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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 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/kg as a two-hour infusion every six hours for 16 doses over four days, combined with cyclophosphamide 60 mg/kg × 2 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 3 lists the non-hematologic adverse reactions events through BMT Day +28 at a rate greater than or equal to 20% in patients treated with busulfan prior to allogeneic hematopoietic cell transplantation. (See Table 3.)
Click on icon to see table/diagram/imageAdditional 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.
Other adverse reactions: 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 have been identified: 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.
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 chronic myelogenous leukemia (CML). The safety outcomes reported in those trials are summarized in Table 4 as follows for a mixed population of hematological malignancies [acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) and CML]. (See Table 4.)
Click on icon to see table/diagram/image
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