BUSULFEX

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

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 a central venous catheter as a two‑hour infusion every six hours for four consecutive days for a total of 16 doses ( 2.1 ) 2.1 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 16 th 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 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+0.91× (height in cm -152) Women: IBW (kg)=45+0.91× (height in cm -152) For obese or severely obese patients, base BUSULFEX dosing on adjusted ideal body weight (AIBW): AIBW= IBW +0.25× (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 5 mL) 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. 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 a 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 a 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 techniq…

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 micromole per min. Monitor serum transaminases, alkaline phosphatase and bilirubin daily ( 5.3 ) Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a 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 0.5 × 10 9 /L at a median of 4 days post-transplant in 100% of patients treated in the BUSULFEX clinical trial. The absolute neutrophil count recovered at a median of 13 days following allogeneic transplantation when prophylactic filgrastim was used in the majority of patients. Thrombocytopenia (less than 25,000/mm 3 or requiring platelet transfusion) occurred at a median of 5 to 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 a history of a 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 micromole per min) 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 a 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% to 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 H…

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

7 DRUG INTERACTIONS 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 a 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.

8.1 Pregnancy Risk Summary BUSULFEX can cause fetal harm when administered to a 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 a pregnant woman. In rats, DMA doses of approximately 40% of the daily dose of DMA in the BUSULFEX dose on a mg/m 2 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 a 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Following 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 a mg/m 2 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.

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) ] 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 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 for 2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of BUSULFEX maintained an AUC less than 1,500 micromole per 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 Bone Marrow Transplantation (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 Adverse Reactions through BMT Day +28 in Patients who Received BUSULFEX Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation Non-Hematological Adverse Reactions Includes all reported adverse reactions regardless of severity (toxicity grades 1 to4) 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 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), hypo…