1. NDAC December 14, 2007 1 Nonprescription Drugs Advisory Committee Meeting Silver Spring, Maryland December 14, 2007 Mary S. Robinson, MS Division of Nonprescription Regulation Development Office of Nonprescription Products OTC Drug Review History of Phenylephrine

2. NDAC December 14, 2007 2 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

3. NDAC December 14, 2007 3 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

4. NDAC December 14, 2007 4 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

5. NDAC December 14, 2007 5 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

6. NDAC December 14, 2007 6 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

7. NDAC December 14, 2007 7 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

8. NDAC December 14, 2007 8  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

9. NDAC December 14, 2007 9 TFM Publication January 1985 TFM FDA concluded that evidence was sufficient based on  the studies  information on clinical use  marketing experience  the Panel’s expertise

10. NDAC December 14, 2007 10 Final Monograph August 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.

11. NDAC December 14, 2007 11 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

12. NDAC December 14, 2007 12  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)

13. NDAC December 14, 2007 13 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

14. NDAC December 14, 2007 14 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