Nonprescription Drug Advisory Committee Meeting - Food and Drug

668 Pages·2007·21.97 MB·English

DISCLAIMER STATEMENT
The attached package contains background information prepared by the Food and Drug Administration
(FDA) for the panel members of the advisory committee. The FDA background package often contains
assessments and/or conclusions and recommendations written by individual FDA reviewers. Such
conclusions and recommendations do not necessarily represent the final position of the Review Division
of Office. We have brought the issue of the effectiveness of phenylephrine as an over-the-counter nasal
decongestant to this Advisory Committee in order to gain the Committee’s insights and opinions, and
the background package may not include all issues relevant to the final regulatory recommendation and
instead is intended to focus on issues identified by the Agency for discussion by the advisory
committee. The FDA will not issue a final determination on the issues at hand until input from the
advisory committee process has been considered and all reviews have been finalized. The final
determination may be affected by issues not discussed at the advisory committee meeting.
Nonprescription Drugs Advisory Committee Meeting

Cold, Cough, Allergy, Bronchodilator, Antiasthmatic Drug Products
for Over-the-Counter Human Use
Effectiveness and Safety of Phenylephrine Hydrochloride and Phenylephrine
Bitartrate as an Oral Nasal Decongestant Drug Product

December 14, 2007

Table of Contents

1. Executive Summary
Susan Johnson, Ph.D., Associate Director
Office of Nonprescription Products

2. Citizen Petition
Petitioners:

Leslie Hendeles, Pharm.D.,
Professor, Pharmacy and Pediatrics
University of Florida;

Randy C. Hatton, Pharm.D., FCCP, BCPS
Co-Direct, Drug Information and Pharmacy Resource Center
Shands at the University of Florida
Clinical Professor, University Florida College of Pharmacy; and

Almut G. Winterstein, Ph.D., Assistant Professor
Department of Pharmacy Healthcare Administration, University of Florida

3. Reviews:
• The Evaluation of Nonprescription Drug Products
Oral Nasal Decongestant Cough/Cold Review Team
Division of Nonprescription Regulation Development

• Review of Effectiveness and Safety Data for Phenylephrine
Hydrochloride and Phenylephrine Bitartrate
Michael Koening, Ph.D., Interdisciplinary Scientist
Division of Nonprescription Regulation Development

• Statistical Review of Meta-analyses
Stan Lin, Ph.D., Division of Biometrics IV, Office of Biostatistics
• Clinical endpoints and General Study Design for the Evaluation of
Efficacy of Nasal Decongestants
Xu Wang, M. D., Ph.D., Medical Officer
Division of Pulmonary and Allergy Drug Products

4. Related Submissions:
• Consumer Healthcare Products Association Final Report January 30, 2007
“Efficacy Meta-analysis of Single-Dose 10 mg Phenylephrine vs
Placebo in Adults with Acute Nasal Congestion Due to Common
Cold”

• Wyeth Consumer Healthcare Phenylephrine Review, November 16, 2006
(EMC140 in Docket No. 1976N-0052N)

• Schering Plough (Study P04579)
“Crossover Study of the Decongestant Effect of Phenylephrine
Compared with Placebo and Pseudoephedrine as Active Control
In SAR Subjects Exposed to Pollen the Vienna Challenge
Chamber”
MEMORANDUM

Department Of Health and Human Services
Food and Drugs Administration
Center For Drug Evaluation and Research
Office of Nonprescription Products
Division of Nonprescription Regulation Development

Date: November 15, 2007

From: Susan Johnson, Ph.D.
Associate Director, Office of Nonprescription Products

Through: Charles Ganley, M.D.
Director, Office of Nonprescription Products

TO: Nonprescription Drugs Advisory Committee for December 14, 2007

Subject: Briefing Package Executive Summary: OTC Monograph Status of
Phenylephrine

FDA received a citizen petition (CP) on February 8, 2007, from Dr. Leslie Hendeles et al.
at the University of Florida regarding the dosing of immediate release formulations for
oral delivery phenylephrine indicated for nasal decongestion (hence, the OTC monograph
terminology “oral nasal decongestant”). The petition is contained in Tab 2. It requests
that the adult dose of phenylephrine provided for in the OTC monograph be increased on
the basis that the current dose is ineffective. The petition also requests that the OTC
monograph be modified to withdraw recommended dosing for children under 12 years of
age. The NDAC is being asked to consider only the moiety phenylephrine and the
appropriate dosing for adults. Any implications that the NDAC deliberation may have on
other aspects of science or regulation will be addressed via other mechanisms.
Additional explanation will be provided throughout the background package and
presentations to NDAC by FDA.

The following is a summary of the factors that are addressed in this background package
and that we believe most pertinent for NDAC consideration.

• Regulatory Status
The OTC Drug Review process for oral nasal decongestant cough cold products is
presented in Tab 3 “The Evaluation of Nonprescription Drug Products.” This process of
review of the available scientific data by an Advisory Panel, followed by a series of
notice and comment rulemakings, established a final monograph that includes two salts
of phenylephrine, hydrochloride and bitartrate in doses equivalent to 10 mg
phenylephrine hydrochloride to be dosed every 4 hours, not to exceed 60 mg (6 doses) in
a 24 hour period. Phenylephrine is also available under the OTC Drug Review for topical
nasal application to treat congestion, and as an ophthalmic or rectal vasoconstrictor.
Phenylephrine is in prescription oral cough/cold combination products approved through
the NDA/ANDA regulatory path, and is used as an injectable vasopressor.

• Pharmacology and Pharmacokinetics

Phenylephrine is a sympathomimetic, primarily with alpha-receptor agonist activity on
the cardiovascular system. In oral doses it has been shown to have a short Tmax and half
life, approximately 2.5 hours, as described in the review found at Tab 3 “Effectiveness
and Safety.” Extensive metabolism occurs in the gut wall, leading to a relatively low
bioavailability of the oral dose. It is expected that the NDAC will hear additional
information about the pharmacokinetics of phenylephrine, based on new research, during
sponsor presentations at the December 14 meeting.

• Efficacy of Phenylephrine

Tab 3 “Review of the Effectiveness and Safety Data for Phenylephrine” contains a short
summary of each of the available efficacy studies. These studies have been reviewed in
various groupings, as designated in the review table of contents. Many of the studies
were considered as part of the OTC Drug Review. The petitioner has conducted a meta-
analysis based on a slightly different group of studies, and the Consumer Health Products
Association (CHPA) has also conducted a meta-analysis on yet a different group of
studies. Finally, new data have become available from two sponsors, Wyeth and
Schering Plough, as part of the public response to the petitioner.

There is substantial variability among the study designs, methods, populations, endpoints,
and outcomes. Most of the studies included only a very limited number of subjects. In
addition, FDA has not had access to full study reports, including protocols and data sets
for most of these studies. The impact of these conditions on the application of meta-
analysis techniques is discussed in FDA’s statistical review, Tab 3 “Statistical Review of
the Meta-analyses.” While the conclusions of the petitioner and CHPA about their meta-
analyses differ, there are important limitations for the NDAC to consider about both.

One aspect of particular interest in evaluating the quality of available efficacy data is the
use of different endpoints among the studies. Primarily, the earlier studies of the
decongestant effects of phenylephrine employed nasal airway resistance (NAR), while
later studies included patient- or healthcare provider- assessed symptom scores. Some
studies included both types of metrics and these studies largely concluded that the
outcomes correlate to some extent. A consult from the Division of Pulmonary and
Allergy Drug Products is included at Tab 3 “Clinical Endpoints and General Study
Design for the Evaluation of Efficacy of Nasal Decongestants” and discusses the merits
of each type of endpoint. FDA currently requires that sponsors developing products for
use in allergic rhinitis to study subjective symptom score endpoints, but continues to
2
encourage sponsors to develop validated objective measures. There is ongoing research
involving NAR and recent publications are provided for reference.
Additional efficacy data are included in Tab 3, as submitted by “Consumer Healthcare
Products Association” and “Wyeth Consumer Healthcare,” and as published by
“Schering-Plough Healthcare Products.”

The petition proposes that the dose of phenylephrine hydrochloride be increased to 25
mg. Some information about the effectiveness of the 25 mg dose is available among the
various studies. However, the petition concludes that the existing data are insufficient
and that regulatory decisions regarding the 25 mg dose would need to be based on the
outcome of additional studies.

• Safety

Although effects on blood pressure and heart rate can be anticipated to correlate with
level of systemic exposure, based on phenylephrine pharmacology, the limited data
available from the published literature about the safety of oral doses of 10 and 25 mg
phenylephrine hydrochloride suggest only negligible effects. In addition, adverse event
reporting in these trials did not show a significant safety signal. Data from FDA’s
spontaneous adverse event reporting system (AERS) regarding oral dosing of single
ingredient phenylephrine products is very limited, identifies no significant safety
concerns, and will be discussed in additional detail at the December 14 meeting.

• Use in Pediatrics

At a joint meeting of NDAC and the Pediatrics Advisory Committee on October 18 and
19, 2007, the use of OTC monograph cough cold ingredients, including phenylephrine, in
pediatric patients was extensively discussed. Minutes of this meeting, including the
outcome of committee votes, is included in this background package (Tab 3
“Effectiveness and Safety”). Full transcripts of the meeting are also available on the
FDA website. The Agency is currently working to determine the actions that will be
taken based on the committee’s recommendations and additional information may be
available at the December 14 meeting. Agency policy regarding the petition request to
withdraw recommended dosing for children under the age of 12 will be made based on
the previous discussion, so that the December 14 meeting will be focused on
considerations for adult dosing.

3
oNP~q~4
CITIZEN'S PETITION
February 1, 2007
Division of Dockets Management
Food and Drug Administration
5630 Fishers Lane
Room 1061 (HFA-305)
Rockvile, MD 20852
The undersigned submit this petition under 21 CFR Part 10.30 to request the
Commissioner of Food and Drugs to amend the dosage of oral phenylephrine
listed in the Final Monograph on oral decongestants 1 and in the Final Rule
adding phenylephrine bitartrate.2
A. Action Reauested
We propose that the maximum dose of oral phenylephrine in the labeling for
patients ~12 years should be increased and that approval for use in children c:12
years should be withdrawn. Additional studies should be required to validate that
a 25-mg dose would be more efficacious than a 10-mg dose of phenylephrine
given every 4 hours, and as safe.
1, Exact Wording of Existing Regulation
a. Phenylephrine hydrochloride (attachment #1)
The existing wording of the Federal Register dated August 23, 1994 on page
434101 under section (1), Oral, nasal decongestants - (i) For products containing
phenylephrine hydrochloride identified in 341.20 (a) (1) is as follows: "Adults and
children 12 years of age and over: 10 mg every 4 hours not to exceed 60 mg in
24 hours. Children 6 to under 12 years of age: 5 mg every 4 hours not to exceed
30 mg in 24 hours. Children 2 to under 6 years of age: 2.5 mg every 4 hours not
to exceed 15 mg in 24 hours. Children under 2 years of age: consult a doctor."
b. Phenylephrine bitartrate (attachment #2)
For dosage listed for phenylephrine bitartrate in the Federal Register, August 1,
2006, page 433622, under (iii) For products containing phenylephrine bitartrate
identified in 341.20 (a) (4) is as follows: "Adults and children 12 years of age and
over: 15.6 mg every 4 hours not to exceed 62.4 mg in 24 hours. Children 6 to
under 12 years of age: 7.8 mg every 4 hours not to exceed 31.2 mg in 24 hours.
Children under 6 years of age: Ask a doctor."
riO tJíP- VOY7 cf i
C:\Documents and Seltings\rice\My Documents\Reports\Cilizens Petition-phenylephrine,doc
February 1, 2007
2
2, Proposed Changes
a. Phenylephrine hydrochloride
Adults and children 12 years of age and over: 25 mq every 4 hours not to exceed
100 mq in 24 hours. Children c:12 years of age: ask a doctor.
b. Phenylephrine bitartrate
Adults and children 12 years of age and over: 40 mq every 4 hours not to exceed
160 mq in 24 hours. Children under 12 years of age: Ask a doctor.
B, Statement of Grounds
In our peer reviewed Letter to the Editor published in the July, 2006 issue of The
Immunology, we concluded that phenylephrine is
Journal of Allergy and Clinical
unlikely to relieve nasal stuffiness at the maximum FDA approved dose of 10 mg
(attachment #3). This was based upon nasal airway resistance data from 11
studies containing a 10-mg dose arm evaluated by the FDA Review Pane14-14 and
two subsequently published studies not reviewed by the Panel; an efficacy study
favoring phenylephrine 15 and a bioavailability study indicatin~ that only 38% of
the dose of phenylephrine reached the systemic circulation.1
Subsequent to the publication of our letter, we conducted a systematic review of
the literature. Fifteen studies were identified;4-15,17-19 12 of them included a 10-
mg dose.4-15 Of these 12 studies, only five (42%; demonstrated a difference from
placebo in decreasing nasal airway resistance.5- ,15 In contrast, 8 of 10 (80%) of
studies includin~ the 25-mg dose demonstrated a significant difference from
placebo.4-7,15,17- 9 In the Cohen study,15 for example, which apparently was not
reviewed by the Panel, there was a statistically significant dose-response for
decreasing nasal airway resistance; the 25-mg dose produced a greater
reduction than either the 10-mg or 15-mg doses. All of these were randomized,
double-blind, crossover studies that measured both symptom scores and
improvement in nasal airway resistance, potentially a "gold standard" for the
objective measurement of obstructed nasal airflow.2o
Eight of the studies including a 10-mg dose met the criteria for a meta-analysis.21
Phenylephrine 10 mg did not affect nasal airway resistance more than placebo;
the mean maximal reduction (95% CI) in relative change of nasal airway
resistance from baseline between phenylephrine and placebo was 10.1 % (-3.8%,
23.9%). (Note that the 95% CI for the difference between phenylephrine and
between
placebo included zero.) In contrast, there was a significant difference
phenylephrine 25 mg and placebo; the mean reduction in maximal nasal airway
resistance was 27.6% (17.5%, 37.7%) (attachment #4). Patient-reported
decongestion was not consistently better for any phenylephrine dose compared
to placebo, and nasal airway resistance was a more sensitive measurement of
£
all!aeaÁ' HoMa\/aJ' ljla jlalaJoBaua!lÁ BaJOSS slnpias iupnpap !U ljl!S wale-
BUBIÁS!S snBBasls doss!qia WaBSnJaWaul q!BS' 1jlls i!WIls ljla aoupnsiou Bqonl
Mjl!ajl ls ljla WOSl all!aepons posa'
Il !S uolaMOJljlÁ ljlBl Bil Ol ljla slnp!as daJloJwap qÁ 31!zBqaljl sloajlawiaBI
sjloMap ljlBl djlauÁladjlpUa MBS s!Bu!llaeullÁ qallaJ ljlBU dlBaaqo JaBBJPlaSS ol
posa nsap'Ç'9'Ü-L6 MjlaJaeS slnpias aoupnpap qÁ oljlaJ IBqoJelopas BauaJBlIÁ
lonup uo p!llaJauaa qalMaau ljla ~ o-wB posa eup dlBaaqo' viso' ljla weBil!lnpa
olljla p!ll8Jauaa qalMaau djlauÁladjlpUa ~O wB eup dlBaaqo )a'B' -71~%( !U ljla
slnp!as aoupnpap qÁ 31!zBqaljl s!oajlaW!aBIç'9'ü_~6 MaJa wnajl IBJBaJ ljlBU ljla
plllaJauaa lonup Bl Oljl8J IBqoJBlOpaS MjlO lonup B p!llaJauaa qalMaau ~ 0 wB BUp
dlBaaqo' lu 81Iulasl #~' lOJ axBwdla' ljla p!llaJauaa MBS OulÁ -~ 9'9%l 1jl!S
Je!sas ljla bnasliou ljlel ljlaJa WBÁ jlB\/a qaau sowa lÁda Ol q!BS !U ljla slnpias
aoupnpap qÁ 3l!zBQaljl sloajlawiaBI OJ iu ljla JadoJlIUB Ol ljla Jasnlls'
'V JaaaulIÁ dnql!sjlap 1!laJBlnJa Ja\/!aM:c:c BUp B 80ajlJBUa ~a\/laMz8 SIWIIBpÁ
aoupnpap ljlel djlauÁladjlpua MBS uol 8llap!\/a OJBlIÁ Mjl!la ljlaJa MBS snddoJl lOJ
ljla alllaBaÁ ol ljl!S pJnB Mjlau BpwiulslaJap BS elod!aBI UBSBI soinl!ou'
Noua ol ljla ~ 9 slnpias Ja\/laMap lOJ ljl!S dam!OU paWOUSlJBlap B SiBUIllaBul
p!llaJauaa lJOW dlBaaqo lOJ jlaeJl JBla OJ qioop dJassnJa lOJ Bil posas slnpiap':cL
1jla 11laJBlnJa saBJajl Ja\/aBlap BPPl!OUBI JadoJls daJl!uaul lo ljlls dam!OU' OJel
paaouBaslBuls ljlBl Jaeajl ljla sÁslaw!a pJanlBl!OU sllwnlBla D~ JaaadloJs lu ljla
UBSBI wnaosB BUp M!II BISo sl!wniela dapdjlaJBI D~ JaaadloJs !U qioop \/assais'
dJopnpuB \/BsoaouSlpal!ou BUp BU !UaJaBSa lU qioop dJassnJa !U B aoUaaUlJBl!OU-
padaupaul WBUUaJ' :cv 8jlnB BUp saupwof a\/elnBlap ljla 1!laJelnJa ou ljla allaps
Ol uou-dJasapdl!ou sÁwdeljlow!wal!a eBauls ou qioop dJassnJa'zç ljlaÁ lonup
ljlBl B posa Ol ;:~GO wB Ol OJBI djlauÁladjlpUa MBS Jabn!Jap lO !UaJaBSa qioop
dJassnJa !U UOJWOlauS!\/a snqfaps' i'a" B posa ljlel Mes Bl iaesl ~ G l!was ljla
anJJaul WBxiwnw :.O'V-BddJo\/ap posa' IU aOUlJBSl' dsanpoadjlappua dJopnaap
B s!Bu!l!aBUl !uaJaesa IU qioop dJassnJa Bl :;~GO wB' i'a" OUIÁ lM!aa ljla WBxiwnw
JaaoWWaupap posa' 1jla 1!!)alÁ axdlBUBlIOU lOJ ljla p!ll8Jauaa !U ljl8JBdanl!a
WBJBIUS qalMaau djlauÁladjlpua BUp dsanpoadjlappua !S ljla jliBjl lIJSl dess
waleqoiisw Ol OJBI djlauÁladjlpUa' ~9 Il !S nUI!!)alÁ ljlBl ljla PIll8Jauaas BJa JalBlap
lO plllaJauaas IU BllIUIlÁ lOJ ljla DL JaaadloJ siuaa \/aJÁ SWBII posas Ol
djlauÁladjlpUa B!\/au !ulJe\/auonslÁ dJopnaa e weJ!)ap dJassoJ allap':cv 'VISO'
8jlnB BUp saupwof plap B laM slnp!as !up!ael!uB ljlBl BPW!UISlJBl!OU Ol
djlauÁladjlpua !U ljla lOJW Ol aÁa pJOds' dBJl!anlepÁ Bl jliBjlaJ aoUaaulJel!oUS' MBS
aBdBqla Ol dJopnpuB BU !uaJaesa !U qioop dJassnJa IU UOJWOlauS!\/a snqfaps':cç
1jla odjlljlBIW!a JOnla :!Janw\/auls ljla snllouBlIOU Ol djlauÁladjlJ!Ua !U ljla Bnl eup
ljla paBW!UBl!OU qÁ WOuoBwiua ox!pesa pnpuB ljla lIJSl dBSs ljlJonBjl !U ljla 1!\/aJ'
31!S al BI:c9 JadoJlap ljlBl 719 wB ol dlLauÁladjlpUa B!\/au BIOUa PIP uol !UaJaBSa
qioop dJassnJa' qnl Mjlau lB!)aUM!ljl e wouoew!ua ox!pesa iujl!q!lOJ )il'VOI(
dJopnaap eu elBJW!UB !uaJaesa !U Sd Jabn!PuB Ja\/aJSel M!ljl djlaUlOIewiua' BU D
4
blocker. They also noted that phenylephrine 10 mg alone did not produce any
effect on blood pressure, but when given concurrently with a MAOI, this dose
produced an increase in blood pressure. These data suggest that monoamine
oxidase plays an important role in the first-pass metabolism of phenylephrine and
blocking the inactivation of phenylephrine by monoamine oxidase allows greater
concentrations to reach 01 receptors.
Since an oral dose of 120 mg or higher of phenylephrine is required to increase
blood pressure in normotensive patients, we believe that increasing the labeled
dose to 25 mg should not increase the risk of systemic adverse effects, It would
be prudent, however, to conduct further safety assessment of the 25-mg dose.
During our systematic review of the literature, an abstract in ClinicalTrials.gov
was discovered that is relevant to this petition.27 Schering-Plough has conducted
a double-blind, randomized, placebo-controlled trial comparing phenylephrine 12
mg and pseudoephedrine 60 mg in patients with seasonal allergic rhinitis. The
congestion score decreased by 7.1 % for phenylephrine compared to 2.2% for
placebo treatment (p=0.56), Phenylephrine was not significantly different from
placebo at any time point. In contrast, pseudoephedrine decreased the
congestion score by 21.7% and was significantly more effective than either
phenylephrine or placebo (attachment #5).
Wyeth submitted to FDA on November 16, 2006 the results of three unpublished
studies that they contend supports the efficacy of phenylephrine (Docket No,
1976N-0052N), We disagree with their contention, In study AHR-GIA, there was
no placebo treatment and the change in nasal airway resistance may have
decreased as a function of time and not treatment. Also, they used a p value of
c:0.1 to indicate "marginally significant", whereas a significant p value is c:0.05.
.10 AHR-401 0-3 there were no statistical differences in the results of five of the six
study sites, Thus, the statistical difference claimed for the pooled data was
driven by only one site, Also, in study #7032 phenylephrine alone was not
significantly different from placebo,
Lastly, none of the studies reviewed by the OTC Panel or found in the systematic
literature search evaluated the effects of phenylephrine in children c:12 years.
Therefore, there are no data on either the safety or efficacy of this drug in this
vulnerable age group, Consequently, we believe that this drug should only be
used in children c:12 years under the advice of a licensed prescriber and that
FDA should withdraw OTC approval for this age group,
Impact Statement
C, Environmental
We do not have the resources to conduct an environmental impact analysis.
However, FDA has previously determined that amending the final monograph to
include phenylephrine bitartrate does not have a significant environmental