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PPA IN OTC DIET AIDS DOES NOT POSE "MAJOR PUBLIC HEALTH RISK," FDA TELLS NDMA

This article was originally published in The Tan Sheet

Executive Summary

PPA IN OTC DIET AIDS DOES NOT POSE "MAJOR PUBLIC HEALTH RISK," FDA TELLS NDMA in a March 9 letter explaining why the ingredient will remain on the market until the agency determines whether phenylpropanolamine use is associated with an increased risk of hemorrhagic stroke. FDA explained to the Nonprescription Drug Manufacturers Association that while "we cannot rule out PPA as a rare cause of strokes," currently available information on PPA- containing OTC weight control products does not indicate a public health risk great enough to warrant the ingredient's removal from the market "while additional data are being obtained." The agency underscored, however, that it is "critical that the proposed case-control study" organized by NDMA "be carried out promptly." FDA said it believes that a "case-control study of PPA and stroke would provide a large enough database to determine if the incidence of stroke associated with ingestion of PPA is greater than the spontaneous rate of stroke, i.e., the rate that would be expected to occur in a similar population not using the drug." PPA is currently available over the counter as a decongestant and in diet aid products such as Thompson Medical's Dexatrim and Ciba Consumer's Acutrim. NDMA submitted a final protocol for the population-based case- control study to FDA on March 4. The association said it expects the "Yale Hemorrhagic Stroke Project" to commence immediately after FDA approval of the protocol at an as-yet-unscheduled meeting. The primary aim of the study is to determine whether PPA users aged 18-54 have an increased risk of hemorrhagic stroke compared to non-users. Secondary objectives include estimating the association between PPA and hemorrhagic stroke separately by the type of PPA and its OTC indications as an appetite suppressant or a cough/cold remedy; and identifying the association between other potential risk factors -- such as family history, oral contraceptive use, and alcohol consumption -- and stroke. As disclosed at a November 1992 "OTC feedback" meeting with FDA, the NDMA study will be conducted at 20 Connecticut hospitals that will identify subjects with suspected hemorrhagic stroke via active surveillance. Diagnoses will be confirmed by a physician blinded to PPA use. Eligible men and women between the ages of 15 and 54 will be enrolled "within 14 days of the stroke event or within 14 days of the corresponding index date for the controls," the protocol says. Subjects will not be admitted if they have a history of previous stroke or transient ischemic attacks. Control subjects (two per case) will be "chosen as a representative sample of the population by random digit-dialing" and matched to cases for age, gender, race and telephone exchange. Controls also must be enrolled within 14 days of the case to ensure that "controls and cases are concurrent by calendar time and chosen from the same season of the year," according to the protocol. NDMA anticipates that, over the 30 months of case enrollment, about 350 cases should occur, with 250 cases (and 500 controls) ultimately enrolled after exclusion of ineligible subjects and refusals. If recruitment proceeds more rapidly than expected, up to 300 cases and 600 controls could be enrolled without exceeding the study budget, according to the protocol. In the letter to NDMA, FDA again clarified that PPA will be placed in Category III (safety and efficacy data insufficient to permit classification) in its upcoming notice of proposed rulemaking for OTC Weight Control Products. The agency emphasized that PPA's final status would be "influenced by the outcome" of the NDMA study. In 1982, an FDA OTC panel recommended that PPA be placed in Category I (safe and effective). The agency informed Rep. Ron Wyden (D-Ore.) that it would place PPA in Category III in a Jan. 14 letter ("The Tan Sheet" March 1, p. 3). The congressman had requested information about the status of FDA's examination of the safety and efficacy of PPA in November 1992, and more recently, asked HHS Secretary Donna Shalala to investigate whether FDA's evaluation of the ingredient could have been conducted more expeditiously. The agency sent a copy of its March 9 NDMA letter to Rep. Wyden, whose House Small Business/Regulation Subcommittee devoted a hearing to the PPA issue in 1990. FDA's letter to NDMA also recounts the obstacles encountered by the agency in ascertaining whether there is a link between PPA and hemorrhagic stroke. For instance, the agency related that "one difficulty in assessing PPA safety is evaluating often incomplete, isolated reports of relatively rare events. The problems are magnified in the OTC setting," where adverse reporting is sporadic. Because of these difficulties, FDA noted that it had asked three outside epidemiologists to review its assessment of available stroke-PPA data. While the consultants did not believe available information proved an association between PPA use and stroke, they did not rule out the possibility of a link. "Other analyses and data also are unable to yield a clear conclusion," FDA wrote. Observations of a higher first-day incidence and possible dose response relationship "could reflect a recognition bias as well as a causal relationship." In addition, the majority of strokes reported are associated with PPA-containing diet aids despite the fact that "80% of PPA- containing drug products are cough/cold products," FDA continued. "The relative lack of reports with cough/cold products could perhaps be explained by a greater tendency" of OTC diet aid users "to exceed the recommended dose, or possibly ingest PPA on an empty stomach, affecting its rate of bioavailability. However, we do not know this to be true," FDA reasoned. Regardless, "a serious attempt to discourage use of more than the recommended dose is clearly in order," the agency concluded.
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