Busulfan

Description

11 DESCRIPTION Busulfan is a bifunctional alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate. The molecular formula of busulfan is CH 3 SO 2 O(CH 2 ) 4 OSO 2 CH 3 with a molecular weight of 246.30 g/mole. Busulfan, USP has the following chemical structure: Busulfan injection is supplied as a clear, colorless, sterile, solution in 10 mL single-dose vials for intravenous administration upon dilution. Each vial contains 60 mg of busulfan in N,N-dimethylacetamide (DMA), 3.3 mL and Polyethylene Glycol 400, 6.7 mL. The solubility of busulfan, USP in water is very slightly soluble in water and the pH of busulfan injection diluted to approximately 0.5 mg per 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. Structure

What Is Busulfan Used For?

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. Busulfan injection is an alkylating drug indicated for: Use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia (CML). (1)

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Pre-medicate with anticonvulsants (e.g., benzodiazepines, phenytoin, valproic acid or levetiracetam) and antiemetic. ( 2.1 , 5.2 ) Dilute and administer as intravenous infusion. Do not administer as intravenous push or bolus. ( 2.1 , 2.3 ) Recommended adult dose: 0.8 mg per kg of ideal body weight or actual body weight, whichever is lower, 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. ( 2.1 ) 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 injection 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 16 th 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 injection. 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 injection administration. Busulfan clearance is best predicted when the busulfan injection dose is administered based on adjusted ideal body weight. Dosing busulfan injection 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 injection dosing on adjusted ideal body weight (AIBW): AIBW= IBW +0.25x (actual weight -IBW). 2.2 Preparation and Administration Precautions Busulfan injection is incompatible with polycarbonate. Do not use any infusion components (syringes, filter needles, intravenous tubing, etc.) containing polycarbonate with Busulfan injection. Use an administration set with minimal residual hold-up volume (2 mL to 5 mL) for product administration. Busulfan injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. Skin reactions may occur with accidental exposure. Use gloves when preparing busulfan injection. If busulfan injection or diluted busulfan injection solution contacts...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 ) ] Seizures [see Warnings and Precautions ( 5.2 ) ] Hepatic Veno-Occlusive Disease (HVOD) [ see Warnings and Precautions ( 5.3) ] Embryo-fetal Toxicity [see Warnings and Precautions ( 5.4) ] Cardiac Tamponade [see Warnings and Precautions ( 5.5 ) ] Bronchopulmonary Dysplasia [see Warnings and Precautions ( 5.6 ) ] Cellular Dysplasia [see Warnings and Precautions ( 5.7 ) ] Most common adverse reactions (incidence > 60%) were: myelosuppression, nausea, stomatitis, vomiting, anorexia, diarrhea, insomnia, fever, hypomagnesemia, abdominal pain, anxiety, headache, hyperglycemia and hypokalemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reaction information is primarily derived from the clinical study (N=61) of busulfan and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, controlled trials identified through a literature review. In the busulfan injection allogeneic stem cell transplantation clinical trial, all patients were treated with busulfan 0.8 mg per kg as a two-hour infusion every six hours for 16 doses over four days, combined with cyclophosphamide 60 mg per kg x2 days. Ninety-three percent (93%) of evaluable patients receiving this dose of busulfan maintained an AUC less than 1,500 μM

Drug Interactions

7 DRUG INTERACTIONS Drugs that Decrease Busulfan Clearance: Metronidazole, itraconazole, iron chelating agents, acetaminophen. ( 7.1 ) Drugs that Increase Busulfan Clearance: Phenytoin. ( 7.2 ) 7.1 Drugs that Decrease Busulfan Clearance Itraconazole decreases busulfan clearance by up to 25%. Metronidazole decreases the clearance of busulfan to a greater extent than does itraconazole; metronidazole co-administration has been associated with increased busulfan toxicity. Fluconazole (200 mg) has been used with busulfan. Decreased clearance of busulfan was observed with concomitant use with deferasirox. The mechanism of this interaction is not fully elucidated. Discontinue iron chelating agents well in advance of administration of busulfan to avoid increased exposure to busulfan. Because busulfan is eliminated from the body via conjugation with glutathione, use of acetaminophen prior to (less than 72 hours) or concurrent with busulfan may result in reduced busulfan clearance based upon the known property of acetaminophen to decrease glutathione levels in the blood and tissues. 7.2 Drugs that Increase Busulfan Clearance Phenytoin increases the clearance of busulfan by 15% or more, possibly due to the induction of glutathione-S-transferase. Since the pharmacokinetics of busulfan was studied in patients treated with phenytoin, the clearance of busulfan at the recommended dose may be lower and exposure (AUC) higher in patients not treated with phenytoin.

Contraindications

4 CONTRAINDICATIONS Busulfan injection is contraindicated in patients with a history of hypersensitivity to any of its components. Busulfan injection is contraindicated in patients with a history of hypersensitivity to any of its components. (4)

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Busulfan 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 dose on a mg/m 2 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 dose on a mg/m 2 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.

8.3 Females and Males of Reproductive Potential Contraception Females Busulfan 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 and for 6 months following cessation of therapy. Males Busulfan 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 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 may cause temporary or permanent infertility in prepubertal girls or in females of child-bearing potential treated with high-dose busulfan in the conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation. Males Sterility, azoospermia, and testicular atrophy have been reported in male patients.

Overdosage

10 OVERDOSAGE There is no known antidote to busulfan other than hematopoietic progenitor cell transplantation. In the absence of hematopoietic progenitor cell transplantation, the recommended dosage for busulfan would constitute an overdose of busulfan. The principal toxic effect is profound bone marrow hypoplasia/aplasia and pancytopenia, but the central nervous system, liver, lungs, and gastrointestinal tract may be affected. Monitor hematologic status closely and institute vigorous supportive measures as medically indicated. Survival after a single 140 mg dose of Myleran ® Tablets in an 18 kg, 4-year old child has been reported. Inadvertent administration of a greater than normal dose of oral busulfan (2.1 mg per kg; total dose of 23.3 mg per kg) occurred in a 2-year old child prior to a scheduled bone marrow transplant without sequelae. An acute dose of 2.4 g was fatal in a 10-year old boy. There is one report that busulfan is dialyzable, thus dialysis should be considered in the case of overdose.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Busulfan injection is supplied as a clear and colorless, sterile solution in 10 mL single-dose clear glass vials each containing 60 mg of busulfan, USP at a concentration of 6 mg per mL for intravenous use. It is available as follows: 60 mg/10 mL (6 mg/mL): 10 mL, Single-Dose Vial: NDC 70121-1244-1 8 Vials in a Carton: NDC 70121-1244-7 16.2 Storage and Handling Unopened vials of busulfan injection must be stored under refrigerated conditions between 2° to 8°C (36° to 46°F). Discard unused portion. Busulfan injection 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. Busulfan injection diluted in 0.9% Sodium Chloride Injection, USP is stable at refrigerated conditions (2° to 8°C) for up to 12 hours but the infusion must be completed within that time. Busulfan injection is a cytotoxic drug. Follow applicable special handling and disposal procedures 1 .