Busulfan

BUSULFAN- busulfan injection, solution, concentrate
Athenex Pharmaceutical Division, LLC.

WARNING: MYELOSUPPRESSION

Busulfan injection causes severe and prolonged myelosuppression at the recommended dosage. Hematopoietic progenitor cell transplantation is required to prevent potentially fatal complications of the prolonged myelosuppression [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

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:
    • Busulfan 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 16th dose of busulfan injection (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 busulfan. 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 administration.
  • Busulfan clearance is best predicted when the busulfan dose is administered based on adjusted ideal body weight. Dosing busulfan based on actual body weight, ideal body weight or other factors can produce significant differences in busulfan 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+0.91x (height in cm -152)
      Women: IBW (kg)=45+0.91x (height in cm -152)
    • For obese or severely obese patients, base busulfan dosing on adjusted ideal body weight (AIBW):

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

2.2 Preparation and Administration Precautions

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

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

Busulfan is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing busulfan. If busulfan or diluted busulfan 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 busulfan vial.

2.3 Preparation for Intravenous Administration

Busulfan 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, 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 busulfan (56 mg total dose).

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

(9.3 mL busulfan) × (10) =93 mL of either diluent plus the 9.3 mL of busulfan 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.

DO NOT put the busulfan into an intravenous bag or large-volume syringe that does not contain normal saline or D5W. Always add the busulfan to the diluent, not the diluent to the busulfan. Mix thoroughly by inverting several times.

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

3 DOSAGE FORMS AND STRENGTHS

Busulfan injection is supplied as a clear, colorless, sterile, solution in 10 mL single-dose vial containing 60 mg of busulfan at a concentration of 6 mg per mL for intravenous use only.

4 CONTRAINDICATIONS

Busulfan is contraindicated in patients with a history of hypersensitivity to any of its components.

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

The most frequent serious consequence of treatment with busulfan 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 0.5×109 /L at a median of 4 days post-transplant in 100% of patients treated in the busulfan 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 to 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.

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.

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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