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.
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