Busulfex Special Precautions

BUSULFEX (busulfan) Injection is a potent cytotoxic drug that results in profound myelosuppression at the recommended dosage. It should be administered under the supervision of a qualified physician who is experienced in hematopoietic stem cell transplantation.
Frequent complete blood counts, including differential white blood cell counts, and platelet counts should be monitored during the treatment and until recovery is achieved.
Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.
The following warnings pertain to different physiologic effects of BUSULFEX in the setting of allogeneic transplantation.
Myelosuppression: The most frequent serious consequence of treatment with BUSULFEX at the recommended dose and schedule is prolonged myelosuppression, occurring in all patients (100%). Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression. Monitor complete blood counts, including white blood cell differentials, and quantitative platelet counts daily during treatment and until engraftment is demonstrated. Absolute neutrophil counts dropped below 0.5x10⁹/L at a median of 4 days post-transplant in 100% of patients treated in the BUSULFEX clinical trial. The absolute neutrophil count recovered at a median of 13 days following allogeneic transplantation when prophylactic filgrastim was used in the majority of patients. Thrombocytopenia (less than 25,000/mm³ or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anemia (hemoglobin less than 8.0 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated.
Bone marrow suppression often results in opportunistic infections that can be lethal. Patients should be monitored for signs of local or systemic infection or bleeding.
Seizures: Seizures have been reported in patients receiving high-dose oral busulfan at doses producing plasma drug levels similar to those achieved following the recommended dosage of BUSULFEX. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of BUSULFEX. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last BUSULFEX dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to BUSULFEX treatment [see Initial Dosing Information under Dosage and Administration]. Use caution when administering the recommended dose of BUSULFEX to patients with a history of a seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs.
Hepatic Veno-Occlusive Disease (HVOD): Hepatic veno-occlusive disease (HVOD) is a major complication that can occur during treatment with BUSULFEX. Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (greater than 1,500 μM·min) may be associated with an increased risk of developing HVOD. Patients who have received prior radiation therapy, greater than or equal to three cycles of chemotherapy, or a prior progenitor cell transplant may be at an increased risk of developing HVOD with the recommended BUSULFEX dose and regimen. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with BUSULFEX in the setting of allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with HVOD were retrospectively found to meet the Jones' criteria. The incidence of HVOD reported in the literature from the randomized, controlled trials was 7.7%- 12% [Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD.
Embryo-fetal Toxicity: BUSULFEX can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman based on findings in animals. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with BUSULFEX [see Use in Pregnancy & Lactation].
Cardiac Tamponade: Cardiac tamponade has been reported in pediatric patients with thalassemia (8/400 or 2% in one series) who received high doses of oral busulfan and cyclophosphamide as the preparatory regimen for hematopoietic progenitor cell transplantation. Six of the eight children died and two were saved by rapid pericardiocentesis. Abdominal pain and vomiting preceded the tamponade in most patients. Monitor for signs and symptoms, promptly evaluate and treat if cardiac tamponade is suspected.
Bronchopulmonary Dysplasia: Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following chronic busulfan therapy. The average onset of symptoms is 4 years after therapy (range 4 months to 10 years).
Cellular Dysplasia: Secondary malignancy has been reported in patients treated with busulfan. Several cases of leukemia have occurred 5-8 years following oral busulfan treatment.
Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix.
Renal Impairment: BUSULFEX has not been studied in patients with renal impairment.
Hepatic Impairment: BUSULFEX has not been administered to patients with hepatic insufficiency.
Use in Children: The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients.
Use in the Elderly: Clinical studies of BUSULFEX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.