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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 (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 to 24 hours after the last dose of busulfan.
Administer antiemetics prior to the first dose of busulfan 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).
Preparation and Administration Precautions: DO NOT USE POLYCARBONATE SYRINGES OR POLYCARBONATE FILTER NEEDLES WITH BUSULFAN.
Use an administration set with minimal residual hold-up volume (2-5cc) for product administration.
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. The diluent quantity should be 10 times the volume of busulfan, so that the final concentration of busulfan is approximately 0.5 mg/ml. Calculation of the dose for a 70 kg patient would be performed as follows: (70 kg patient) × (0.8 mg/kg) ÷ (6 mg/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 5% Dextrose Injection) as calculated as follows: (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/ml (9.3 ml × 6 mg/ml ÷102.3 ml = 0.54 mg/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 5% Dextrose Injection. 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. WARNING: RAPID INFUSION OF BUSULFAN HAS NOT BEEN TESTED AND IS NOT RECOMMENDED.
Pediatric Use: The effectiveness of busulfan in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of busulfan in 24 pediatric patients receiving busulfan as part of a conditioning regimen administered prior to hematopoietic progenitor cell transplantation for a variety of malignant hematologic (N=15) or non-malignant diseases (N=9). Patients ranged in age from 5 months to 16 years (median 3 years). Busulfan dosing was targeted to achieve an area under the plasma concentration curve (AUC) of 900-1350 µM·min with an initial dose of 0.8 mg/kg or 1.0 mg/kg (based on ABW) if he patient was > 4 or ≤ 4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1.
Patients received busulfan doses every six hours as a two-hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg/kg once daily for four days. After one rest day, hematopoietic progenitor cells were infused. All patients received phenytoin as seizure prophylaxis. The target AUC (900-1350±5% µM·min) for busulfan was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. Busulfan levels were within the target range for 21 of 23 evaluable patients. All 24 patients experienced neutropenia (absolute neutrophil count <0.5×109/L) and thrombocytopenia (platelet transfusions or platelet count <20,000/mm3). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count <0.1×109). In 23 patients, the ANC recovered to >0.5×109/L (median time to recovery = BMT day +13; range = BMT day +9 to +22). One patient who died on day +20 had not recovered to an ANC >0.5×109/L.
Four (17%) patients died during the study. Two patients died within 28 days of transplant; one with pneumonia and capillary leak syndrome, and the other with pneumonia and veno-occlusive disease. Two patients died prior to day 100; one due to progressive disease and one due to multi-organ failure.
Adverse events were reported in all 24 patients during the study period (BMT day -10 through BMT day +28) or post-study surveillance period (day +29 through +100). These included vomiting (100%), nausea (83%), stomatitis (79%), hepatic veno-occlusive disease (HVOD) (21%), graft-versus host disease (GVHD) (25%), and pneumonia (21%).
Based on the results of this 24-patient clinical trial, a suggested dosing regimen of busulfan in pediatric patients is shown in the following dosing nomogram: (See Table 2.)
Click on icon to see table/diagram/imageSimulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target busulfan exposure (AUC) between 900 to 1350 µM·min with the first dose of busulfan using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of busulfan is recommended.
Dose Adjustment Based on Therapeutic Drug Monitoring: Instructions for measuring the AUC of busulfan at dose 1 (see Blood Sample Collection for AUC Determination as follows), and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 µM∙min), are provided as follows.
Adjusted dose (mg) = Actual Dose (mg) × Target AUC (µM·min)/Actual AUC (µM·min)
For example, if a patient received a dose of 11 mg busulfan and if the corresponding AUC measured was 800 µM·min, for a target AUC of 1125 µM·min, the target mg dose would be: Mg dose =11 mg ×1125 µM·min/800 µM∙min=15.5 mg.
Busulfan dose adjustment may be made using this formula and instructions as follows.
Blood Sample Collection for AUC Determination: Calculate the AUC (µM·min) based on blood samples collected at the following time points: For dose 1:2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled busulfan administration). Actual sampling times should be recorded.
For doses other than dose 1: Pre-infusion (baseline), 2 hr (end of infusion), 4 hr and 6 hr (immediately prior to the next scheduled busulfan administration).
AUC calculations based on fewer than the three specified samples may result in inaccurate AUC determinations.
For each scheduled blood sample, collect one to three ml of blood into heparinized (Na or Li heparin) Vacutainer tubes. The blood samples should be placed on wet ice immediately after collection and should be centrifuged (at 4°C) within one hour. The plasma, harvested into appropriate cryovial storage tubes, is to be frozen immediately at -20°C. All plasma samples are to be sent in a frozen state (i.e., on dry ice) to the assay laboratory for the determination of plasma busulfan concentrations.
Calculation of AUC: Busulfan AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula: Dose 1 AUCinfinity Calculation: AUCinfinity = AUC0-6hr + AUCextrapolated, where AUC0-6hr is to be estimated using the linear trapezoidal rule and AUC extrapolated can be computed by taking the ratio of the busulfan concentration at Hour 6 and the terminal elimination rate constant, λz. The λz must be calculated from the terminal elimination phase of the busulfan concentration vs. time curve. A "0" pre-dose busulfan concentration should be assumed, and used in the calculation of AUC.
If the AUC is assessed subsequent to Dose 1, steady-state AUCss (AUC0-6hr) is to be estimated from the trough, 2 hr, 4 hr and 6 hr concentrations using the linear trapezoidal rule.
Instructions for Drug Administration and Blood Sample Collection for Therapeutic Drug Monitoring: Use an administration set with minimal residual hold up (priming) volume (1-3 ml) for drug infusion to ensure accurate delivery of the entire prescribed dose and to ensure accurate collection of blood samples for therapeutic drug monitoring and dose adjustment.
Prime the administration set tubing with drug solution to allow accurate documentation of the start time of busulfan infusion. Collect the blood sample from a peripheral IV line to avoid contamination with infusing drug. If the blood sample is taken directly from the existing central venous catheter (CVC), DO NOT COLLECT THE BLOOD SAMPLE WHILE THE DRUG IS INFUSING to ensure that the end of infusion sample is not contaminated with any residual drug. At the end of infusion (2 hr), disconnect the administration tubing and flush the CVC line with 5 cc of normal saline prior to the collection of the end of infusion sample from the CVC port. Collect the blood samples from a different port than that used for the busulfan infusion. When recording the busulfan infusion stop time, do not include the time required to flush the indwelling catheter line. Discard the administration tubing at the end of the two-hour infusion.
See Preparation for intravenous administration as previously mentioned for detailed instructions on drug preparation.
