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American Regent, Inc.
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This is a boxed warning product. Please see below for Important Safety Information, including BOXED WARNING.
For Intravenous Use Only
INDICATIONS 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: MYELOSUPPRESSION 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.
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.
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. Initiate anticonvulsant 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. Monitor serum transaminase, alkaline phosphatase and bilirubin through Bone Marrow Transplantation (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. Abdominal pain and vomiting preceded the tamponade in most patients.
Bronchopulmonary Dysplasia - Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following chronic busulfan therapy.
Cellular Dysplasia - Busulfan injection may cause cellular dysplasia in many organs.
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 relationship to drug exposure. The following adverse reactions have been identified during post-approval use of busulfan injection: febrile neutropenia; tooth hypoplasia; tumor lysis syndrome; thrombotic microangiopathy; severe bacterial, viral and fungal infections; and sepsis.
DRUG INTERACTIONS – Itraconazole, metronidazole and deferasirox decrease busulfan clearance. Use of acetaminophen prior (less than 72 hours) or concurrent with busulfan injection may result in reduced busulfan clearance. Phenytoin increases the clearance of Busulfan.
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.
It is not known whether busulfan injection is present in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity, discontinue breastfeeding during treatment with busulfan injection.
Females and Males of Reproductive Potential
Females: Ovarian suppression and amenorrhea commonly occur in premenopausal women. Busulfan injection may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose busulfan injection.
Males: Busulfan injection may damage spermatozoa and testicular tissue. Sterility, azoospermia and testicular atrophy have been reported.
Females and Males 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.
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.
You are encouraged to report Adverse Drug Events (ADEs) to American Regent, Inc. at 1-800-734-9236 or to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.