E7-13950. Determination That Brethine (Terbutaline Sulfate) Injection Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Notice.

SUMMARY:

The Food and Drug Administration (FDA) is announcing its determination that Brethine (Terbutaline Sulfate) Injection was not withdrawn from sale for reasons of safety or effectiveness. This determination will allow FDA to approve abbreviated new drug applications (ANDAs) for terbutaline sulfate injection if all other legal and regulatory requirements are met.

FOR FURTHER INFORMATION CONTACT:

Carol E. Drew, Center for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

In 1984, Congress enacted the Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) (the 1984 amendments), which authorized the approval of duplicate versions of drug products approved under an ANDA procedure. ANDA applicants must, with certain exceptions, show that the drug for which they are seeking approval contains the same active ingredient in the same strength and dosage form as the “listed drug,” which is a version of the drug that was previously approved under a new drug application (NDA). ANDA applicants do not have to repeat the extensive clinical testing otherwise necessary to gain approval of an NDA. The only clinical data required in an ANDA are data to show that the drug that is the subject of the ANDA is bioequivalent to the listed drug.

The 1984 amendments include what is now section 505(j)(7) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(j)(7)), which requires FDA to publish a list of all approved drugs. FDA publishes this list as part of the “Approved Drug Products With Therapeutic Equivalence Evaluations,” which is known generally as the “Orange Book.” Under FDA regulations, drugs are removed from the list if the agency withdraws or suspends approval of the drug's NDA or ANDA for reasons of safety or effectiveness, or if FDA determines that the listed drug was withdrawn from sale for reasons of safety or effectiveness (21 CFR 314.162). Regulations also provide that the agency must make a determination as to whether a listed drug was withdrawn from sale for reasons of safety or effectiveness before an ANDA that refers to that listed drug may be approved (§ 314.161(a)(1) (21 CFR 314.161(a)(1))). FDA may not approve an ANDA that does not refer to a listed drug.

On February 9, 2007, West-ward Pharmaceutical Corp. (West-ward), on behalf of Hikma Farmaceutica (Portugal), S.A., submitted a citizen petition (Docket No. 2007P-0052/CP1) to FDA under 21 CFR 10.30. The petition requests that the agency determine whether Brethine (terbutaline sulfate) injection (NDA 18-571), manufactured by AaiPharma, was withdrawn from sale for reasons of safety or effectiveness. AaiPharma ceased manufacture of Brethine injection and it was moved from the prescription drug product list to the “Discontinued Drug Product List” section of the Orange Book in August of 2006.

Brethine injection was first approved in 1981; this approval was for a glass ampoule container closure system. In 2004 AaiPharma received approval of a glass vial container closure system for a Brethine injection formulation that contained 0.055 percent disodium edetate. When Brethine injection was discontinued, an approved generic was chosen as the replacement reference listed drug. The replacement reference listed drug does not contain 0.055 disodium edetate and is based on the original glass ampoule formulation. Therefore, West-ward requests that the agency make a determination that the reformulated version of Brethine injection was not withdrawn for safety or efficacy reasons.

FDA has reviewed its records and, under § 314.161, has determined that Brethine (terbutaline sulfate) injection was not withdrawn from sale for reasons of safety or effectiveness. The petitioner identified no data or other information suggesting that Brethine containing 0.055 disodium edetate was withdrawn for reasons of safety or effectiveness. FDA has independently evaluated relevant literature and data for possible postmarketing adverse events and has found no information that would indicate that this product was withdrawn from sale for reasons of safety or effectiveness. Furthermore we have determined that the change in formulation was not for safety or efficacy reasons. Our files indicate that disodium edetate was added as a protectant against certain oxidation-derived terbutaline impurities and degradants when the manufacturing site and container closure system were changed. Accordingly, the agency will continue to list terbutaline sulfate injection in the “Discontinued Drug Product List” section of the Orange Book. The “Discontinued Drug Product List” delineates, among other items, drug products that have been discontinued from marketing for reasons other than safety or effectiveness. ANDAs that refer to terbutaline sulfate injection may be approved by the agency if all other legal and regulatory requirements for the approval of ANDAs are met. If FDA determines that labeling for this drug product should be revised to meet current standards, the Agency will advise ANDA applicants to submit such labeling.

Dated: July 12, 2007.

Jeffrey Shuren,

Assistant Commissioner for Policy.