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.

• Pre-medicate with anticonvulsants (e.g. benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic (
  2.1 Initial Dosing Information

  • Administer busulfan injection in combination with cyclophosphamide as a conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement. For patients weighing more than 12 kg, the recommended doses are:

  o Busulfan injection 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4).

  o Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16^thdose of busulfan injection (Days -3 and -2).

  o Administer hematopoietic progenitor cells on Day 0.

  • Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose busulfan injection. Administer anticonvulsants 12 hours prior to busulfan injection to 24 hours after the last dose of busulfan injection

  [see Warnings and Precautions (5.2)].

  • Administer antiemetics prior to the first dose of busulfan injection and continue on a fixed schedule through busulfan injection administration.

  • Busulfan injection clearance is best predicted when the busulfan injection dose is administered based on adjusted ideal body weight. Dosing busulfan injection based on actual body weight, ideal body weight or other factors can produce significant differences in busulfan injection clearance among lean, normal and obese patients.

  o Calculate ideal body weight (IBW) as follows (height in cm and weight in kg):

  Men: IBW (kg) = 50+0.91x (height in cm -152)
  
  Women: IBW (kg) = 45+0.91x (height in cm -152)

  o For obese or severely obese patients, base busulfan injection dosing on adjusted ideal body weight (AIBW):

  AIBW= IBW + 0.25x (actual weight -IBW).
  ,
  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.
  )
• Dilute and administer as intravenous infusion. Do not administer as intravenous push or bolus (
  2.1 Initial Dosing Information

  • Administer busulfan injection in combination with cyclophosphamide as a conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement. For patients weighing more than 12 kg, the recommended doses are:

  o Busulfan injection 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4).

  o Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16^thdose of busulfan injection (Days -3 and -2).

  o Administer hematopoietic progenitor cells on Day 0.

  • Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose busulfan injection. Administer anticonvulsants 12 hours prior to busulfan injection to 24 hours after the last dose of busulfan injection

  [see Warnings and Precautions (5.2)].

  • Administer antiemetics prior to the first dose of busulfan injection and continue on a fixed schedule through busulfan injection administration.

  • Busulfan injection clearance is best predicted when the busulfan injection dose is administered based on adjusted ideal body weight. Dosing busulfan injection based on actual body weight, ideal body weight or other factors can produce significant differences in busulfan injection clearance among lean, normal and obese patients.

  o Calculate ideal body weight (IBW) as follows (height in cm and weight in kg):

  Men: IBW (kg) = 50+0.91x (height in cm -152)
  
  Women: IBW (kg) = 45+0.91x (height in cm -152)

  o For obese or severely obese patients, base busulfan injection dosing on adjusted ideal body weight (AIBW):

  AIBW= IBW + 0.25x (actual weight -IBW).
  ,
  2.3 Preparation for Intravenous Administration

  Busulfan injection must be diluted prior to intravenous infusion with either 0.9% Sodium Chloride Injection, USP (normal saline) or 5% Dextrose Injection, USP (D5W). The diluent quantity should be 10 times the volume of busulfan injection, so that the final concentration of busulfan is approximately 0.5 mg per mL. Calculation of the dose for a 70 kg patient would be performed as follows:

  (70 kg patient) x (0.8 mg per kg) ÷ (6 mg per mL) = 9.3 mL busulfan injection (56 mg total dose).

  To prepare the final solution for infusion, add 9.3 mL of busulfan injection to 93 mL of diluent (normal saline or D5W) as calculated below:

  (9.3 mL busulfan injection) x (10) = 93 mL of either diluent plus the 9.3 mL of busulfan injection to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL x 6 mg per mL ÷ 102.3 mL =0.54 mg per mL).

  All transfer procedures require strict adherence to aseptic techniques, preferably employing a vertical laminar flow safety hood while wearing gloves and protective clothing.

  Always add the busulfan injection to the diluent, not the diluent to the busulfan injection. Mix thoroughly by inverting several times. Discard unused portion.

  Infusion pumps should be used to administer the diluted busulfan injection solution. Set the flow rate of the pump to deliver the entire prescribed busulfan injection dose over two hours. Prior to and following each infusion, flush the indwelling catheter line with approximately 5 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. WARNING: RAPID INFUSION OF BUSULFAN INJECTION HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.
  )
• Recommended adult dose: 0.8 mg per kg of ideal body weight or actual body weight, whichever is lower, administered intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (
  2.1 Initial Dosing Information

  • Administer busulfan injection in combination with cyclophosphamide as a conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement. For patients weighing more than 12 kg, the recommended doses are:

  o Busulfan injection 0.8 mg per kg (ideal body weight or actual body weight, whichever is lower) intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses (Days -7, -6, -5 and -4).

  o Cyclophosphamide 60 mg per kg intravenously as a one-hour infusion on each of two days beginning no sooner than six hours following the 16^thdose of busulfan injection (Days -3 and -2).

  o Administer hematopoietic progenitor cells on Day 0.

  • Premedicate patients with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) to prevent seizures reported with the use of high dose busulfan injection. Administer anticonvulsants 12 hours prior to busulfan injection to 24 hours after the last dose of busulfan injection

  [see Warnings and Precautions (5.2)].

  • Administer antiemetics prior to the first dose of busulfan injection and continue on a fixed schedule through busulfan injection administration.

  • Busulfan injection clearance is best predicted when the busulfan injection dose is administered based on adjusted ideal body weight. Dosing busulfan injection based on actual body weight, ideal body weight or other factors can produce significant differences in busulfan injection clearance among lean, normal and obese patients.

  o Calculate ideal body weight (IBW) as follows (height in cm and weight in kg):

  Men: IBW (kg) = 50+0.91x (height in cm -152)
  
  Women: IBW (kg) = 45+0.91x (height in cm -152)

  o For obese or severely obese patients, base busulfan injection dosing on adjusted ideal body weight (AIBW):

  AIBW= IBW + 0.25x (actual weight -IBW).
  )

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 (
  8.2 Lactation

  Risk Summary
  
  

  
  
  It is not known whether busulfan is present in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for busulfan in human and animal studies, discontinue breastfeeding during treatment with busulfan.
  )