Busulfan

Busulfan injection is indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia.

Injection: 60 mg/10 mL (6 mg/mL) as a clear, colorless, sterile, solution in a single-dose vial for

• Lactation: Advise women not to breastfeed.

• Seizures: Initiate anticonvulsant prophylactic therapy prior to treatment with busulfan. Monitor patients with history of seizure disorder, head trauma or receiving epileptogenic drugs.
  5.2 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 busulfan. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of busulfan. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last busulfan dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to busulfan treatment

  [see Dosage and Administration (2.1)]

  . Use caution when administering the recommended dose of busulfan 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): Increased risk of developing HVOD at AUC greater than 1,500 μM•min. Monitor serum transaminases, alkaline phosphatase and bilirubin daily.
  5.3 Hepatic Veno-Occlusive Disease (HVOD)

  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 busulfan dose and regimen. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with busulfan 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% to 12%

  [see Clinical Studies (14)].

  Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD

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• Embryo-fetal Toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception. (
  5.4 Embryo-fetal Toxicity

  Busulfan 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 busulfan

  [see Use in Specific Populations (8.1

  ,

  8.3)].

  
  
  
  , 8.1, 8.3)
  
• Cardiac tamponade has been reported in pediatric patients with thalassemia who received high doses of oral busulfan and cyclophosphamide. Abdominal pain and vomiting preceded the tamponade in most patients. (
  5.5 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.
  )