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For Intravenous Use OnlyINDICATIONS AND USAGE
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). IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING
WARNING: MYELOSUPPRESSIONCONTRAINDICATIONS Busulfan injection is contraindicated in patients with a history of hypersensitivity to any of its components. WARNINGS AND PRECAUTIONS The following warnings pertain to different physiologic effects of busulfan injection in the setting of allogeneic transplantation.
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.
Myelosuppression — The most frequent serious consequence of treatment with busulfan injection is prolonged myelosuppression, occurring in all patients (100%). Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Monitor complete blood counts, including white blood cell differentials, and quantitative platelet counts daily during treatment and until engraftment is demonstrated.
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 injection. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy prior to busulfan injection treatment. Use caution when administering the recommended dose of busulfan injection to patients with a history of a seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs.
Hepatic Veno-Occlusive Disease (HVOD) — Current literature suggests that high busulfan area under the plasma concentration verses time curve values (greater than 1,500 µM•min) may be associated with an increased risk of developing HVOD. Patients who have received prior radiation therapy, greater than or equal to three or more cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended busulfan injection dose and regimen. The incidence of HVOD reported in the literature from the randomized, controlled trials was 7.7% to 12%. Monitor serum transaminase, alkaline phosphatase and bilirubin through BMT Day +28.
Embryo-fetal Toxicity — Busulfan injection and the solvent DMA can cause fetal harm when administered to a pregnant woman based on animal data. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with busulfan injection.
Cardiac Tamponade — Cardiac tamponade has been reported in pediatric patients with thalassemia 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.
Bronchopulmonary Dysplasia — Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication follow chronic busulfan therapy.
Cellular Dysplasia — Busulfan may cause cellular dysplasia in many organs. 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.
The following adverse reactions are discussed in more detail in other sections of the labeling: Myelosuppresson, seizures, HVOD, embryo-fetal toxicity, cardiac tamponade, bronchopulmonary dysplasia and cellular dysplasia.
Below is a summary of the Incidence (greater than or equal to 20%) of Non-Hematologic Adverse Reactions through BMT Day +28 in patients treated with Busulfan Injection prior to allogeneic hematopoietic cell transplantation. (Includes all reported adverse reactions regardless of severity — toxicity grades 1 to 4.)
- 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%
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 to drug exposure. The following adverse reactions have been identified during postapproval use of busulfan injection: febrile neutropenia; tooth hypoplasia; tumor lysis syndrome; thrombotic microangiopathy; severe bacterial, viral and fungal infections; and sepsis.
DRUG INTERACTIONS — Itraconazole decreases busulfan clearance by up to 25%. Phenytoin increases the clearance of busulfan by 15% or more. Use of acetaminophen prior (less than 72 hours) or concurrent with busulfan injection may result in reduced busulfan clearance.
USE IN SPECIFIC POPULATIONS
Pregnancy — Busulfan can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females to discontinue breastfeeding during treatment.
Females and Males of Reproductive Potential
Females: Ovarian suppression and amenorrhea commonly occur in premenopausal women. Males: Busulfan injection may damage spermatozoa and testicular tissue. Sterility, azoospermia and testicular atrophy have been reported. Males and females should use effective contraception during and after treatment.
Pediatric Use — The effectiveness of busulfan injection in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of busulfan injection in 24 pediatric patients receiving busulfan injection as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic (N=15) or non-malignant diseases (N=9).
Carcinogenesis, Mutagenesis, Impairment of Fertility Busulfan is a mutagen and a clastogen.
For additional Important Safety Information, including BOXED WARNING, please see Full Prescribing Information.