DuPont Merck Coumadin (warfarin) gains post-MI prevention of death and reinfarction indication.

DUPONT MERCK COUMADIN POST-MI MORTALITY/HEART ATTACK PREVENTION INDICATION clears FDA on April 28 and will be launched by the company in June. Coumadin (warfarin) tablet and injectable formulations are indicated "to reduce the risk of death, recurrent myocardial infarction and thromboembolic events such as stroke or systemic embolization after myocardial infarction," labeling states.

The supplemental NDA (09-218/S76) for Coumadin in the prevention of mortality and recurrent heart attacks post-MI became approvable on March 31 ("The Pink Sheet" April 10, 1995). DuPont Merck submitted the application on Aug. 16, 1993, putting FDA's first action time at 31.5 months and total approval time at 32.4 months. The company filed 12 amendments to the application starting in February 1994 through April 7.

Coumadin labeling cites the results of the double blind, randomized placebo-controlled 1,214-patient Warfarin Re-Infarction Study (WARIS) conducted in Norway in the 1980s in support of the new indication. In the study, warfarin therapy produced a 24% risk reduction in mortality, a 34% reduction in recurrent MI, and a 54% reduction in cerebrovascular events. Aspirin by comparison has shown about a 20% reduction in mortality and nonfatal myocardial infarctions. Based on the data, FDA's Cardiovascular & Renal Drugs Advisory Committee recommended approval for the new indication at its Feb. 23 meeting ("The Pink Sheet" Feb. 27, p. 9).

The advisory committee recommended that labeling address potential risks of hemorrhage from Coumadin by limiting the International Normalized Ratio. INR is related to prothrombin time in coagulation. Labeling recommends that "Coumadin therapy should be initiated early (two to four weeks post infarction) and dosage should be adjusted to maintain an INR of 2.5 to 3.5 long-term." Labeling adds that "in patients thought to be at an increased risk of bleeding complications or on aspirin therapy, maintenance of Coumadin therapy at the lower end of this INR range is recommended."

The post-MI indication for Coumadin will be launched in June. DuPont Merck has been aggressively pursuing new uses for the 40-year old drug.

An injectable 5 mg/ml vial formulation of Coumadin was approved on Feb. 7. Labeling notes that "administration of Coumadin via the intravenous route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier." The label adds, however, that "the full anticoagulant effect of a dose of warfarin may not be achieved until 72-96 hours after dosing, indicating that the administration of I.V. Coumadin should not provide any increased biological effect or earlier onset of action." The average wholesale price of the I.V. formulation is $18 for a 5 mL vial.

Coumadin gained an indication for reduction of thromboembolic events in cardiac valve replacement patients in March 1994 ("The Pink Sheet" May 2, 1994, In Brief) and added information on use in atrial fibrillation patients in 1993. The drug also is available for the prevention and treatment of venous thrombosis and pulmonary embolism. DuPont Merck's ongoing 6,000-patient Coumadin Aspirin Reinfarction Study (CARS) will provide data on combination low-dose Coumadin plus low-dose aspirin prevention of death, reinfarction and stroke in post-MI patients.

DuPont Merck has been running ads in major medical journals seeking to encourage physicians to expand Coumadin use in the atrial fibrillation setting. The ad cites previously diagnosed, elderly, noncompliant, and non-English speaking patients as candidates for anticoagulation and provides a 24-hour toll-free "800" number to request Patient Re-evaluation Resources, Elderly Reassessment Resources, Compliance Enhancement Resources and Multilingual Patient Information.