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

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

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

Marketing Status During OTC Review

Category Panel(ANPR)

ProposedRule (TFM)

FinalRule(FM)

I Permitted Permitted Permitted

II Permitted Permitted NotPermitted

III Permitted Permitted NotPermitted

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

Status of PPA in the OTC Review

Decongestant Weight Control

PanelReport

Cat. I: 25 mg/4 hr 50 mg/8 hr150 mg Total/Day

Cat. I: 25-50 mg 150 mg Timed150 mg Total/Day

ANPRCat. I: 25 mg/4 hr 50 mg/8 hr150 mg Total/Day

FDA: 25-37.5 mg 75 mg Timed 75 mg Total Dose

ProposedRule PPA Deferred ------------------------

FinalRule PPA Deferred -------------------------

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

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

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

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

1991: Public Meeting on the Safety and Effectiveness of PPA

• Effectiveness

• Possible misuse

• Blood pressure effects

• Central nervous system adverse events

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

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

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

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

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

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

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

October 19, 2000Agenda:

• Yale Hemorrhagic Stroke Project (HSP)

• Consumer Healthcare Products Association (CHPA)

• FDA’s Office of Postmarketing Drug Risk Assessment (OPDRA)

• Nonprescription Drugs Advisory Committee (NDAC)