Risk Summary
Busulfan Injection can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman. In rats, DMA doses of approximately 40% of the daily dose of DMA in the Busulfan Injection dose on a mg/m2 basis given during organogenesis caused significant developmental anomalies (see Data). There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
Animal Data
Following administration during organogenesis in animals, busulfan caused malformations and anomalies, including significant alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries. The solvent, N,N-dimethylacetamide (DMA), administered to rats at doses of 400 mg/kg/day (about 40% of the daily dose of DMA in the Busulfan Injection dose on a mg/m2 basis) during organogenesis caused significant developmental anomalies. The most striking abnormalities included anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious anomalies of the vessels of the heart.
Contraception
Females
Busulfan Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Busulfan Injection and for 6 months following cessation of therapy.
Males
Busulfan Injection 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 treatment with Busulfan Injection and for 3 months after cessation of therapy [see Nonclinical Toxicology (13.1)].
Infertility
Females
Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. Busulfan Injection may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose Busulfan Injection in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.
The effectiveness of Busulfan Injection in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of Busulfan Injection 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 Injection 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 per kg or 1.0 mg per kg (based on Actual Body Weight (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 Busulfan Injection doses every six hours as a two-hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg per 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 Injection was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. Busulfan Injection levels were within the target range for 21 of 23 evaluable patients.
All 24 patients experienced neutropenia (absolute neutrophil count (ANC) less than 0.5×109/L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm3). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1×109). In 23 patients, the ANC recovered to greater than 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 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 Busulfan Injection in pediatric patients is shown in the following dosing nomogram:
| Patient's Actual Body Weight (ABW) | Busulfan Injection Dosage |
|---|---|
| less than or equal to 12 kgs | 1.1 (mg per kg) |
| greater than 12 kgs | 0.8 (mg per kg) |
Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target Busulfan Injection exposure (AUC) between 900 to 1350 µM∙min with the first dose of Busulfan Injection using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of Busulfan Injection 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 below.
| 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 Injection dose adjustment may be made using this formula and instructions below.
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 Injection 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 Injection 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 Injection AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula:
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 to 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 mL 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 Injection infusion. When recording the Busulfan Injection 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 and Administration (2.3)].
Risk Summary
Busulfan Injection can cause fetal harm when administered to a pregnant woman based on animal data. Busulfan was teratogenic in mice, rats, and rabbits following administration during organogenesis. The solvent, DMA, may also cause fetal harm when administered to a pregnant woman. In rats, DMA doses of approximately 40% of the daily dose of DMA in the Busulfan Injection dose on a mg/m2 basis given during organogenesis caused significant developmental anomalies (see Data). There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
Animal Data
Following administration during organogenesis in animals, busulfan caused malformations and anomalies, including significant alterations in the musculoskeletal system, body weight gain, and size. In pregnant rats, busulfan produced sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries. The solvent, N,N-dimethylacetamide (DMA), administered to rats at doses of 400 mg/kg/day (about 40% of the daily dose of DMA in the Busulfan Injection dose on a mg/m2 basis) during organogenesis caused significant developmental anomalies. The most striking abnormalities included anasarca, cleft palate, vertebral anomalies, rib anomalies, and serious anomalies of the vessels of the heart.
Contraception
Females
Busulfan Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Busulfan Injection and for 6 months following cessation of therapy.
Males
Busulfan Injection 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 treatment with Busulfan Injection and for 3 months after cessation of therapy [see Nonclinical Toxicology (13.1)].
Infertility
Females
Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. Busulfan Injection may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose Busulfan Injection in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation.
The effectiveness of Busulfan Injection in the treatment of CML has not been specifically studied in pediatric patients. An open-label, uncontrolled study evaluated the pharmacokinetics of Busulfan Injection 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 Injection 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 per kg or 1.0 mg per kg (based on Actual Body Weight (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 Busulfan Injection doses every six hours as a two-hour infusion over four days for a total of 16 doses, followed by cyclophosphamide 50 mg per 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 Injection was achieved at dose 1 in 71% (17/24) of patients. Steady state pharmacokinetic testing was performed at dose 9 and 13. Busulfan Injection levels were within the target range for 21 of 23 evaluable patients.
All 24 patients experienced neutropenia (absolute neutrophil count (ANC) less than 0.5×109/L) and thrombocytopenia (platelet transfusions or platelet count less than 20,000/mm3). Seventy-nine percent (19/24) of patients experienced lymphopenia (absolute lymphocyte count less than 0.1×109). In 23 patients, the ANC recovered to greater than 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 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 Busulfan Injection in pediatric patients is shown in the following dosing nomogram:
| Patient's Actual Body Weight (ABW) | Busulfan Injection Dosage |
|---|---|
| less than or equal to 12 kgs | 1.1 (mg per kg) |
| greater than 12 kgs | 0.8 (mg per kg) |
Simulations based on a pediatric population pharmacokinetic model indicate that approximately 60% of pediatric patients will achieve a target Busulfan Injection exposure (AUC) between 900 to 1350 µM∙min with the first dose of Busulfan Injection using this dosing nomogram. Therapeutic drug monitoring and dose adjustment following the first dose of Busulfan Injection 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 below.
| 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 Injection dose adjustment may be made using this formula and instructions below.
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 Injection 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 Injection 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 Injection AUC calculations may be made using the following instructions and appropriate standard pharmacokinetic formula:
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 to 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 mL 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 Injection infusion. When recording the Busulfan Injection 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 and Administration (2.3)].
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