Busulfex
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Questions & Answers
Side Effects & Adverse Reactions
BUSULFEX should be administered under the supervision of a qualified physician experienced in hematopoietic stem cell transplantation. Appropriate management of complications arising from its administration is possible only when adequate diagnostic and treatment facilities are readily available.
The following warnings pertain to different physiologic effects of BUSULFEX in the setting of allogeneic transplantation.
Hematologic:The most frequent serious consequence of treatment with BUSULFEX at the recommended dose and schedule is profound myelosuppression, occurring in all patients. Severe granulocytopenia, thrombocytopenia, anemia, or any combination thereof may develop. Frequent complete blood counts, including white blood cell differentials, and quantitative platelet counts should be monitored during treatment and until recovery is achieved. 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. Antibiotic therapy and platelet and red blood cell support should be used when medically indicated.
Neurological:Seizures have been reported in patients receiving highdose 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. Anti-convulsant prophylactic therapy should be initiated prior to BUSULFEX treatment. Caution should be exercised 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.
Hepatic:Current literature suggests that high busulfan area under the plasma concentration verses time curve (AUC) values (>1,500 µM•min) may be associated with an increased risk of developing hepatic venoocclusive disease (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, hepatic veno-occlusive disease 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 (see CLINICAL STUDIES) was 7.7%-12%.
Cardiac: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. No patients treated in the BUSULFEX (busulfan) Injection clinical trials experienced cardiac tamponade.
Pulmonary: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 is a mutagen and a clastogen. In in vitro tests it caused mutations in Salmonella typhimuriumand Drosophila melanogaster. Chromosomal aberrations induced by busulfan have been reported in vivo(rats, mice, hamsters, and humans) and in vitro (rodent and human cells). The intravenous administration of busulfan (48 mg/kg given as biweekly doses of 12 mg/kg, or 30% of the total BUSULFEX dose on a mg/m2 basis ) has been shown to increase the incidence of thymic and ovarian tumors in mice. Four cases of acute leukemia occurred among 19 patients who became pancytopenic in a 243 patient study incorporating busulfan as adjuvant therapy following surgical resection of bronchogenic carcinoma. Clinical appearance of leukemia was observed 5-8 years following oral busulfan treatment. Busulfan is a presumed human carcinogen.
Ovarian suppression and amenorrhea commonly occur in premenopausal women undergoing chronic, low-dose busulfan therapy for chronic myelogenous leukemia. Busulfan depleted oocytes of female rats. Busulfan induced sterility in male rats and hamsters. Sterility, azoospermia and testicular atrophy have been reported in male patients.
The solvent DMA may also impair fertility. A DMA daily dose of 0.45 g/kg/d given to rats for nine days (equivalent to 44% of the daily dose of DMA contained in the recommended dose of BUSULFEX on a mg/m2 basis) significantly decreased spermatogenesis in rats. A single sc dose of 2.2 g/kg (27% of the total DMA dose contained in BUSULFEX on a mg/m2 basis) four days after insemination terminated pregnancy in 100% of tested hamsters.
Busulfan may cause fetal harm when administered to a pregnant woman. Busulfan produced teratogenic changes in the offspring of mice, rats and rabbits when given during gestation. Malformations and anomalies included 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, DMA, may also cause fetal harm when administered to a pregnant woman. In rats, DMA doses of 400 mg/kg/d (about 40% of the daily dose of DMA in the BUSULFEX dose on a mg/m2 basis) given 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. There are no adequate and well-controlled studies of either busulfan or DMA in pregnant women. If BUSULFEX is used during pregnancy, or if the patient becomes pregnant while receiving BUSULFEX, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Legal Issues
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FDA Safety Alerts
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Manufacturer Warnings
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FDA Labeling Changes
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Uses
BUSULFEX® (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.
History
There is currently no drug history available for this drug.
Other Information
Busulfan is a bifunctional alkylating agent known chemically as 1,4- butanediol, dimethanesulfonate. BUSULFEX® (busulfan) Injection is intended for intravenous administration. It is supplied as a clear, colorless, sterile, solution in 10 mL single use vials.
Each vial of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a white crystalline powder with a molecular formula of CH3SO2O(CH2)4OSO2CH3 and a molecular weight of 246 g/mole. Busulfan is dissolved in N,N-dimethylacetamide (DMA) 33% vol/vol and Polyethylene Glycol 400, 67% vol/vol. The solubility of busulfan in water is 0.1 g/L and the pH of BUSULFEX diluted to approximately 0.5 mg/mL busulfan in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects the pH of the diluent used and ranges from 3.4 to 3.9.
BUSULFEX is intended for dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to intravenous infusion.
Sources
Busulfex Manufacturers
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Esp Pharma, Inc.
![Busulfex (Busulfan) Injection [Esp Pharma, Inc.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Busulfex | Esp Pharma, Inc.
When BUSULFEX (busulfan) Injection is administered as a component of the BuCy conditioning regimen prior to bone marrow or peripheral blood progenitor cell replacement, the recommended doses are as follows:
Adults (BuCy2):The usual adult dose is 0.8 mg/kg of ideal body weight or actual body weight, whichever is lower, administered every six hours for four days (a total of 16 doses). For obese, or severely obese patients, BUSULFEX should be administered based on adjusted ideal body weight. Ideal body weight (IBW) should be calculated as follows (height in cm, and weight in kg): IBW (kg; men)= 50 + 0.91x (height in cm -152); IBW (kg; women)= 45 + 0.91x (height in cm - 152). Adjusted ideal body weight (AIBW) should be calculated as follows: AIBW= IBW + 0.25x (actual weight -IBW). Cyclophosphamide is given on each of two days as a one-hour infusion at a dose of 60 mg/kg beginning on BMT day –3, no sooner than six hours following the 16 th dose of BUSULFEX.
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 (busulfan) Injection clearance among lean, normal and obese patients.
BUSULFEX should be administered intravenously via a central venous catheter as a two-hour infusion every six hours for four consecutive days for a total of 16 doses. All patients should be premedicated with phenytoin as busulfan is known to cross the blood brain barrier and induce seizures. Phenytoin reduces busulfan plasma AUC by 15%. Use of other anticonvulsants may result in higher busulfan plasma AUCs, and an increased risk of VOD or seizures. In cases where other anticonvulsants must be used, plasma busulfan exposure should be monitored (See DRUG INTERACTIONS). Antiemetics should be administered prior to the first dose of BUSULFEX and continued on a fixed schedule through administration of BUSULFEX. Where available, pharmacokinetic monitoring may be considered to further optimize therapeutic targeting.
Pediatrics:The effectiveness of BUSULFEX in the treatment of CML has not been specifically studied in pediatric patients. For additional information see Special Populations -Pediatric section.
Preparation and Administration Precautions:An administration set with minimal residual hold-up volume (2-5 cc) should be used for product administration.
As with other cytotoxic compounds, caution should be exercised in handling and preparing the solution of BUSULFEX. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If BUSULFEX or diluted BUSULFEX solution contacts the skin or mucosa, wash the skin or mucosa thoroughly with water. BUSULFEX is a clear, colorless solution. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever the solution and container permit. If particulate matter is seen in the BUSULFEX ampoule the drug should not be used.
Preparation for Intravenous Administration:BUSULFEX must be diluted prior to use 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/mL. Calculation of the dose for a 70 kg patient, would be performed as follows:
(70kg patient) x (0.8 mg/kg) ÷ (6 mg/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)x(10)=93 mL of either diluent plus the 9.3 mL of BUSULFEX to yield a final concentration of busulfan of 0.54 mg/mL (9.3 mL x 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 BUSULFEX into an intravenous bag or large-volume syringe that does not contain normal saline or D5W. Always add the BUSULFEX to the diluent, not the diluent to the BUSULFEX. Mix thoroughly by inverting several times. DO NOT USE POLYCARBONATE SYRINGES OR POLYCARBONATE FILTER NEEDLES WITH BUSULFEX.
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 5mL 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.
STABILITY
Unopened vials of BUSULFEX are stable until the date indicated on the package when stored under refrigeration at 2°-8°C (36°-46°F).
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°-8°C) for up to 12 hours but the infusion must be completed within that time.
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Otsuka America Pharmaceutical Inc.
Busulfex | Otsuka America Pharmaceutical, Inc.
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: o 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). o 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). o 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. o 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) o For obese or severely obese patients, base BUSULFEX dosing on adjusted ideal body weight (AIBW): AIBW= IBW +0.25x (actual weight -IBW). 2.2 Preparation and Administration PrecautionsDO NOT USE POLYCARBONATE SYRINGES OR POLYCARBONATE FILTER NEEDLES WITH BUSULFEX.
Use an administration set with minimal residual hold-up volume (2-5 cc) 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 AdministrationBUSULFEX 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) x (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) x (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 x 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 BUSULFEX into an intravenous bag or large-volume syringe that does not contain normal saline or D5W. Always add the BUSULFEX to the diluent, not the diluent to the BUSULFEX. Mix thoroughly by inverting several times.
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.
![Busulfex (Busulfan) Injection [Otsuka America Pharmaceutical Inc.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=5cb9d285-1803-4a99-946a-d0b239b32df6&name=busulfan002.jpg)
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