BUSULFEX Solution for injection Ref.[11121] Active ingredients: Busulfan

2.1 Initial Dosing Information

• Administer BUSULFEX 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:
  • BUSULFEX 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).
  • 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^th dose of BUSULFEX (Days -3 and -2).
  • 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 BUSULFEX. Administer anticonvulsants 12 hours prior to BUSULFEX to 24 hours after the last dose of BUSULFEX [see Warnings and Precautions (5.2)].
• Administer antiemetics prior to the first dose of BUSULFEX and continue on a fixed schedule through BUSULFEX administration.
• BUSULFEX clearance is best predicted when the BUSULFEX dose is administered based on adjusted ideal body weight. Dosing BUSULFEX based on actual body weight, ideal body weight or other factors can produce significant differences in BUSULFEX clearance among lean, normal and obese patients.
• Calculate ideal body weight (IBW) as follows (height in cm, and weight in kg):

Men: IBW (kg) = 50 + 0.91 × (height in cm-152)

Women: IBW (kg) = 45 + 0.91 × (height in cm-152

• For obese or severely obese patients, base BUSULFEX dosing on adjusted ideal body weight (AIBW):

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

2.2 Preparation and Administration Precautions

BUSULFEX is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with BUSULFEX.

Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration.

BUSULFEX is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing BUSULFEX. If BUSULFEX or diluted BUSULFEX solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if particulate matter is seen in the BUSULFEX vial.

2.3 Preparation for Intravenous Administration

BUSULFEX 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 BUSULFEX, 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) × (0.8 mg per kg) / (6 mg per mL) = 9.3 mL BUSULFEX (56 mg total dose).

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

(9.3 mL BUSULFEX) × (10) = 93 mL of either diluent plus the 9.3 mL of BUSULFEX to yield a final concentration of busulfan of 0.54 mg per mL (9.3 mL × 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 BUSULFEX to the diluent, not the diluent to the BUSULFEX. Mix thoroughly by inverting several times. Discard unused portion.

Infusion pumps should be used to administer the diluted BUSULFEX solution. Set the flow rate of the pump to deliver the entire prescribed BUSULFEX 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 BUSULFEX HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.

There is no known antidote to BUSULFEX other than hematopoietic progenitor cell transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for BUSULFEX would constitute an overdose of busulfan. The principal toxic effect is profound bone marrow hypoplasia/aplasia and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract may be affected. Monitor hematologic status closely and institute vigorous supportive measures as medically indicated. Survival after a single 140 mg dose of Myleran Tablets in an 18 kg, 4‑year old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan (2.1 mg per kg; total dose of 23.3 mg per kg) occurred in a 2‑year old child prior to a scheduled bone marrow transplant without sequelae. An acute dose of 2.4 g was fatal in a 10‑year old boy. There is one report that busulfan is dialyzable, thus dialysis should be considered in the case of overdose.

Unopened vials of BUSULFEX must be stored under refrigerated conditions between 2°C to 8°C (36°F to 46°F). Discard unused portion.

BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP is stable at room temperature (25°C) for up to 8 hours but the infusion must be completed within that time.

BUSULFEX diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2°C to 8°C) for up to 12 hours but the infusion must be completed within that time.

BUSULFEX is a cytotoxic drug. Follow applicable special handling and disposal procedures¹.