1. 1 Regulatory History of OTC Phenylpropanolamine Hydrochloride (PPA) Robert L. Sherman Division of OTC Drug Products Center for Drug Evaluation and Research Food and Drug Administration

2. 2 1972: The OTC Drug Review OTC Advisory Review Panels Panels submit reports to FDA Advance Notice of Proposed Rulemaking (ANPR) Public comment and additional data * * * Tentative Final Monograph (Proposed Rule) Public comment and additional data Final Monograph (Final Rule)

3. 3 Classification Categories Category I: Generally Recognized as Safe and Effective Category II: Not Generally Recognized as Safe and Effective Category III: Insufficient Data to Permit Final Classification

4. 4 Marketing Status During OTC Review

5. 5 OTC PPA Rulemakings: 1. Nasal Decongestant Drug Products: Advisory Panel on OTC Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products 2. Weight Control Drug Products Advisory Panel on OTC Miscellaneous Internal Drug Products

6. 6 Status of PPA in the OTC Review

7. 7 1982 Weight Control ANPR Case reports indicate that PPA doses higher than marketed for weight control cause elevation of blood pressure FDA requests information regarding PPA’s effects on blood pressure and the dissolution rates of timed-release products FDA limits PPA to single doses of 25-37.5 mg; 75 mg timed-release, total daily limit: 75 mg

8. 8 Nasal Decongestant Rulemaking PPA deferred from the 1985 proposed rule because of safety issues PPA deferred from the 1994 final monograph Marketing permitted under provisions of the OTC Drug Review

9. 9 1990: FDA’s Conclusions Regarding the Blood Pressure (BP) Studies: PPA causes a biphasic BP response Initially, BP rises above baseline (pressor effect); then falls below baseline (depressor effect) Pressor/depressor effects are dose-related BP effects diminish with repeated dosing Tolerance to the pressor effects develops within a few hours Data inadequate to respond to FDA’s safety concerns

10. 10 House of Representatives Hearing on Dieting, PPA, and Federal Research September 24, 1990 Testimony claiming wide misuse Some witnesses call for removal of PPA FDA receives submissions in rebuttal to Hearing testimony and objecting to data used to support misuse of PPA diet drugs

11. 11 1991: Public Meeting on the Safety and Effectiveness of PPA Effectiveness Possible misuse Blood pressure effects Central nervous system adverse events

12. 12 1994: FDA’s Conclusion on Effectiveness Based on three 6 to 12-week studies: 75mg controlled-release PPA combined with a reduced-calorie diet is effective for weight control use (up to 3 months) Existing data (reviewed by Panel) are inadequate to support the effectiveness of single doses of 25-50mg PPA for weight control use

13. 13 1991: FDA Reviews Spontaneous Reporting System (SRS) Cases 1977-1991 22 spontaneous reports of intracranial bleeding associated with PPA suggest that PPA may increase the risk of hemorrhagic stroke Most reports associated with PPA weight control products and first day of use FDA concludes a case-control study of hemorrhagic stroke would be the most feasible approach to test this hypothesis

14. 14 Difficulties In Assessing PPA Safety: Incomplete, isolated reports of rare events Lack of precise time and dose information Apparent rapid tolerance to the hypertensive effects of PPA Low rate of reported cases associated with widely-used cough-cold products Unknown reporting rate

15. 15 1992: Epidemiologist Consultants Review the Stroke Data Interpretation of the data depends critically upon the reporting rate of ADRs (unknown) Available data do not show a causal relationship between PPA and stroke An association between PPA and stroke cannot be ruled out A case-control study is recommended

16. 16 In 1992, FDA Concluded: Although an association between PPA and an increased risk of stroke cannot be ruled out The available data do not warrant removal of PPA from the OTC market while additional data are obtained

17. 17 Yale Hemorrhagic Stroke Project (HSP) Nov 1992: NDMA (now CHPA) proposes study Mar 1993: NDMA submits protocol and voluntary labeling for weight control products Jun 1993: FDA concerns include sample size and exposure window Aug 1993: Comments from Yale investigators Aug 1993: Public Feedback Meeting on protocol Oct 1993: NDMA response to Feedback Meeting Apr 1994: NDMA submits revised final protocol Sep 1994: Case-control study begins

18. 18 1996: FDA Proposed Stronger Label Warnings For All OTC PPA Products “Do not use with any allergy, asthma, cough-cold, nasal decongestant, or weight control product containing phenylpropanolamine, phenylephrine, pseudoephedrine, or ephedrine.” “Do not take more than the recommended dose. Taking more can be harmful.” “…Taking more WILL NOT increase weight loss and can be harmful.”

19. 19 October 19, 2000 Agenda: Yale Hemorrhagic Stroke Project (HSP) Consumer Healthcare Products Association (CHPA) FDA’s Office of Postmarketing Drug Risk Assessment (OPDRA) Nonprescription Drugs Advisory Committee (NDAC)