BOXED WARNING SECTION.

WARNING: MYELOSUPPRESSION. BUSULFEX (busulfan) Injection causes severe and prolonged myelosuppression at the recommended dosage. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression [see Warnings and Precautions (5.1)]. WARNING: MYELOSUPPRESSIONSee full prescribing information for complete boxed warning.Causes severe and prolonged myelosuppression. (5.1)Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. (5.1). Causes severe and prolonged myelosuppression. (5.1). Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. (5.1).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in more detail in other sections of the labeling:Myelosuppression [see Warnings and Precautions (5.1)] Seizures [see Warnings and Precautions (5.2)] Hepatic Veno-Occlusive Disease (HVOD) [see Warnings and Precautions (5.3)] Embryo-fetal Toxicity [see Warnings and Precautions (5.4)] Cardiac Tamponade [see Warnings and Precautions (5.5)] Bronchopulmonary Dysplasia [see Warnings and Precautions (5.6)] Cellular Dysplasia [see Warnings and Precautions (5.7)] Myelosuppression [see Warnings and Precautions (5.1)] Seizures [see Warnings and Precautions (5.2)] Hepatic Veno-Occlusive Disease (HVOD) [see Warnings and Precautions (5.3)] Embryo-fetal Toxicity [see Warnings and Precautions (5.4)] Cardiac Tamponade [see Warnings and Precautions (5.5)] Bronchopulmonary Dysplasia [see Warnings and Precautions (5.6)] Cellular Dysplasia [see Warnings and Precautions (5.7)] Most common adverse reactions (incidence >60%) were: myelosuppression, nausea, stomatitis, vomiting, anorexia, diarrhea, insomnia, fever, hypomagnesemia, abdominal pain, anxiety, headache, hyperglycemia and hypokalemia (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 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 uMmin for dose 9, which has generally been considered the level that minimizes the risk of HVOD.Table lists the non-hematologic adverse reactions events through Bone Marrow Transplantation (BMT) Day +28 at 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 Adverse Reactions through BMT Day +28 in Patients who Received BUSULFEX Prior to Allogeneic Hematopoietic Progenitor Cell TransplantationNon-Hematological Adverse ReactionsIncludes all reported adverse reactions regardless of severity (toxicity grades 1-4) Percent IncidenceBODY AS WHOLE Fever80 Headache69 Asthenia51 Chills46 Pain44 Edema General28 Allergic Reaction26 Chest Pain26 Inflammation at Injection Site25 Back Pain23CARDIOVASCULAR SYSTEM Tachycardia44 Hypertension36 Thrombosis33 Vasodilation25DIGESTIVE SYSTEM Nausea98 Stomatitis (Mucositis)97 Vomiting95 Anorexia85 Diarrhea84 Abdominal Pain72 Dyspepsia44 Constipation38 Dry Mouth26 Rectal Disorder25 Abdominal Enlargement23METABOLIC AND NUTRITIONAL SYSTEM Hypomagnesemia77 Hyperglycemia66 Hypokalemia64 Hypocalcemia49 Hyperbilirubinemia49 Edema36 SGPT Elevation31 Creatinine Increased21NERVOUS SYSTEM Insomnia84 Anxiety72 Dizziness30 Depression23RESPIRATORY SYSTEM Rhinitis44 Lung Disorder34 Cough28 Epistaxis25 Dyspnea25SKIN AND APPENDAGES Rash57 Pruritus28. Additional Adverse Reactions by Body System Hematologic: Prolonged prothrombin timeGastrointestinal: Esophagitis, ileus, hematemesis, pancreatitis, rectal discomfort Hepatic: Alkaline phosphatase increases, jaundice, hepatomegalyGraft-versus-host disease: Graft-versus-host disease. There were deaths (5%) attributed to GVHD.Edema: Hypervolemia, or documented weight increaseInfection: 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 single case)Neurologic: Cerebral hemorrhage, coma, delirium, agitation, encephalopathy, confusion, hallucinations, lethargy, somnolence Renal: BUN increased, dysuria, oliguria, hematuria, hemorrhagic cystitisSkin: Alopecia, vesicular rash, maculopapular rash, vesiculo-bullous rash, exfoliative dermatitis, erythema nodosum, acne, skin discolorationMetabolic: Hypophosphatemia, hyponatremiaOther Events: Injection site pain, myalgia, arthralgia, ear disorder. 6.2 Postmarketing Experience. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of BUSULFEX (busulfan) Injection:Blood and Lymphatic System Disorders: febrile neutropeniaGastrointestinal Disorders: tooth hypoplasiaMetabolism and Nutrition Disorders: tumor lysis syndromeVascular Disorders: thrombotic microangiopathy (TMA)Infections and Infestations: severe bacterial, viral (e.g., cytomegalovirus viremia) and fungal infections; and sepsis.. 6.3 Oral Busulfan Literature Review. literature review identified four randomized, controlled trials that evaluated high-dose oral busulfan-containing conditioning regimen for allogeneic bone marrow transplantation in the setting of CML [see Clinical Studies (14)]. The safety outcomes reported in those trials are summarized in Table below for mixed population of hematological malignancies (AML, CML, and ALL).Table 2: Summary of safety analyses from the randomized, controlled trials utilizing high dose oral busulfan-containing conditioning regimen that were identified in literature review.CliftCML Chronic PhaseTRMTRM Transplantation Related Mortality VODVOD Veno-Occlusive Disease of the liver GVHDGVHD Graft versus Host Disease PulmonaryHemorrhagic CystitisSeizureDeath <=100d =4.1% (3/73)No ReportAcute>=Grade 2=35%Chronic=41% (30/73)1 death from Idiopathic Interstitial Pneumonitis And death from Pulmonary FibrosisNo ReportNo ReportDevergieCML Chronic PhaseTRMVODGVHDPulmonaryHemorrhagic CystitisSeizure38%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 ReportRingdenCML, AML, ALLTRMVODGVHDPulmonaryHemorrhagic CystitisSeizure28%12%Acute>=Grade GVHD=26% Chronic GVHD =45%Interstitial Pneumonitis =14%24%6%BlumeCML, AML, ALLTRMVODGVHDPulmonaryHemorrhagic CystitisSeizureNo ReportDeaths =4.9%Acute>=Grade GVHD=22% (13/58 at risk)Chronic GVHD =31% (14/45 at risk)No ReportNo ReportNo Report.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Busulfan is mutagen and clastogen. In in vitro tests it caused mutations in Salmonella typhimurium and Drosophila melanogaster. Chromosomal aberrations induced by busulfan have been reported in vivo (rats, mice, hamsters, and humans) and in vitro (rodent and human cells). The intravenous administration of busulfan (48 mg/kg given as biweekly doses of 12 mg/kg, or 30% of the total BUSULFEX dose on mg/m2 basis) has been shown to increase the incidence of thymic and ovarian tumors in mice.Busulfan depleted oocytes of female rats and induced sterility in male rats and hamsters. The solvent DMA may also impair fertility. DMA daily dose of 0.45 g/kg/day given to rats for nine days (equivalent to 44% of the daily dose of DMA contained in the recommended dose of BUSULFEX on mg/m2 basis) significantly decreased spermatogenesis in rats. single subcutaneous dose of 2.2 g/kg (27% of the total DMA dose contained in BUSULFEX on mg/m2 basis) four days after insemination terminated pregnancy in 100% of tested hamsters [see Use in Specific Populations (8.3)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Busulfan is bifunctional alkylating agent in which two labile methanesulfonate groups are attached to opposite ends of 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.. 12.3 Pharmacokinetics. The pharmacokinetics of BUSULFEX were studied in 59 patients participating in prospective trial of BUSULFEX-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg BUSULFEX every six hours, for 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 uMmin).Table 3: Steady State Pharmacokinetic Parameters Following BUSULFEX(R) (busulfan) Infusion (0.8 mg per kg; N=59)MeanCV (%)RangeCmax (ng per mL)122218496-1684AUC (uMmin)116720556-1673CL (mL per min per kg)Clearance normalized to actual body weight for all patients. 2.52251.49-4.31BUSULFEX pharmacokinetics showed consistency between dose and dose 13 as demonstrated by reproducibility of steady state Cmax and 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 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 were 4.04 L/hr per 20 kg (3.37 mL per min per kg; interpatient variability 23%); and 12.8 per 20 kg (0.64 per kg; interpatient variability 11%).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Documentation of the safety and efficacy of busulfan as component of conditioning regimen prior to allogeneic hematopoietic progenitor cell reconstitution is derived from two sources:i) analysis of prospective clinical trial of BUSULFEX that involved 61 patients diagnosed with various hematologic malignancies, and ii) the published reports of randomized, controlled trials that employed high-dose oral busulfan as component of conditioning regimen for transplantation, which were identified in literature review of five established commercial databases.. Prospective Clinical Trial of BUSULFEX: The prospective trial was single-arm, open-label study in 61 patients who received BUSULFEX as part of 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 Hodgkins disease or non-Hodgkins 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 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 hours as two-hour infusion for 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 platelet count less than 20,000/mm3 or 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 days. All evaluable patients (60/60) engrafted at median of 13 days post-transplant (range to 29 days); one patient was considered non-evaluable because he died of 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 chromosomal sex marker or leukemic marker (43/43), and no patient with chimeric evidence of allogeneic engraftment suffered 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 median of 183 days post-transplant (range 36 to 406 days). Sixty-two percent of patients (38/61) were free from disease with median follow-up of 269 days post-transplant (range 20 to 583 days). Forty-three patients (70%) were alive with 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 median of 199 days post-transplant (range 113 to 275 days).. Oral Busulfan Literature Review: Four publications of randomized, controlled trials that evaluated high-dose oral busulfan-containing conditioning regimen (busulfan 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). 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 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 summarizes the efficacy analyses reported from these studies.Table 4: Summary of efficacy analyses from the randomized, controlled trials utilizing high dose oral busulfan-containing conditioning regimen identified in literature review.BU BusulfanCY CyclophosphamideTBI Total Body IrradiationDFS Disease Free SurvivalANC Absolute Neutrophil CountClift, 1994CML Chronic Phase;3 year Overall Survival3 year DFS(p=0.43)RelapseTime to Engraftment(ANC greater than or equal to 500)BU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBI80%80%71%68%13%13%22.6 days22.3 daysDevergie, 1995CML Chronic Phase;5 year Overall Survival5 year DFS (p=0.75)Relapse (Relative Risk analysis BU/CY:CY/TBI)Time to Engraftment(ANC greater than or equal to 500) (p=0.5) (p=0.04)BU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBI60.6% +-11.7%65.8% +-12.5%59.1% +-11.8%51.0% +-14% 4.10(95%CI =1.00-20.28)None GivenNone GivenRingden, 1994CML, 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/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBIBU/CYCY/TBI62%76%56%67%22%26%20 days20 daysBlume, 1993Eto etoposide. TBI was combined with etoposide in the comparator arm of this study. CML, AML, ALL; Relative Risk Analysis BU/CY: Etoposide/TBIRR of MortalityDFSRR of Relapse(Relative Risk analysis BU/CY:Eto/TBI)Time to EngraftmentBU/CYEto/TBIBU/CYEto/TBIBU/CYEto/TBIBU/CYEto/TBI0.97(95% CI=0.64-1.48)Not Given 1.02(95% CI=0.56-1.86)Not Given.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. BUSULFEX is contraindicated in patients with history of hypersensitivity to any of its components.. BUSULFEX is contraindicated in patients with history of hypersensitivity to any of its components (4). BUSULFEX is contraindicated in patients with history of hypersensitivity to any of its components (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Busulfan is bifunctional alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate. The molecular formula of busulfan is CH3SO2O(CH2)4OSO2CH3 with molecular weight of 246 g/mole. Busulfan has the following chemical structure:BUSULFEX (busulfan) Injection is supplied as clear, colorless, sterile, solution in 10 mL single-dose vials for intravenous administration upon dilution. Each vial contains 60 mg of busulfan 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 per 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.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Pre-medicate with anticonvulsants (e.g. benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic (2.1, 5.2)Dilute and administer as intravenous infusion. Do not administer as intravenous push or bolus (2.1, 2.3)Recommended adult dose: 0.8 mg per kg of ideal body weight or actual body weight, whichever is lower, administered intravenously via central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (2.1). Pre-medicate with anticonvulsants (e.g. benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic (2.1, 5.2). Dilute and administer as intravenous infusion. Do not administer as intravenous push or bolus (2.1, 2.3). Recommended adult dose: 0.8 mg per kg of ideal body weight or actual body weight, whichever is lower, administered intravenously via central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (2.1). 2.1 Initial Dosing Information. Administer BUSULFEX in combination with cyclophosphamide as 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 central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (Days -7, -6, -5 and -4). Cyclophosphamide 60 mg per kg intravenously as 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 (5.2)]. Administer antiemetics prior to the first dose of BUSULFEX and continue on 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 +0.25x (actual weight -IBW). Administer BUSULFEX in combination with cyclophosphamide as 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 central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (Days -7, -6, -5 and -4). Cyclophosphamide 60 mg per kg intravenously as 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. BUSULFEX 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (Days -7, -6, -5 and -4). Cyclophosphamide 60 mg per kg intravenously as 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 (5.2)]. Administer antiemetics prior to the first dose of BUSULFEX and continue on 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 +0.25x (actual weight -IBW). 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 +0.25x (actual weight -IBW). AIBW= IBW +0.25x (actual weight -IBW).. 2.2 Preparation and Administration Precautions. BUSULFEX is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with BUSULFEX.Use an administration set with minimal residual hold-up volume (2 mL to mL) for product administration.BUSULFEX is 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.. 2.3 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 70 kg patient would be performed as follows:(70 kg patient) (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) (10) =93 mL of either diluent plus the 9.3 mL of BUSULFEX to yield final concentration of busulfan of 0.54 mg per mL (9.3 mL 6 mg per mL /102.3 mL =0.54 mg per mL).All transfer procedures require strict adherence to aseptic techniques, preferably employing vertical laminar flow safety hood while wearing gloves and protective clothing.Always add the BUSULFEX to the diluent, not the diluent to the BUSULFEX. Mix thoroughly by inverting several times. Discard unused portion.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 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 60 mg/10 mL (6 mg/mL) as clear, colorless, sterile, solution in single-dose vial for intravenous use only.. Injection: 60 mg/10 mL (6 mg/mL) single-dose vial (3). Injection: 60 mg/10 mL (6 mg/mL) single-dose vial (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs that Decrease BUSULFEX Clearance: Metronidazole, itraconazole, iron chelating agents, acetaminophen. (7.1)Drugs that Increase BUSULFEX Clearance: Phenytoin. (7.2). Drugs that Decrease BUSULFEX Clearance: Metronidazole, itraconazole, iron chelating agents, acetaminophen. (7.1). Drugs that Increase BUSULFEX Clearance: Phenytoin. (7.2). 7.1 Drugs that Decrease BUSULFEX Clearance. Itraconazole decreases busulfan clearance by up to 25%. Metronidazole decreases the clearance of busulfan to greater extent than does itraconazole; metronidazole coadministration has been associated with increased busulfan toxicity. Fluconazole (200 mg) has been used with BUSULFEX. Decreased clearance of busulfan was observed with concomitant use with deferasirox. The mechanism of this interaction is not fully elucidated. Discontinue iron chelating agents well in advance of administration of BUSULFEX to avoid increased exposure to busulfan.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.. 7.2 Drugs that Increase BUSULFEX Clearance. 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.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of BUSULFEX in 24 pediatric patients receiving BUSULFEX as part of conditioning regimen administered prior to hematopoietic progenitor cell transplantation for variety of malignant hematologic (N=15) or non-malignant diseases (N=9). Patients ranged in age from months to 16 years (median years). BUSULFEX dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900-1350 uMmin with an initial dose of 0.8 mg per kg or 1.0 mg per kg (based on Actual Body Weight (ABW)) if the patient was greater than or less than or equal to years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1.Patients received BUSULFEX doses every six hours as two-hour infusion over four days for total of 16 doses, followed by cyclophosphamide 50 mg per kg once daily for four days. After one rest day, hematopoietic progenitor cells were infused. All patients received phenytoin as seizure prophylaxis. The target AUC (900-1350+-5% uMmin) for BUSULFEX was achieved at dose in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose and 13. BUSULFEX levels were within the target range for 21 of 23 evaluable patients.All 24 patients experienced neutropenia (absolute neutrophil count (ANC) less than 0.5x109/L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm3). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1x109). In 23 patients, the ANC recovered to greater than 0.5x109/L (median time to recovery BMT day +13; range BMT day +9 to +22). One patient who died on day +20 had not recovered to an ANC >0.5x109/L.Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure.Adverse reactions were reported in all 24-patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), HVOD (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%).Based on the results of this 24-patient clinical trial, suggested dosing regimen of BUSULFEX in pediatric patients is shown in the following dosing nomogram:BUSULFEX Dosing NomogramPatients Actual Body Weight (ABW)BUSULFEX Dosageless than or equal to12 kgs1.1 (mg per kg)greater than 12 kgs0.8 (mg per kg)Simulations based on pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve target BUSULFEX exposure (AUC) between 900 to 1350 uMmin with the first dose of BUSULFEX using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of BUSULFEX is recommended.. Dose Adjustment Based on Therapeutic Drug MonitoringInstructions for measuring the AUC of busulfan at dose (see Blood Sample Collection for AUC Determination) and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 uMmin), are provided below. Adjusted dose (mg) Actual Dose (mg) Target AUC (uMmin)/Actual AUC (uMmin)For example, if patient received dose of 11 mg busulfan and if the corresponding AUC measured was 800 uMmin, for target AUC of 1125 uMmin, the target mg dose would be:Mg dose =11 mg 1125 uMmin /800 uMmin =15.5 mgBUSULFEX dose adjustment may be made using this formula and instructions below.. Blood Sample Collection for AUC DeterminationCalculate the AUC (uMmin) based on blood samples collected at the following time points:For dose 1:2 hr (end of infusion), hr and hr (immediately prior to the next scheduled BUSULFEX administration). Actual sampling times should be recorded. For doses other than dose 1: Pre-infusion (baseline), hr (end of infusion), hr and hr (immediately prior to the next scheduled BUSULFEX administration).AUC calculations based on fewer than the three specified samples may result in inaccurate AUC determinations.For each scheduled blood sample, collect one to three mL of blood into heparinized (Na or Li heparin) Vacutainer(R) tubes. The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4C) within one hour. The plasma, harvested into appropriate cryovial storage tubes, is to be frozen immediately at -20C. All plasma samples are to be sent in frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations.. Calculation of AUCBUSULFEX AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula:Dose AUCinfinity Calculation: AUCinfinity AUC0-6hr +AUCextrapolated, where AUC0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour and the terminal elimination rate constant, z. The must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. 0 pre-dose busulfan concentration should be assumed, and used in the calculation of AUC.If the AUC is assessed subsequent to Dose 1, steady-state AUCss (AUC0-6hr) is to be estimated from the trough, hr, hr and hr concentrations using the linear trapezoidal rule.. Dose AUCinfinity Calculation: AUCinfinity AUC0-6hr +AUCextrapolated, where AUC0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour and the terminal elimination rate constant, z. The must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. 0 pre-dose busulfan concentration should be assumed, and used in the calculation of AUC.. Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug MonitoringUse an administration set with minimal residual hold up (priming) volume (1 to mL) for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for therapeutic drug monitoring and dose adjustment.Prime the administration set tubing with drug solution to allow accurate documentation of the start time of BUSULFEX infusion. Collect the blood sample from peripheral IV line to avoid contamination with infusing drug. If the blood sample is taken directly from the existing central venous catheter (CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSING to ensure that the end of infusion sample is not contaminated with any residual drug. At the end of infusion (2 hr), disconnect the administration tubing and flush the CVC line with mL of normal saline prior to the collection of the end of infusion sample from the CVC port. Collect the blood samples from different port than that used for the BUSULFEX infusion. When recording the BUSULFEX infusion stop time, do not include the time required to flush the indwelling catheter line. Discard the administration tubing at the end of the two-hour infusion [see Dosage and Administration (2.3)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Contraception. FemalesBUSULFEX can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with BUSULFEX and for months following cessation of therapy.. MalesBUSULFEX may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during treatment with BUSULFEX and for months after cessation of therapy [see Nonclinical Toxicology (13.1)]. Infertility. Females Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. BUSULFEX may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose BUSULFEX in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.. MalesSterility, azoospermia, and testicular atrophy have been reported in male patients.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of BUSULFEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. BUSULFEX is packaged as sterile solution in 10 mL Single-dose clear glass vials, NDC 59148-070-90.BUSULFEX is distributed as unit carton of eight vials NDC 59148-070-91.. 16.2 Storage and Handling. Unopened vials of BUSULFEX must be stored under refrigerated conditions between 2C to 8C (36F to 46F). Discard unused portion.BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25C) for up to hours but the infusion must be completed within that time.BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2C to 8C) for up to 12 hours but the infusion must be completed within that time.BUSULFEX is cytotoxic drug. Follow applicable special handling and disposal procedures1.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. BUSULFEX is indicated for use in combination with cyclophosphamide as conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.. BUSULFEX is an alkylating drug indicated for:Use in combination with cyclophosphamide as conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (CML) (1). Use in combination with cyclophosphamide as conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (CML) (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. MyelosuppressionAdvise 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 (5.1)]. SeizuresAdvise patients of the possibility of seizures and that they will be given medication to prevent them. Patients should be asked to report history of seizure or head trauma [see Warnings and Precautions (5.2)]. Hepatic Veno-Occlusive Disease (HVOD)Advise 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 veno-occlusive liver disease [see Warnings and Precautions (5.3)]. Embryo-fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to inform their healthcare provider with known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)].. Females of Reproductive PotentialAdvise females of reproductive potential to use effective contraception during treatment with BUSULFEX and for months following cessation of therapy [see Use in Specific Populations (8.3)].. Males of Reproductive PotentialAdvise males with female sexual partners of reproductive potential to use effective contraception during treatment with BUSULFEX and for months following cessation of therapy [see Use in Specific Populations (8.3)]. LactationAdvise females to discontinue breastfeeding during treatment with BUSULFEX [see Use in Specific Populations (8.2)]. InfertilityAdvise females and males of reproductive potential that BUSULFEX may cause temporary or permanent infertility [see Use in Specific Populations (8.3)]. Cardiac TamponadeAdvise patients of the risk of cardiac tamponade. Instruct patients to report to their healthcare provider symptoms of abdominal pain and vomiting [see Warnings and Precautions (5.5)].. Bronchopulmonary DysplasiaAdvise patients of the possibility of bronchopulmonary dysplasia with pulmonary fibrosis with chronic BUSULFEX therapy. Instruct patients to report symptoms of shortness of breath and cough to their healthcare provider. These symptoms could occur several months or years after therapy with BUSULFEX [see Warnings and Precautions (5.6)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryIt is not known whether BUSULFEX is present in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies, discontinue breastfeeding during treatment with BUSULFEX.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Busulfan is bifunctional alkylating agent in which two labile methanesulfonate groups are attached to opposite ends of 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Busulfan is mutagen and clastogen. In in vitro tests it caused mutations in Salmonella typhimurium and Drosophila melanogaster. Chromosomal aberrations induced by busulfan have been reported in vivo (rats, mice, hamsters, and humans) and in vitro (rodent and human cells). The intravenous administration of busulfan (48 mg/kg given as biweekly doses of 12 mg/kg, or 30% of the total BUSULFEX dose on mg/m2 basis) has been shown to increase the incidence of thymic and ovarian tumors in mice.Busulfan depleted oocytes of female rats and induced sterility in male rats and hamsters. The solvent DMA may also impair fertility. DMA daily dose of 0.45 g/kg/day given to rats for nine days (equivalent to 44% of the daily dose of DMA contained in the recommended dose of BUSULFEX on mg/m2 basis) significantly decreased spermatogenesis in rats. single subcutaneous dose of 2.2 g/kg (27% of the total DMA dose contained in BUSULFEX on mg/m2 basis) four days after insemination terminated pregnancy in 100% of tested hamsters [see Use in Specific Populations (8.3)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. 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 single 140 mg dose of Myleran(R) Tablets in an 18 kg, 4-year old child has been reported. Inadvertent administration of greater than normal dose of oral busulfan (2.1 mg per kg; total dose of 23.3 mg per kg) occurred in 2-year old child prior to scheduled bone marrow transplant without sequelae. An acute dose of 2.4 was fatal in 10-year old boy. There is one report that busulfan is dialyzable, thus dialysis should be considered in the case of overdose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 10 mL Vial Label. Rx onlyNDC 59148-070-90SterileIVBusulfex(R) (busulfan) Injection60 mg/10 mL (6 mg/mL) 10 mL VialSingle-Dose VialDiscard Unused PortionCaution: Must be diluted before use.. PRINCIPAL DISPLAY PANEL 10 mL Vial Label.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of BUSULFEX were studied in 59 patients participating in prospective trial of BUSULFEX-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg BUSULFEX every six hours, for 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 uMmin).Table 3: Steady State Pharmacokinetic Parameters Following BUSULFEX(R) (busulfan) Infusion (0.8 mg per kg; N=59)MeanCV (%)RangeCmax (ng per mL)122218496-1684AUC (uMmin)116720556-1673CL (mL per min per kg)Clearance normalized to actual body weight for all patients. 2.52251.49-4.31BUSULFEX pharmacokinetics showed consistency between dose and dose 13 as demonstrated by reproducibility of steady state Cmax and 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 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 were 4.04 L/hr per 20 kg (3.37 mL per min per kg; interpatient variability 23%); and 12.8 per 20 kg (0.64 per kg; interpatient variability 11%).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBUSULFEX can cause fetal harm when administered to pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis. The solvent, DMA, may also cause fetal harm when administered to pregnant woman. In rats, DMA doses of approximately 40% of the daily dose of DMA in the BUSULFEX dose on mg/m2 basis given during organogenesis caused significant developmental anomalies (see Data ). There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.. Animal DataFollowing administration during organogenesis in animals, busulfan caused malformations and anomalies, including significant alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries. The solvent, N,N-dimethylacetamide (DMA), administered to rats at doses of 400 mg/kg/day (about 40% of the daily dose of DMA in the BUSULFEX dose on mg/m2 basis) during organogenesis caused significant developmental anomalies. The most striking abnormalities included anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious anomalies of the vessels of the heart.

REFERENCES SECTION.

15 REFERENCES. 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 18, 2014 from http://www.osha.gov/SLTC/hazardousdrugs/index.html].

SPL UNCLASSIFIED SECTION.

2.1 Initial Dosing Information. Administer BUSULFEX in combination with cyclophosphamide as 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 central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (Days -7, -6, -5 and -4). Cyclophosphamide 60 mg per kg intravenously as 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 (5.2)]. Administer antiemetics prior to the first dose of BUSULFEX and continue on 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 +0.25x (actual weight -IBW). Administer BUSULFEX in combination with cyclophosphamide as 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 central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (Days -7, -6, -5 and -4). Cyclophosphamide 60 mg per kg intravenously as 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. BUSULFEX 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via central venous catheter as two-hour infusion every six hours for four consecutive days for total of 16 doses (Days -7, -6, -5 and -4). Cyclophosphamide 60 mg per kg intravenously as 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 (5.2)]. Administer antiemetics prior to the first dose of BUSULFEX and continue on 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 +0.25x (actual weight -IBW). 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 +0.25x (actual weight -IBW). AIBW= IBW +0.25x (actual weight -IBW).

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Unopened vials of BUSULFEX must be stored under refrigerated conditions between 2C to 8C (36F to 46F). Discard unused portion.BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25C) for up to hours but the infusion must be completed within that time.BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2C to 8C) for up to 12 hours but the infusion must be completed within that time.BUSULFEX is cytotoxic drug. Follow applicable special handling and disposal procedures1.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed (8.2). Lactation: Advise women not to breastfeed (8.2). 8.1 Pregnancy. Risk SummaryBUSULFEX can cause fetal harm when administered to pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis. The solvent, DMA, may also cause fetal harm when administered to pregnant woman. In rats, DMA doses of approximately 40% of the daily dose of DMA in the BUSULFEX dose on mg/m2 basis given during organogenesis caused significant developmental anomalies (see Data ). There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.. Animal DataFollowing administration during organogenesis in animals, busulfan caused malformations and anomalies, including significant alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries. The solvent, N,N-dimethylacetamide (DMA), administered to rats at doses of 400 mg/kg/day (about 40% of the daily dose of DMA in the BUSULFEX dose on mg/m2 basis) during organogenesis caused significant developmental anomalies. The most striking abnormalities included anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious anomalies of the vessels of the heart.. 8.2 Lactation. Risk SummaryIt is not known whether BUSULFEX is present in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies, discontinue breastfeeding during treatment with BUSULFEX.. 8.3 Females and Males of Reproductive Potential. Contraception. FemalesBUSULFEX can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with BUSULFEX and for months following cessation of therapy.. MalesBUSULFEX may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during treatment with BUSULFEX and for months after cessation of therapy [see Nonclinical Toxicology (13.1)]. Infertility. Females Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. BUSULFEX may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose BUSULFEX in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.. MalesSterility, azoospermia, and testicular atrophy have been reported in male patients.. 8.4 Pediatric Use. The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of BUSULFEX in 24 pediatric patients receiving BUSULFEX as part of conditioning regimen administered prior to hematopoietic progenitor cell transplantation for variety of malignant hematologic (N=15) or non-malignant diseases (N=9). Patients ranged in age from months to 16 years (median years). BUSULFEX dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900-1350 uMmin with an initial dose of 0.8 mg per kg or 1.0 mg per kg (based on Actual Body Weight (ABW)) if the patient was greater than or less than or equal to years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1.Patients received BUSULFEX doses every six hours as two-hour infusion over four days for total of 16 doses, followed by cyclophosphamide 50 mg per kg once daily for four days. After one rest day, hematopoietic progenitor cells were infused. All patients received phenytoin as seizure prophylaxis. The target AUC (900-1350+-5% uMmin) for BUSULFEX was achieved at dose in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose and 13. BUSULFEX levels were within the target range for 21 of 23 evaluable patients.All 24 patients experienced neutropenia (absolute neutrophil count (ANC) less than 0.5x109/L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm3). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1x109). In 23 patients, the ANC recovered to greater than 0.5x109/L (median time to recovery BMT day +13; range BMT day +9 to +22). One patient who died on day +20 had not recovered to an ANC >0.5x109/L.Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure.Adverse reactions were reported in all 24-patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), HVOD (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%).Based on the results of this 24-patient clinical trial, suggested dosing regimen of BUSULFEX in pediatric patients is shown in the following dosing nomogram:BUSULFEX Dosing NomogramPatients Actual Body Weight (ABW)BUSULFEX Dosageless than or equal to12 kgs1.1 (mg per kg)greater than 12 kgs0.8 (mg per kg)Simulations based on pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve target BUSULFEX exposure (AUC) between 900 to 1350 uMmin with the first dose of BUSULFEX using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of BUSULFEX is recommended.. Dose Adjustment Based on Therapeutic Drug MonitoringInstructions for measuring the AUC of busulfan at dose (see Blood Sample Collection for AUC Determination) and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 uMmin), are provided below. Adjusted dose (mg) Actual Dose (mg) Target AUC (uMmin)/Actual AUC (uMmin)For example, if patient received dose of 11 mg busulfan and if the corresponding AUC measured was 800 uMmin, for target AUC of 1125 uMmin, the target mg dose would be:Mg dose =11 mg 1125 uMmin /800 uMmin =15.5 mgBUSULFEX dose adjustment may be made using this formula and instructions below.. Blood Sample Collection for AUC DeterminationCalculate the AUC (uMmin) based on blood samples collected at the following time points:For dose 1:2 hr (end of infusion), hr and hr (immediately prior to the next scheduled BUSULFEX administration). Actual sampling times should be recorded. For doses other than dose 1: Pre-infusion (baseline), hr (end of infusion), hr and hr (immediately prior to the next scheduled BUSULFEX administration).AUC calculations based on fewer than the three specified samples may result in inaccurate AUC determinations.For each scheduled blood sample, collect one to three mL of blood into heparinized (Na or Li heparin) Vacutainer(R) tubes. The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4C) within one hour. The plasma, harvested into appropriate cryovial storage tubes, is to be frozen immediately at -20C. All plasma samples are to be sent in frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations.. Calculation of AUCBUSULFEX AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula:Dose AUCinfinity Calculation: AUCinfinity AUC0-6hr +AUCextrapolated, where AUC0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour and the terminal elimination rate constant, z. The must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. 0 pre-dose busulfan concentration should be assumed, and used in the calculation of AUC.If the AUC is assessed subsequent to Dose 1, steady-state AUCss (AUC0-6hr) is to be estimated from the trough, hr, hr and hr concentrations using the linear trapezoidal rule.. Dose AUCinfinity Calculation: AUCinfinity AUC0-6hr +AUCextrapolated, where AUC0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour and the terminal elimination rate constant, z. The must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. 0 pre-dose busulfan concentration should be assumed, and used in the calculation of AUC.. Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug MonitoringUse an administration set with minimal residual hold up (priming) volume (1 to mL) for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for therapeutic drug monitoring and dose adjustment.Prime the administration set tubing with drug solution to allow accurate documentation of the start time of BUSULFEX infusion. Collect the blood sample from peripheral IV line to avoid contamination with infusing drug. If the blood sample is taken directly from the existing central venous catheter (CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSING to ensure that the end of infusion sample is not contaminated with any residual drug. At the end of infusion (2 hr), disconnect the administration tubing and flush the CVC line with mL of normal saline prior to the collection of the end of infusion sample from the CVC port. Collect the blood samples from different port than that used for the BUSULFEX infusion. When recording the BUSULFEX infusion stop time, do not include the time required to flush the indwelling catheter line. Discard the administration tubing at the end of the two-hour infusion [see Dosage and Administration (2.3)]. 8.5 Geriatric Use. Clinical studies of BUSULFEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with BUSULFEX. Monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs (5.2)Hepatic Veno-Occlusive Disease (HVOD): Increased risk of developing HVOD at AUC greater than 1,500 uMmin. Monitor serum transaminases, alkaline phosphatase and bilirubin daily (5.3)Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of effective contraception (5.4, 8.1, 8.3)Cardiac tamponade has been reported in pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide. Abdominal pain and vomiting preceded the tamponade in most patients (5.5). Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with BUSULFEX. Monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs (5.2). Hepatic Veno-Occlusive Disease (HVOD): Increased risk of developing HVOD at AUC greater than 1,500 uMmin. Monitor serum transaminases, alkaline phosphatase and bilirubin daily (5.3). Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to fetus and use of effective contraception (5.4, 8.1, 8.3). Cardiac tamponade has been reported in pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide. Abdominal pain and vomiting preceded the tamponade in most patients (5.5). 5.1 Myelosuppression The most frequent serious consequence of treatment with BUSULFEX at the recommended dose and schedule is prolonged myelosuppression, occurring in all patients (100%). Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. Monitor complete blood counts, including white blood cell differentials, and quantitative platelet counts daily during treatment and until engraftment is demonstrated. Absolute neutrophil counts dropped below 0.5x109/L at median of days post-transplant in 100% of patients treated in the BUSULFEX clinical trial. The absolute neutrophil count recovered at median of 13 days following allogeneic transplantation when prophylactic filgrastim was used in the majority of patients. Thrombocytopenia (less than 25,000/mm3 or requiring platelet transfusion) occurred at median of 5-6 days in 98% of patients. Anemia (hemoglobin less than 8.0 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated.. 5.2 Seizures. Seizures have been reported in patients receiving high-dose oral busulfan at doses producing plasma drug levels similar to those achieved following the recommended dosage of BUSULFEX. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of BUSULFEX. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last BUSULFEX dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to BUSULFEX treatment [see Dosage and Administration (2.1)]. Use caution when administering the recommended dose of BUSULFEX to patients with history of seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs.. 5.3 Hepatic Veno-Occlusive Disease (HVOD). Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (greater than 1,500 uMmin) may be associated with an increased risk of developing HVOD. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended BUSULFEX dose and regimen. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with BUSULFEX in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones criteria. The incidence of HVOD reported in the literature from the randomized, controlled trials was 7.7%-12% [see Clinical Studies (14)]. Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD. 5.4 Embryo-fetal Toxicity. BUSULFEX can cause fetal harm when administered to pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits. The solvent, DMA, may also cause fetal harm when administered to pregnant woman based on findings in animals. Advise pregnant women of the potential risk to fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with BUSULFEX [see Use in Specific Populations (8.1, 8.3)].. 5.5 Cardiac Tamponade. Cardiac tamponade has been reported in pediatric patients with thalassemia (8/400 or 2% in one series) who received high doses of oral busulfan and cyclophosphamide as the preparatory regimen for hematopoietic progenitor cell transplantation. Six of the eight children died and two were saved by rapid pericardiocentesis. Abdominal pain and vomiting preceded the tamponade in most patients. Monitor for signs and symptoms, promptly evaluate and treat if cardiac tamponade is suspected.. 5.6 Bronchopulmonary Dysplasia. Bronchopulmonary dysplasia with pulmonary fibrosis is rare but serious complication following chronic busulfan therapy. The average onset of symptoms is years after therapy (range months to 10 years). 5.7 Cellular Dysplasia. BUSULFEX may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix.