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Nda 9-218/S-101 CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: APPLICATION NUMBER: NDA 9-218/S-101 ® ® Name: Coumadin Tablets and Coumadin Injection Sponsor: Bristol-Myers Squibb Company Approval Date: September 2, 2005 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 9-218/S-101 CONTENTS Reviews / Information Included in this Review Approval Letter X Approvable Letter Labeling X Division Director’s Memo Labeling Reviews X Medical Review Chemistry Review Environmental Assessment Pharmacology / Toxicology Review Statistical Review Microbiology Review Clinical Pharmacology & Biopharmaceutics Review Administrative and Correspondence Documents X CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 9-218/S-101 APPROVAL LETTER DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Rockville, MD 20857 NDA 9-218/S-101 Bristol-Myers Squibb Company Attention: David L. Silberstein Associate Director New Opportunities and Product Development Global Regulatory Strategy P.O. Box 4000 Princeton, NJ 08543-4000 Dear Mr. Silberstein: Please refer to your supplemental new drug application dated April 6, 2005, received April 7, 2005, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for COUMADIN® Tablets (Warfarin Sodium Tablets, USP) Crystalline and COUMADIN® for Injection (Warfarin Sodium for Injection, USP). This “Changes Being Effected” supplemental new drug application provides for revisions to the Coumadin package insert to include information relating to drug interactions with Proton Pump Inhibitors (PPIs) and language cautioning against the ingestion of cranberry products, which have been reported to affect the response of patients to Coumadin. We completed our review of this application. This application is approved, effective on the date of this letter, for use as recommended in the agreed-upon labeling text with the correction listed below. In the seventh paragraph, first sentence of the DOSAGE AND ADMINISTRATION section that reads “An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.” in the final printed labeling (FPL) to this supplement, retain the bolding, as in the currently approved labeling. The FPL must be identical, and include the revision indicated, to the enclosed labeling (text for the package insert) and/or submitted labeling (package insert submitted April 6, 2005). This revision is a term of the approval of this application. Please submit an electronic version of the FPL according to the guidance for industry titled Providing Regulatory Submissions in Electronic Format - NDA. Alternatively, you may submit 20 paper copies of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15 of the copies on heavy-weight paper or similar material. For administrative purposes, designate this submission "FPL for approved supplement NDA 9-218/S-101.” Approval of this submission by FDA is not required before the labeling is used. NDA 9-218/S-101 Page 2 If you issue a letter communicating important information about this drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to the following address: MEDWATCH, HFD-410 FDA 5600 Fishers Lane Rockville, MD 20857 We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). If you have any questions, call Diane Moore, Regulatory Project Manager, at (301) 827-7476. Sincerely, {See appended electronic signature page} Joyce Korvick, M.D., M.P.H. Deputy Division Director Division of Gastrointestinal and Coagulation Drug Products (HFD-180) Office of Drug Evaluation III Center for Drug Evaluation and Research enclosure --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Kathy Robie-Suh 9/2/2005 02:46:13 PM signing for Dr. Joyce Korvick CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 9-218/S-101 LABELING Bristol-Myers Squibb Company Rx only COUMADIN TABLETS Anticoagulant (Warfarin Sodium Tablets, USP) Crystalline COUMADIN FOR INJECTION (Warfarin Sodium for Injection, USP) DESCRIPTION COUMADIN (crystalline warfarin sodium) is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4- hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4, and its structural formula may be represented by the following: O O H C ONa CH2COCH3 Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether. COUMADIN Tablets for oral use also contain: All strengths: Lactose, starch and magnesium stearate 1 mg: D&C Red No. 6 Barium Lake 2 mg: FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 2-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 3 mg: FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake 4 mg: FD&C Blue No. 1 Aluminum Lake 5 mg: FD&C Yellow No. 6 Aluminum Lake 1 Approved 1.0 proposed.pdf Page 001 Bristol-Myers Squibb Company 6 mg: FD&C Yellow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake 7-1/2 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake 10 mg: Dye Free COUMADIN for Injection is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL sterile Water for Injection, contains: Warfarin Sodium 2 mg/mL Sodium Phosphate, Dibasic, Heptahydrate 4.98 mg/mL Sodium Phosphate, Monobasic, Monohydrate 0.194 mg/mL Sodium Chloride 0.1 mg/mL Mannitol 38.0 mg/mL Sodium Hydroxide, as needed for pH adjustment to 8.1 to 8.3 CLINICAL PHARMACOLOGY COUMADIN and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4-6 hours, IX - 24 hours, and X - 48-72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factors VII, IX, X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%. An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent 2 Approved 1.0 proposed.pdf Page 002 Bristol-Myers Squibb Company secondary thromboembolic complications which may result in serious and possibly fatal sequelae. Pharmacokinetics COUMADIN is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance. Absorption COUMADIN is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours. Distribution There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins. Metabolism The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated
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