The following warnings pertain to different physiologic effects of BUSULFEX in the setting of allogeneic transplantation.
The most frequent serious consequence of treatment with BUSULFEX 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 (see Patient Counseling Information). Absolute neutrophil counts dropped below 0.5x109
/L at a median of 4 days post-transplant in 100% of patients treated in the BUSULFEX clinical trial. The absolute neutrophil count recovered at a median of 13 days following allogeneic transplantation when prophylactic G-CSF was used in the majority of patients. Thrombocytopenia (<25,000/mm3
or requiring platelet transfusion) occurred at a median of 5-6 days in 98% of patients. Anemia (hemoglobin <8.0 g/dL) occurred in 69% of patients. Use antibiotic therapy and platelet and red blood cell support when medically indicated.
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 BUSULFEX. Despite prophylactic therapy with phenytoin, one seizure (1/42 patients) was reported during an autologous transplantation clinical trial of BUSULFEX. This episode occurred during the cyclophosphamide portion of the conditioning regimen, 36 hours after the last BUSULFEX dose. Initiate phenytoin therapy or any other alternative anti-convulsant prophylactic therapy (e.g., benzodiazepines, valproic acid or levetiracetam) prior to BUSULFEX treatment (see Dosage & Administration). Use caution when administering the recommended dose of BUSULFEX to patients with a history of a seizure disorder or head trauma or who are receiving other potentially epileptogenic drugs (see Patient Counseling Information).
Hepatic Veno-Occlusive Disease (HVOD):
Current literature suggests that high busulfan area under the plasma concentration versus time curve (AUC) values (>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 BUSULFEX dose and regimen. Based on clinical examination and laboratory findings, HVOD was diagnosed in 8% (5/61) of patients treated with BUSULFEX 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%-12% (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). Monitor serum transaminases, alkaline phosphatase, and bilirubin daily through BMT Day +28 to detect hepatotoxicity, which may herald the onset of HVOD (see Patient Counseling Information).
BUSULFEX 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 BUSULFEX (see Use in Specific Populations).
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.
Bronchopulmonary dysplasia with pulmonary fibrosis is a rare but serious complication following chronic busulfan therapy. The average onset of symptoms is 4 years after therapy (range 4 months to 10 years).
Busulfan may cause cellular dysplasia in many organs. Cytologic abnormalities characterized by giant, hyperchromatic nuclei have been reported in lymph nodes, pancreas, thyroid, adrenal glands, liver, lungs and bone marrow. This cytologic dysplasia may be severe enough to cause difficulty in the interpretation of exfoliative cytologic examinations of the lungs, bladder, breast and the uterine cervix.
Bone marrow suppression often results in opportunistic infection that can be lethal. Patients should be monitored for signs of local or systemic infection or bleeding. Their hematologic status should be evaluated appropriately. Prophylactic or empiric use of anti-infectives (bacterial, fungal, viral) should be considered for the prevention and management of infections during the neutropenic period.
Use in Specific Populations:
Females and Males of Reproductive Potential: Contraception: Females: BUSULFEX can cause fetal harm when administered to a pregnant woman (see Use in Specific Populations). Advise females of reproductive potential to use effective contraception during and after treatment with BUSULFEX.
Males: BUSULFEX may damage spermatozoa and testicular tissue, resulting in possible genetic fetal abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during and after treatment with BUSULFEX (see Pharmacology: Nonclinical Toxicology under Actions).
Infertility: Females: Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia.
Males: Sterility, azoospermia, and testicular atrophy have been reported in male patients.
Use in Children:
The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of BUSULFEX in 24 pediatric patients receiving BUSULFEX 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). BUSULFEX 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 the patient was greater than 4 or less than or equal to 4 years, respectively. The dose was adjusted based on plasma concentration after completion of dose 1.
Patients received BUSULFEX 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 BUSULFEX was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. BUSULFEX levels were within the target range for 21 of 23 evaluable patients.
All 24 patients experienced neutropenia (absolute neutrophil count <0.5x109
/L) and thrombocytopenia (platelet transfusions or platelet count <20,000/mm3
). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count <0.1x109
). In 23 patients, the ANC recovered to >0.5x109
/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 >0.5x109
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 reactions 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%), 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 BUSULFEX in pediatric patients is shown in the following dosing nomogram: (See Table 3.)
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Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target BUSULFEX exposure (AUC) between 900 to 1350 μM•min with the first dose of BUSULFEX using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of BUSULFEX 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) and the formula for adjustment of subsequent doses to achieve the desired target AUC (1125 μM•min), are provided as follows. (See Equation 3.)
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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: (See Equation 4.)
Click on icon to see table/diagram/image
Busulfex 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 BUSULFEX 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 BUSULFEX 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:
BUSULFEX AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula: Dose 1 AUCinfinity
, 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
) 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 BUSULFEX 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 BUSULFEX infusion. When recording the BUSULFEX 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 Dosage & Administration).
Use in the Elderly:
Five of sixty-one patients treated in the BUSULFEX clinical trial were over the age of 55 (range 57-64). All achieved myeloablation and engraftment.
BUSULFEX has not been studied in patients with renal impairment.
BUSULFEX has not been administered to patients with hepatic insufficiency.
Since busulfan is mainly metabolized through the liver, caution should be observed when BUSULFEX is used in patients with pre-existing impairment of liver function, especially in those with severe hepatic impairment (see Precautions).