NDAC December 14, 20071

Nonprescription Drugs Advisory Committee MeetingSilver Spring, MarylandDecember 14, 2007

Mary S. Robinson, MSDivision of Nonprescription Regulation DevelopmentOffice of Nonprescription Products

OTC Drug Review History of Phenylephrine

NDAC December 14, 20072

OTC Drug Review Initiated January 1972

Over 800 active ingredients in marketed OTC drug products

FDA divided these ingredients into 26 therapeutic categories

FDA determined that the review would be a three step process

NDAC December 14, 20073

OTC Drug Review Process Step 1

Advisory Review Panel’s (Panel) review and evaluation of the data

Publication Advanced Notice of Proposed Rulemaking (ANPR)

Step 2 FDA’s tentative review of Panel report and evaluation of

comments submitted to ANPR Publication Tentative Final Monograph (TFM) in the form of

a proposed rule

Step 3 FDA’s review of updated literature and comments submitted

in response to the TFM Publication Final Monograph (FM) to establish regulation in

the Code of Federal Regulations

NDAC December 14, 20074

Panel Review and ANPR The Advisory Review Panel on over-the-counter

(OTC) Cold, Cough, Allergy, Bronchodilator and Antiasthmatic Products

The panel defined nasal decongestants as agents that reduce nasal congestion in patients with acute or chronic rhinitis

Administered topically as drops, sprays or inhaled vapors or orally in a solid or liquid dosage forms

Phenylephrine hydrochloride (PEH) and pseudoephedrine were the only active ingredients considered as both oral and nasal decongestants

NDAC December 14, 20075

Charge to the Panel

The Panel was charged with: Making recommendations based on their experience and

the available data to establish conditions of use with respect to dosing, directions, warnings and in some cases testing and final formulations

Applying effectiveness standards in accordance with 21 CFR § 330.10(a)(4)(ii)

Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed

NDAC December 14, 20076

Panel Recommendations

Categorized Ingredients Category I – Generally recognized as safe and

effective (GRASE) for the claimed therapeutic indication

Category II – Not generally recognized as safe and effective (NGRASE) for the claimed therapeutic indication

Category III – Insufficient data to determine safety and effectiveness

PEH was classified as Category I (GRASE) at a dose of 10 mg every 4 hours not to exceed 60 mg in 24 hours

NDAC December 14, 20077

ANPR

A public comment period follows to allow interested person to submit comments, objections, new data and requests for hearings

ANPR Publication

September 1976

Upon conclusion of the Panel deliberations, the agency published a report of the unaltered

conclusions and recommendations of the Panel

NDAC December 14, 20078

FDA reviewed: ANPR recommendations Public comment submitted in response to ANPR New data and scientific literature (if any)

One comment questioned Panel’s finding of effectiveness of PEH Based on heterogeneity of the findings among the

studies and overall strength of the findings

Tentative Final Monograph

NDAC December 14, 20079

TFM PublicationJanuary 1985

TFM

FDA concluded that evidence was sufficient based on the studies information on clinical use marketing experience the Panel’s expertise

NDAC December 14, 200710

Final MonographAugust 1994

FM

Manufacturers are given an effective date at which time their drug product must be in compliance with the monograph.

No additional comments were received about PEH

Promulgated regulation that establish standard for labeling to be used in an OTC therapeutic drug category.

NDAC December 14, 200711

Phenylephrine Hydrochloride

Active ingredient   Phenylephrine HCl Purpose Nasal decongestant

Uses temporarily relieves nasal congestion due to the common

cold, hay fever or other upper respiratory allergies temporarily relieves sinus congestion and pressure

Directions take 10 mg every 4 hours do not take more than 6 doses in 24 hours

NDAC December 14, 200712

Can amend monograph with submission of a Citizen Petition (CP), per 21 CFR 10.30

CP submitted March 2002 requested that PEB in effervescent dosage form be GRASE Nonmonograph in FM

CP contained Domestic and global marketing history data Pharmacokinetic data

PEH and PEB have comparable bioavailability profiles

Monograph amended to allow for PEB in effervescent dosage form PR published November 2004 FR published August 2006

Phenylephrine Bitartrate (PEB)

NDAC December 14, 200713

Other Nasal Decongestants in Final Monograph

Oral Phenylephrine hydrochloride Pseudoephedrine hydrochloride Pseudoephedrine sulfate

Topical Ephedrine Ephedrine hydrochloride Ephedrine sulfate Naphazoline hydrochloride Oxymetazoline hydrochloride Phenylephrine hydrochloride Propylhexedrine Xylometazoline hydrochloride

NDAC December 14, 200714

Current CP Submission

The petition states that: PEH at the dose of 10 mg every 4 hours is not

effective PEB at the dose of 15.6 mg every 4 hours is not

effective The petition requests that:

the maximum dose of PEH and PEB be increased FDA require additional studies to validate that a 25-

mg dose of PEH is more efficacious than 10-mg dose of phenylephrine and is as safe.

No new data were submitted in the CP