BUSULFAN Injection
  • The first and only AP-rated, therapeutically equivalent generic to BUSULFEX®*
  • Preservative Free
  • Vial closure is not made with natural rubber latex




NDC Number
Strength
Size
Shelf Pack
Availability
Product Information
Arrow Up 0517-0920-01 60 mg/10 mL 10 mL 8 In Stock Product Label
Full Prescribing Information
Safety Data Sheet
Bottle
Wholesaler Numbers
ABC/SAP Cardinal HD Smith McKesson Morris & Dickson
10174274 5330758 5640974 3634219 886358
Case Information
Unit of Sale NDC Order Size Case Size Case Per Tier
0920-01 10 10 540


*BUSULFEX® is a registered trademark of Otsuka Pharmaceutical Co., Ltd.


NDC Number
Arrow Up 0517-0920-01
Strength
60 mg/10 mL
Size
10 mL
Shelf Pack
8
Availability
In Stock
Product Information
Product Label
Full Prescribing Information
Safety Data Sheet
Bottle
Wholesaler Numbers
ABC/SAP Cardinal HD Smith McKesson Morris & Dickson
10174274 5330758 5640974 3634219 886358
Case Information
Unit of Sale NDC Order Size Case Size Case Per Tier
0920-01 10 10 540






Rx 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.
CONTRAINDICATIONS 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 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 0.5x109/L at a median of 4 days post-transplant in 100% of patients treated in the busulfan injection clinical trial. The absolute neutrophil count recovered at a median of 13 days following allogeneic transplantation when prophylactic G-CSF was used in the majority of patients. Thrombocytopenia (less than 25,000/mm3 or requiring platelet transfusion) occurred at a median of 5 to 6 days in 98% of patients. Anemia (hemoglobin less than 8 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated. 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. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of busulfan injection. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last busulfan injection dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) 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 (AUC) 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 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. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with busulfan injection 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%. Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD. Embryo-fetal Toxicity Busulfan injection can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman based on findings in animals. 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 (8/400 or 2% in one series) 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. Monitor for signs and symptoms, promptly evaluate and treat if cardiac tamponade is suspected. Bronchopulmonary Dysplasia Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following chronic busulfan therapy. The average onset of symptoms is 4 years after therapy (range 4 months to 10 years). Cellular Dysplasia Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. 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. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling:Myelosuppression, seizures, HVOD, embryo-fetal toxicity, cardiac tamponade, bronchopulmonary dysplasia and cellular dysplasia. 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 Injection Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation

Non-Hematological Adverse Reactions1 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
tomatitis (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
1. Includes all reported adverse reactions regardless of severity (toxicity grades 1 to 4)
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 DRUG INTERACTIONS Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC greater than 1500 μM•min in some patients. Fluconazole (200 mg) has been used with busulfan injection. Phenytoin increases the clearance of busulfan by 15% or more. Use of acetaminophen prior to dose less than 72 hours or concurrent with busulfan may result in reduced busulfan clearance. Caution should be exercised in these cases. USE IN SPECIFIC POPULATIONS Pregnancy Busulfan can cause fetal harm when administered to a pregnant woman. Ovarian suppression and amenorrhea commonly occur in premenopausal woman undergoing chronic, low-dose busulfan therapy. In males, busulfan may damage spermatozoa and testicular tissue resulting in possible genetic fetal abnormalities. Sterility, azoospermia and testicular atrophy have been reported. 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). Patients ranged in age from 5 months to 16 years (median 3 years). Busulfan injection dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900 to 1350 μM•min with an initial dose of 0.8 mg per kg or 1 mg per kg (based on ABW) if the patient was greater than 4 or less than or equal to 4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1. Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure. Adverse reactions were reported in all 24 patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), HVOD (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%). NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Busulfan is a mutagen and a clastogen. For additional Safety Information, including BOXED WARNING please see Full Prescribing Information. You are encouraged to report side effects 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.




Rx 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.
CONTRAINDICATIONS 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 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 0.5x109/L at a median of 4 days post-transplant in 100% of patients treated in the busulfan injection clinical trial. The absolute neutrophil count recovered at a median of 13 days following allogeneic transplantation when prophylactic G-CSF was used in the majority of patients. Thrombocytopenia (less than 25,000/mm3 or requiring platelet transfusion) occurred at a median of 5 to 6 days in 98% of patients. Anemia (hemoglobin less than 8 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated. 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. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of busulfan injection. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last busulfan injection dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) 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 (AUC) 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 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. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with busulfan injection 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%. Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD. Embryo-fetal Toxicity Busulfan injection can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman based on findings in animals. 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 (8/400 or 2% in one series) 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. Monitor for signs and symptoms, promptly evaluate and treat if cardiac tamponade is suspected. Bronchopulmonary Dysplasia Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following chronic busulfan therapy. The average onset of symptoms is 4 years after therapy (range 4 months to 10 years). Cellular Dysplasia Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. 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. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling:Myelosuppression, seizures, HVOD, embryo-fetal toxicity, cardiac tamponade, bronchopulmonary dysplasia and cellular dysplasia. 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 Injection Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation

Non-Hematological Adverse Reactions1 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
tomatitis (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
1. Includes all reported adverse reactions regardless of severity (toxicity grades 1 to 4)
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 DRUG INTERACTIONS Itraconazole decreases busulfan clearance by up to 25%, and may produce an AUC greater than 1500 μM•min in some patients. Fluconazole (200 mg) has been used with busulfan injection. Phenytoin increases the clearance of busulfan by 15% or more. Use of acetaminophen prior to dose less than 72 hours or concurrent with busulfan may result in reduced busulfan clearance. Caution should be exercised in these cases. USE IN SPECIFIC POPULATIONS Pregnancy Busulfan can cause fetal harm when administered to a pregnant woman. Ovarian suppression and amenorrhea commonly occur in premenopausal woman undergoing chronic, low-dose busulfan therapy. In males, busulfan may damage spermatozoa and testicular tissue resulting in possible genetic fetal abnormalities. Sterility, azoospermia and testicular atrophy have been reported. 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). Patients ranged in age from 5 months to 16 years (median 3 years). Busulfan injection dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900 to 1350 μM•min with an initial dose of 0.8 mg per kg or 1 mg per kg (based on ABW) if the patient was greater than 4 or less than or equal to 4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1. Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure. Adverse reactions were reported in all 24 patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), HVOD (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%). NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Busulfan is a mutagen and a clastogen. For additional Safety Information, including BOXED WARNING please see Full Prescribing Information. You are encouraged to report side effects 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.




© 2017, American Regent, Inc., A Luitpold Pharmaceuticals, Inc. Company
PP-AS-US-0014     4/2017