Alkylating Drug

Busulfan

Approved 18 Apr 2019InjectionInjectable

The FDA lists this product in 15 strengths and forms.

Indications

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 )

Contraindications

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

Warnings and precautions

Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with busulfan injection. Monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs ( 5.2 ) Hepatic Veno-Occlusive Disease (HVOD): Increased risk of developing HVOD at AUC greater than 1,500 μMmin. Monitor serum transaminases, alkaline phosphatase and bilirubin daily ( 5.3 ) Embryo-fetal Toxicity: Can cause fetal harm.

Advise of potential risk to a fetus and use of effective contraception ( 5.4 , 8.1 , 8.3 ) Cardiac tamponade has been reported in pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide. Abdominal pain and vomiting precede the tamponade in most patients ( 5.5 )

5.1Myelosuppression

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.

Absolute neutrophil counts dropped below 0.5x10 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 5-6 days in 98% of patients.

At a glance

Brand name: Busulfan
Pharmacologic class: Alkylating Drug
Route: Injection
Dosage form: Injectable
Applicant: Shilpa
Status: Prescription
FDA approval: 18 Apr 2019
Application: ANDA210931-001

Indications

( 1 )

Warnings and precautions

5.1Myelosuppression

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 Shilpa Medicare Limited at 1-888-557-1212 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trial 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 injection Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation 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 1. Includes all reported adverse reactions regardless of severity (toxicity grades 1-4) 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

6.2Postmarketing 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.

6.3Oral 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.

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) Interstitial 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 1 TRM = Transplantation Related Mortality 2 VOD = Veno-Occlusive Diseases of the Liver 3 GVHD = Graft versus Host Disease

Busulfan

Indications

Contraindications

Warnings and precautions

5.1Myelosuppression

At a glance

Two medicines in one question?

Busulfan

Indications

Contraindications

Warnings and precautions

5.1Myelosuppression

At a glance

Two medicines in one question?

5.2Seizures

5.3Hepatic Veno-Occlusive Disease (HVOD)

5.4Embryo-fetal Toxicity

5.5Cardiac Tamponade

5.6Bronchopulmonary Dysplasia

5.7Cellular Dysplasia

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trial Experience

6.2Postmarketing Experience

6.3Oral Busulfan Literature Review

Composition

Strengths and forms

Official product information