Busulfan

g. 2 ) Dilute and administer as intravenous infusion. 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.

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.

, benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose busulfan injection. 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.

25x (actual weight -IBW). 2 Preparation and Administration Precautions Busulfan injection is incompatible with polycarbonate. ) 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. 9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W).

gov/medwatch . 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.

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.

5 WARNINGS AND PRECAUTIONS Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with busulfan. 2 ) Hepatic Veno-Occlusive Disease (HVOD): Increased risk of developing HVOD at AUC greater than 1,500 µM·min. 3 ) Embryo-fetal Toxicity: Can cause fetal harm.

3 ) Cardiac tamponade has been reported in pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide. 1 Myelosuppression The most frequent serious consequence of treatment with busulfan 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 .

5x10 9 /L at a median of 4 days post-transplant in 100% of patients treated in the busulfan 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. 0 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated.

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 busulfan. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of busulfan.

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