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BUSULFAN INJECTION Adverse Reactions (busulfan injection)

6 ADVERSE REACTIONS

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

6.1 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 Busulfan Injection 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 Injection 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 × 2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of Busulfan Injection 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 Injection 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*Percent Incidence
*
Includes all reported adverse reactions regardless of severity (toxicity grades 1–4)
  BODY AS A WHOLE
    Fever80
    Headache69
    Asthenia51
    Chills46
    Pain44
    Edema General28
    Allergic Reaction26
    Chest Pain26
    Inflammation at Injection Site25
    Back Pain23
  CARDIOVASCULAR SYSTEM
    Tachycardia44
    Hypertension36
    Thrombosis33
    Vasodilation25
  DIGESTIVE SYSTEM
    Nausea98
    Stomatitis (Mucositis)97
    Vomiting95
    Anorexia85
    Diarrhea84
    Abdominal Pain72
    Dyspepsia44
    Constipation38
    Dry Mouth26
    Rectal Disorder25
    Abdominal Enlargement23
  METABOLIC AND NUTRITIONAL SYSTEM
    Hypomagnesemia77
    Hyperglycemia66
    Hypokalemia64
    Hypocalcemia49
    Hyperbilirubinemia49
    Edema36
    SGPT Elevation31
    Creatinine Increased21
  NERVOUS SYSTEM
    Insomnia84
    Anxiety72
    Dizziness30
    Depression23
  RESPIRATORY SYSTEM
    Rhinitis
    Lung Disorder
    Cough
    Epistaxis
    Dyspnea

44
34
28
25
25
  SKIN AND APPENDAGES
    Rash57
    Pruritus28

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

6.2 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:

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.

6.3 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 (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.
*
TRM = Transplantation Related Mortality
VOD = Veno-Occlusive Disease of the liver
GVHD = Graft versus Host Disease
Clift
CML Chronic Phase
TRM*VODGVHDPulmonaryHemorrhagic CystitisSeizure
Death ≤100d=4.1% (3/73)No ReportAcute≥Grade 2=35%
Chronic=41% (30/73)
1 death from Idiopathic Interstitial Pneumonitis And 1 death from Pulmonary FibrosisNo ReportNo Report
Devergie
CML Chronic Phase
TRMVODGVHDPulmonaryHemorrhagic CystitisSeizure
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
TRMVODGVHDPulmonaryHemorrhagic CystitisSeizure
28%12%Acute≥Grade 2 GVHD=26%
Chronic GVHD=45%
Interstitial Pneumonitis=14%24%6%
Blume
CML, AML, ALL
TRMVODGVHDPulmonaryHemorrhagic CystitisSeizure
No ReportDeaths =4.9%Acute≥Grade 2 GVHD=22% (13/58 at risk)
Chronic GVHD=31% (14/45 at risk)
No ReportNo ReportNo Report
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