 *Includes all reported adverse reactions regardless of severity (toxicity grades 1-4 ) Additional Adverse Reactions By Body System Hematologic: Prolonged prothrombin time Gastrointestinal: Esophagitis, ileus, hematemesis, pancreatitis, rectal discomfort Hepatic: Alkaline phosphatase increases, jaundice, hepatomegaly Graft-versus -host disease: Graft-versus-host disease. There were 3 deaths (5%) attributed to GVHD. Edema: Hypervolemia, or documented weight increase Infection: Infection, pneumonia (fatal in one patient and life-threatening in 3% of patients) Cardiovascular: Arrhythmia, atrial fibrillation, ventricular extrasystoles, third degree heart block, thrombosis (all episodes were associated with the central venous catheter), hypotension, flushing and hot flashes, cardiomegaly, ECG abnormality, left-sided heart failure, and pericardial effusion Pulmonary: Hyperventilation, alveolar hemorrhage (fatal in 3%), pharyngitis, hiccup, asthma, atelectasis, pleural effusion, hypoxia, hemoptysis, sinusitis, and interstitial fibrosis (fatal in a single case) Neurologic: Cerebral hemorrhage, coma, delirium, agitation, encephalopathy, confusion, hallucinations, lethargy, somnolence Renal: BUN increased, dysuria, oliguria, hematuria, hemorrhagic cystitis Skin: Alopecia, vesicular rash, maculopapular rash, vesiculo-bullous rash, exfoliative dermatitis, erythema nodosum, acne, skin discoloration Metabolic: Hypophosphatemia, hyponatremia Other Events : Injection site pain, myalgia, arthralgia, ear disorder Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.The following adverse reactions (reported as MedRA terms) have been identified during post-approval use of BUSULFEX (busulfan) Injection: Blood and Lymphatic System Disorders: febrile neutropenia Gastrointestinal Disorders: tooth hypoplasia Metabolism and Nutrition Disorders: tumor lysis syndrome Vascular Disorders: thrombotic microangiopathy (TMA) Infections and Infestations: severe bacterial, viral (e.g., cytomegalovirus viremia) and fungal infections; and sepsis. Oral Busulfan Literature Review A literature review identified four randomized, controlled trials that evaluated a high-dose oral busulfan-containing conditioning regimen for allogeneic bone marrow transplantation in the setting of CML [see Clinical Studies]. The safety outcomes reported in those trials are summarized in Table 2 below for a mixed population of hematological malignancies (AML, CML, and ALL). Table 2: Summary of safety analyses from the randomized, controlled trials utilizing a high dos e oral busulfan-containing conditioning regimen that were identified in a literature review. Clift CML Chronic Phase TRM* VOD† GVHD‡ Pulmonary Hemorrhagic Cystitis Seizure Death ≤ 100d =4.1% (3/73) No Report Acute ≥ Grade 2 =35% Chronic=41% (30/73) 1 death from Idiopathic Interstitial Pneumonitis And 1 death from Pulmonary Fibrosis No Report No Report Devergie CML Chronic Phase TRM VOD GVHD Pulmonary Hemorrhagic Cystitis Seizure 38% 7.7% (5/65) Deaths=4.6% (3/65) Acute ≥ Grade 2 =41% (24/59 at risk) Interstitial Pneumonitis= 16.9% (11/65) 10.8% (7/65) No Report Ringden CML, AML, ALL TRM VOD GVHD Pulmonary Hemorrhagic Cystitis Seizure 28% 12% Acute ≥ Grade 2 GVHD=26% Chronic GVHD =45% Interstitial Pneumonitis =14% 24% 6% Blume CML, AML, ALL TRM VOD GVHD Pulmonary Hemorrhagic Cystitis Seizure No Report Deaths =4.9% Acute ≥ Grade 2GVHD =22% (13/58 at risk) Chronic GVHD =31% (14/45 at risk) No Report No Report No Report *TRM = Transplantation Related Mortality †VOD = Veno-Occlusive Disease of the liver ‡GVHD = Graft versus Host Disease DRUG INTERACTIONS Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC greater than 1500 μM•min in some patients. Fluconazole (200 mg) has been used with BUSULFEX. Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of BUSULFEX were studied in patients treated with phenytoin, the clearance of BUSULFEX at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin. Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (less than 72 hours) or concurrent with BUSULFEX may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues.