6 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)]
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.
|Non-Hematological Adverse Reactions*||Percent Incidence|
|BODY AS A WHOLE|
|Inflammation at Injection Site||25|
|METABOLIC AND NUTRITIONAL SYSTEM|
| RESPIRATORY SYSTEM|
|SKIN AND APPENDAGES|
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).
CML Chronic Phase
|Death ≤100d=4.1% (3/73)||No Report||Acute≥Grade 2=35% |
|1 death from Idiopathic Interstitial Pneumonitis And 1 death from Pulmonary Fibrosis||No Report||No Report|
CML Chronic Phase
|38%||7.7% (5/65) |
|Acute≥Grade 2=41% (24/59 at risk)||Interstitial Pneumonitis=16.9% (11/65)||10.8% (7/65)||No report|
CML, AML, ALL
|28%||12%||Acute≥Grade 2 GVHD=26% |
CML, AML, ALL
|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|