# Presentation: 914881

## Effectiveness and Safety of Phenylephrine as an OTC Oral Nasal Decongestant 

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

**1**12 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

- Effectiveness
- Studies Included in Current Review
- Endpoints
- Studies Demonstrating Statistically Significant Effects
- Pharmacokinetics
- Safety
- 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

- Effectiveness
- Studies Included in Current Review
- Endpoints
- Studies Demonstrating Statistically Significant Effects
- Pharmacokinetics
- Safety
- Cardiovascular Risks
- Review of Studies
- Adverse Events
- 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

- Effectiveness
- Studies Included in Current Review
- Endpoints
- Studies Demonstrating Statistically Significant Effects
- Pharmacokinetics
- Safety
- Cardiovascular Risks
- Review of Studies
- Adverse Events
- 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

- Effectiveness
- Studies Included in Current Review
- Endpoints
- Studies Demonstrating Statistically Significant Effects
- Pharmacokinetics
- Safety
- Cardiovascular Risks
- Review of Studies
- Adverse Events
- 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
- Pharmacokinetics
- Safety
- Cardiovascular Risks
- Review of Studies
- Adverse Events
- 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

- Effectiveness
- Studies Included in Current Review
- Endpoints
- Studies Demonstrating Statistically Significant Effects
- Pharmacokinetics
- Safety
- 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 - NAR

- Eliz2

- 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

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

- 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

- * 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)

- 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

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

## 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

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