ndac december 14, 2007 1 effectiveness and safety of phenylephrine as an otc oral nasal decongestant...

NDAC December 14, 20071

Effectiveness and Safety of Phenylephrine as an OTC Oral Nasal Decongestant

Michael L. Koenig, Ph.D. Michael L. Koenig, Ph.D. Division of Nonprescription Regulation Development Division of Nonprescription Regulation Development Office of Nonprescription ProductsOffice of Nonprescription Products


Overview

• Effectiveness– Studies Included in Current Review– Endpoints– Studies Demonstrating Statistically Significant

Effects

• Pharmacokinetics• Safety

– Cardiovascular Risks– Review of Studies– AERS Database

• Summary


Understanding the Handout

Study ANPR CP CHPA

Patient Condition

Effectiveness

↓ NAR Symptom Relief

10 mg 25 mg 10 mg

25 mg

Sterling-Winthrop ■ Healthy ■ ■

Eliz1 ■ Cold ■* ■*

Eliz2 ■ ■ ■ Cold ■* ■* ■* ■

Eliz3 ■ Cold ■* ■

Eliz4 ■ Cold ■* ■

Eliz5 ■ ■ ■ Cold ■* ■* ■ ■*

McLaurin et al. ■ Various4 ■ ■

Blanchard et al.1 ■

*Statistically significant effect


Studies Cited by the Panel

• 15 Studies (1959-1975)– Excluded (2)1

– Elizabeth Biochemical Labs (5)– Cintest (Hill Top) Labs (3)– Huntingdon Research Center (2)– Sterling-Winthrop Research Institute (1)– McLaurin et al., 1961 (1)– Bio-Evaluation, Inc. (Cohen, 1975) (1)

1See handout


Additional Relevant Studies

• 6 Studies (1967-2007)– Cohen, 1972– Wyeth Consumer Healthcare/AHR (3)

• 7032, 1967

• G1-A, 1973

• 4010-3, 1983

– SP P04579, 20061

– SP/Merck P04822, 2007

112 mg dose


Study Characteristics

• Randomized: 18• Double-blind: 17• Controls

– Placebo: 18– Active: 8

• Design– Crossover: 15– Parallel: 4


Study Characteristics• Single dose: 17• Doses tested: 5 – 75 mg

– 10 mg (16)– 25 mg (10)– 10 and 25 mg in same study (7)

• Number patients tested per dose: 5 – 126– Fewer than 20 (12)– 20 or more (7)

• Ages of patients– Adult/not specified: 19

• Adults > 75 y: 2• Children < 18: 1 (range lists 3 in 10 – 19 y group)


Study Characteristics

• Patient condition– Common cold: 12– Allergy/SAR: 3– URTI: 2– Various: 1 (footnote 5 on handout)– Healthy/not congested: 1

• Origin of condition– Naturally occurring (17)– Induced (exposure to pollen in a chamber) (2)


Overview


Effects


– Cardiovascular Risks– Review of Studies– Adverse Events

• Summary


Effectiveness Endpoints

• Nasal Airway Resistance (NAR)– 17/19 studies (only endpoint in 4)

• Symptom scores– 15/19 studies (only endpoint in 2)

• Both endpoints used in the same study– 13 studies


Nasal Airway Resistance?

• Congestion (swelling of nasal mucosa) obstructs nasal cavity and increases resistance to air flow

• Decongestion decreases resistance by opening the airway.

www.entsolwash.com


Rhinomanometry

• Process used since 1894

• Widely used in 1960s and 1970s

• Used today– Eccles, Cardiff University, Wales– Schumacher, Univ. of Arizona, Tucson

“Measurement of air flow and pressure within the nose during respiration”


No Standardization

• Based on different methods– Sternstein and Schur, 1936; McLaurin, 1960– Anterior vs. posterior measurement

• Utilized different instruments– Butler-Ivy and modifications, Respiron

• Evaluation of NAR– Over different time courses (1 – 5 hours)– At different time intervals (15 min – 3 hours)– Different numbers of replicate measurements

at each time point


Symptom Scores

Degree of Congestion Score

Nose feels clear 0

Almost clear 1

Stuffy 2

Very stuffy 3

Completely blocked 4

Elizabeth, Huntingdon, and Cintest Studies

Ordinal Scale

5-point


Overview


Effects



• Summary


Evidence of Effectiveness

Dose (mg)

No.

Studies

Statistically Significant

↓ NAR Symptom Relief

10 16 7/14 5/12

25 10 7/10 3/8

10 and 25 mg Doses


Studies Demonstrating Significant Effects (10 mg)

Study n Controls Onset

(h)

Last

Eff. TP*

↓ NAR Sympt.

Relief

Eliz 2 16 Placebo Eph 0.25 2/2 0.01 0.01

Eliz 5 10 Placebo 0.5 3/4 0.01 NS

Cin 1 16 Placebo PPA 1.5 3/4 0.05 0.05

BEI 25/100 Placebo 0.25 2/2 0.05 0.05

Cohen, 72 16 Placebo 0.5 2/2 0.01-0.05

0.05

Wyeth G1-A 8 Baseline 1 2.5/4.5 0.005 0.05

Wyeth 4010

(multi-site)

66 Placebo PPA 0.5 3/4 0.001-0.05**

NS

**Evaluated at only 1 of 6 sites (n = 12)*Last effective time point/observation period (h)


Studies Demonstrating Significant Effects (25 mg)

Study n Controls Onset

(h)

Last Eff. TP*

↓ NAR Sympt.

Relief

Eliz 1 12 Placebo Eph 0.5 2/2 0.01 0.01

Eliz 2 6 Placebo Eph 0.5 2/2 0.01-.05 NS

Eliz 3 9 Placebo PPA 0.5 3/4 0.05 NS

Eliz 4 9 Placebo Eph 0.75 3/4 0.01 NS

Eliz 5 9 Placebo 0.5 4/4 0.01 0.05

Cin 1 15 Placebo PPA 2 4/4 0.025-0.05

NS

Cohen 72 16 Placebo 0.25 2/2 0.01-0.05 0.05

*Last effective time point/observation period (h)


Overview


Effects



• Summary


Pharmacokinetics

• Absorption– Bioavailability (oral) ≤ 38% (relative to IV)– Cmax: Variation

PE Oral Dose

(mg)

Cmax

(ng/ml)

Reference

Total 9 207, 298 Cavallito et al., 1963; Bogner and Walsh, 1964; Kanfer, 1993

10 ~60 SP CL2005-07, 2005

Parent 1 0.9 Hengstmann & Gorozny, 1982

10 ~0.6 SP CL2005-07, 2005


Pharmacokinetics

• Tmax: 1 – 1.33 h (total); 0.5 – 1.25 h (parent)

• Distribution– Serum levels decline monoexponentially– Minimal penetration into brain; no data on protein

binding

• Metabolism– Gut wall, liver → primarily sulfate conjugates– Deamination by MAO– Glucuronidation

• Excretion– Urine (Elimination t1/2: 2.1 – 3.4 h)


Overview


Effects



• Summary


Cardiovascular Risks

• Increased blood pressure– Vasoconstriction in many vascular beds

(including nasal mucosa)– GRASE for OTC treatment of hemorrhoids

• Reflex bradycardia– Pulse rate slowed by compensatory vagal

discharge as bp increases


Keys and Violante, 1941

• 250 mg• Oral


Overview

• Effectiveness– Endpoints– Review of Studies



• Summary


Studies Evaluating Safety

BPSystolic BPDiastolic Pulse Rate

Studies 151 151 141

NS 13 14 11

Sig. ↑ 1 1 2

Sig. ↓ 1 0 1

10 mg Dose

1Includes 1 study at 12 mg dose


Studies Evaluating Safety

BPSystolic BPDiastolic Pulse Rate

Studies 8 8 8

NS 6 6 2

Sig. ↑ 1 0 4*

Sig. ↓ 1 2 3*

25 mg Dose

*1 study showed significant ↑ and ↓


Adverse Events

• None reported– 6 of 10 at 10 (or 12) mg dose– 1 of 2 at 25 mg dose

Dose (mg)

Study Side Effects

10 McLaurin Headache, Nausea, Dizziness, Lightheadedness, Drowsy, and others

BEI Felt warm, Dizzy, Flush, Extra systoles, Nasal dryness, Slightly shaky

Cohen, 72 Dry mouth, Dry nose

SP P04822 Epistaxis, 2 severe AEs during post-treatment observation

25 Cohen, 72 Dry mouth, Dry nose, Irritability, Nervousness, Malaiase, Lightheadedness, Breathlessness, Gaseousness


Adverse Event Reporting System* (1969 – 10/3/07)

• 26 unique cases assoc with oral single ingredient phenylephrine– Serious outcome: 4 cases

• 1 Death (suicide)– Cardio-respiratory arrest from ingestion of several drugs (i.e.

hydrocodone)• 3 Hospitalizations

– Hemorrhagic stroke in a 44yo female; limited information– Elevated BP in a 15yo male; attributed to nephritis– Paralysis, depressed LOC, dysarthria, etc. in a 13yo male; illicit drug

use suspected; unlikely single dose caused 6 day event

• 13 cases (50%) involved an overdose– 5 medication errors– 3 intentional overdoses– 1 accidental exposure– 4 unknown intent

* Limitations of AERS: underreporting, variable quality of reports, causality of drug uncertain, and inaccurate numerator and no denominator


Adverse Event Reporting System (1969 – 10/3/07)

All 5 medication errors involved confusion between Sudafed (pseudoephedrine) and Sudafed PE (phenylephrine)– Both tablets are similar in appearance (small, round, red) and packaged

in foil bubble blisters perforated in units of two (even though the recommended adult dose for Sudafed PE is one 10 mg tablet)

– Mistakenly ingested 20 mg (2 tabs); 1 case reported HA and nausea

Conclusions:• Adverse event reports occurred with overdoses (50%)

and non-overdoses (31%); 19% did not report any dosing information

• Adverse events and ED visits have been reported following use of oral single ingredient phenylephrine


Overview


Effects


– Cardiovascular risks– Review of Studies– AERS Database

• Summary


Summary• Effectiveness

– Significant Effects (NAR)• 10 mg: 7/14 studies • 25 mg: 7/10 studies

– Significant Effects (symptom relief)• 10 mg: 5/12• 25 mg: 3/8


Summary

• Pharmacokinetics– 38% bioavailability may be high– Cmax: 60 – 300 ng/ml (total PE)

• 100-fold lower for parent PE

– Tmax: 1 – 1.3 h (total PE)• 0.5 – 1.25 h (parent PE)

– Elimination: urine; t1/2: 2.1 – 3.4 h


Summary• Safety – Studies

– Inconsistent effects on systolic and diastolic blood pressure and pulse rate

– Majority of studies showed no effect– “Minor” or “moderate” adverse events with

most studies reporting none

• Safety – AERS database (1969 – 2007)


Acknowledgements

• Review Team– Michael L. Chasey– Mary S. Robinson– Debbie L. Lumpkins

• Administrative Support– Delores Pinkney– Walter Ellenberg


Additional Slides

Koenig


Panel Review - Effectiveness

• Objective (NAR) measurements– Corroborating symptom scores – 1 study

• Studies demonstrating decongestion• Onset 15 – 20 min• Maximum effect: 30 - 90 minutes• Duration 2 – 4 hours• 25 mg more effective than 10 mg

• Studies not demonstrating decongestion• Greater apparent placebo response• Variability in patient response


Panel Review - Safety

• Cited 12 studies– BP and pulse rate responses

• 10 and 15 mg doses: equal to placebo• 25 mg dose

– BP: occasional ↑ up to 7 mm Hg– Pulse rate: occasional changes of ± 4-13 beats/min

– Adverse events• 10 mg dose: placebo• 15 and 25 mg: symptoms associated with mild

CNS stimulation


SP P04579

• 2006• Primary objective: PE vs. placebo• R, investigator-blind, placebo and active (PSE) controls,

3-way crossover, single-dose• 3 treatment visits; 5-day washout• n = 38 with 2-y history of SAR due to grass pollen• Congestion induced by 6 h pollen exposure in EEU

(chamber)• PE, 12 mg, IR, orally-administered• Primary endpoint: subjective change from baseline over

6 hour period• PE not significantly different from placebo; PSE

significantly more effective than placebo


SP P04822

• 2007• Primary objective: Loratidine-Montelukast (LMC) vs.

placebo• R, double blind, placebo control, parallel, single-dose • PE arm: n = 126 (vs. 126 placebo)• Congestion induced by exposure to ragweed in

EEU (chamber)• PE, 10 mg, IR, orally-administered• Primary endpoint: subjective change from baseline

every 20 min over 8 hour period• LMC significantly more effective than placebo; PE not

significantly different from placebo over the first 6 h


Why NAR?• Preferred if interested in physiological (vs.

symptomatic) change– Eccles: “Decongestant claim should be backed up with

objective demonstration of effectiveness; claims of symptom relief should be supported by changes in symptom scores.”

• Sensation of respiration determined partly by sensation of cooling of nasal epithelium in anterior 1/3 of nose– Menthol provides sensation of improved airflow

• Asymptomatic nasal obstruction• No obstruction but complain of congestion


Significant Effect - NAREliz2

10 mg dose

25 mg dose


Study Concerns

• Summary memoranda– No protocols– Lack details (e.g. of statistical tests)

• Heterogeneity in methodology (both objective and subjective measures)

• Small (pilot studies?)

• NAR technique not standardized– 1984, 2000 international standards



• 16 unique cases in which the only drug exposure reported was to an oral, single ingredient phenylephrine product

• Serious outcome: 1 case – 44 yo female experienced hemorrhagic stroke. Amount of

PE ingested, duration of treatment and temporal relationship to AE not reported

• Hypersensitivity: 3 cases– URT swelling, pruritis and dyspnea following ingestion of 10

mg dose PE in three patients 45 – 47 yo • Miscellaneous Events: 2 cases

– 50 yo female experienced chest pain following single 10 mg dose

– 37 yo male experienced abnormal behavior, depressed level of consciousness, hyperhidrosis, paresthesia following 10 mg qd x 2 days




• Overdose: 10 cases– Accidental overdose: 3 cases

• Increased HR in 18 mo following ingestion of 40 mg• Headache in 40 yo female following 2 x 60 mg doses (5

hrs apart)• Dizziness, falling in ?yo male following 20 mg q 4-6 h

– Intentional overdose: 2 cases - no sequelae reported• 150 mg single dose• 240 mg per 24 hrs

– Medication errors: 5 cases• Sudafed PE reformulation of Sudafed dosed per

instructions for pseudoephedrine



Sale of single-ingredient phenylephrine products by dosage forms, Years 2002 - September 2007

• The sale of single-ingredient OTC phenylephrine products have increased nearly 5-fold from year 2002 to year 2006

113.4

158.2 156.1

41.3 41.8 41.0

38.7

33.3 27.7

15.0 5.3

0.0

50.0

100.0

150.0

200.0

250.0

2002 2003 2004 2005 2006 Jan-Sep 2007

Year

Exte

nd

ed

Un

its (

mil

lio

ns)

Ophthalmics

Mouth & Throat

Nasal

Orals

IMS Health, IMS National Sales Perspectives™, Years 2002 – September 2007; Source file: 0712phnl.dvr

ndac december 14, 2007 1 effectiveness and safety of phenylephrine as an otc oral nasal decongestant...

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