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The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Myelosuppression [see WARNINGS AND PRECAUTIONS]
  • Embryo-fetal Toxicity [see WARNINGS AND PRECAUTIONS]
  • Cardiac Tamponade [see WARNINGS AND PRECAUTIONS]
  • Bronchopulmonary Dysplasia [see WARNINGS AND PRECAUTIONS]
  • Cellular Dysplasia [see WARNINGS AND PRECAUTIONS]

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 BUSULFEX and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review.

In the BUSULFEX (busulfan) Injection allogeneic stem cell transplantation clinical trial, all patients were treated with BUSULFEX 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 BUSULFEX 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 BMT Day +28 at a rate greater than or equal to 20% in patients treated with BUSULFEX 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 BUSULFEX Prior to Allogeneic Hematopoietic Progenitor Cell Transplantation

Non-Hematological Adverse Reactions1 Percent Incidence
  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
  Tachycardia 44
  Hypertension 36
  Thrombosis 33
  Vasodilation 25
  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
  Hypomagnesemia 77
  Hyperglycemia 66
  Hypokalemia 64
  Hypocalcemia 49
  Hyperbilirubinemia 49
  Edema 36
  SGPT Elevation 31
  Creatinine Increased 21
  Insomnia 84
  Anxiety 72
  Dizziness 30
  Depression 23
  Rhinitis 44
  Lung Disorder 34
  Cough 28
  Epistaxis 25
  Dyspnea 25
  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

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure. The following adverse reactions (reported as MedRA terms) have been identified during post-approval use of BUSULFEX (busulfan) Injection:

Blood and Lymphatic System Disorders: febrile neutropenia

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.

Oral 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]. 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 busulfancontaining conditioning regimen that were identified in a literature review.

Clift CML Chronic Phase
TRM1 VOD2 GVHD3 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%
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 Disease of the liver
3GVHD = Graft versus Host Disease