Busulfan

1 INDICATIONS AND USAGE Busulfan injection is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia. Busulfan injection 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 busulfan injection 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: o Busulfan injection 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). o 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 busulfan injection (Days -3 and -2). o 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 busulfan injection. Administer anticonvulsants 12 hours prior to busulfan injection to 24 hours after the last dose of busulfan injection [see Warnings and Precautions (5.2) ]. • Administer antiemetics prior to the first dose of busulfan injection and continue on a fixed schedule through busulfan injection administration. • Busulfan injection clearance is best predicted when the busulfan injection dose is administered based on adjusted ideal body weight. Dosing busulfan injection based on actual body weight, ideal body weight or other factors can produce significant differences in busulfan injection clearance among lean, normal and obese patients. o 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) o For obese or severely obese patients, base busulfan injection dosing on adjusted ideal body weight (AIBW): AIBW= IBW + 0.25x (actual weight -IBW). 2.2 Preparation and Administration Precautions Busulfan injection is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with busulfan injection. Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration. Busulfan injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing busulfan injection. If busulfan injection or diluted busulfan injection 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 busulfan injection vial. 2.3 Preparation for Intravenous Administration Busulfan injection 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 busulfan injection, 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 busulfan injection (56 mg total dose). To prepare the final solution for infusion, add 9.3 mL of busulfan injection to 93 mL of diluent (normal saline or D5W) as calculated below: (9.3 mL busulfan injection) x (10) = 93 mL of either diluent plus the 9.3 mL of busulfan injection 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. Always add the busulfan injection to the diluent, not the diluent to the busulfan injection. Mix thoroughly by inverting several times. Discard unused portion. Infusion pumps should be used to administer the diluted busulfan injection solution. Set the flow rate of the pump to deliver the entire prescribed busulfan injection 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 BUSULFAN INJECTION HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.

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 Eugia US LLC at 1-866-850-2876 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 busulfan and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review. In the busulfan injection allogeneic stem cell transplantation clinical trial, all patients were treated with busulfan 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 busulfan 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 Bone Marrow Transplantation (BMT) Day +28 at a rate greater than or equal to 20% in patients treated with busulfan 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 Busulfan Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation 1. Includes all reported adverse reactions regardless of severity (toxicity grades 1 to 4) Non-Hematological Adverse Reactions 1 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), 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 6.2 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 have been identified during post-approval use of 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. 6.3 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 (14) ]. 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 dose oral busulfan-containing conditioning regimen that were identified in a literature review. 1. TRM = Transplantation Related Mortality 2. VOD = Veno-Occlusive Disease of the liver 3. GVHD = Graft versus Host Disease Clift CML Chronic Phase TRM 1 VOD 2 GVHD 3 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) Interstital 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 2 GVHD=22% (13/58 at risk) Chronic GVHD =31% (14/45 at risk) No Report No Report No Report

12.3 Pharmacokinetics The pharmacokinetics of busulfan were studied in 59 patients participating in a prospective trial of a busulfan-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg busulfan every six hours, for a total of 16 doses over four days. Fifty-five of fifty-nine patients (93%) administered busulfan maintained AUC values below the target value (less than 1500 μM•min). Table 3: Steady State Pharmacokinetic Parameters Following Busulfan Infusion (0.8 mg per kg; N=59) 1. Clearance normalized to actual body weight for all patients. Mean CV (%) Range C max (ng per mL) 1222 18 496 to 1684 AUC (µM•min) 1167 20 556 to 1673 CL (mL per min per kg) 1 2.52 25 1.49 to 4.31 Busulfan pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by reproducibility of steady state C max 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 14 C-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 busulfan in 24 pediatric patients, the population pharmacokinetic (PPK) estimates of busulfan 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%).