IV Busulfex Adverse Reactions

The following adverse reactions are discussed in more detail in other sections of the labeling: Myelosuppression (see Precautions); Seizures (see Precautions); HVOD (see Precautions); Embryo-fetal Toxicity (see Precautions); Cardiac Tamponade (see Precautions); Bronchopulmonary Dysplasia (see Precautions); Cellular Dysplasia (see 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 Busulfan (IV 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 Busulfan (IV Busulfex) Injection allogeneic stem cell transplantation clinical trial, all patients were treated with Busulfan (IV 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 Busulfan (IV 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 4 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 (IV Busulfex) prior to allogeneic hematopoietic cell transplantation. (See Table 4.)

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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 reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions (reported as MedDRA terms) have been identified during post-approval use of Busulfan (IV Busulfex) 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.
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 Pharmacology: Pharmacodynamics: Clinical Studies under Actions). The safety outcomes reported in those trials are summarized in Table 5 as follows for a mixed population of hematological malignancies (AML, CML, and ALL). (See Table 5.)

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