# Presentation: 242497

## Literature Review: Safety & Efficacy of OTC Cough & Cold Drug Products in Pediatric Patients

**Joint Meeting of the Nonprescription Drugs Advisory Committee and Pediatric Advisory Committee    **
- October 18 & 19, 2007
**Lolita A. Lopez, M.D.**
- Medical Officer** **
**Division of Nonprescription Clinical Evaluation**
**Office of Nonprescription Products**

** ****Center for Drug Evaluation and Research**** **

## Literature Review:

**Safety & Efficacy of **
**OTC Cough & Cold Drug Products **
**in Pediatric Patients **

## Outline

**Published Clinical Studies in Children**** **
**Adverse Events from Case Reports**** **
**Guidelines/Policy Statements from Healthcare Professional Organizations**
**Overall Summary**

## 
Published 
Clinical Studies 
in Children

**Published **
**Clinical Studies **
**in Children**

## Clinical Studies in Children: Summary 

**11 clinical trials published in the last 50 yrs **
- 4 studies from 1951-1966
- 1 study in 1984
- 6 studies from 1990-2004
**Drug class studied**
- Antitussives-3
- Antihistamines-3
- Combination Products-5
**Adverse events**
- No deaths or serious adverse events

## Published Studies in Children: Active Ingredients Included in the Studies

**	**** ****Antihistamine**
** ****brompheniramine maleate***
** ****chlorpheniramine maleate* **
** ****diphenhydramine***
** ****clemastine fumarate**
** ****t****ripelennamine **
** ****azatadine maleate**
** ****pheniramine maleate**
** ****pyrilamine maleate**
** ****triprolidine**** **
**Antitussive****   **
**dextromethorphan* **
**diphenhydramine***** **
**	**** ****Nasal Decongestant **
**pseudoephedrine***
**phenylephrine***** **
**	**** ****Expectorant**
**guaifenesin* (glyceryl guaicolate)**** **

***Common Active Ingredients Found in OTC Cough/Cold Products Used in Children**

## Summary of Published Studies in Children (1951-1984)

| Author | Drug Class/Indication | N | Age  | Efficacy
(Author) |
| --- | --- | --- | --- | --- |
| 1951-1966 |  |  |  |  |
| Fisher |  Antihistamine/Common Cold | 74 | 9y-16y | No |
| McGovern | Antihistamine/Nasal allergy | 485 | 2m-14y | Yes* |
| Lipschutz | Decongestant ± Antihistamine
Allergy & non-allergy sx | 200 | 4m-17y | Yes |
| Reece |  Combination Product /Cough (Decong + Antihistamine +
Antitussive) | 64 | 2m-12y | Yes |
| 1984 |  |  |  |  |
| Weipple | Combination Product/
Cough & cold symptoms | 56 | ≥ 4y | Yes* |

***No placebo arm**

## Summary of Published Studies in Children (1990-2004)

| Author | Drugs/Indication | N | Age  | Efficacy
(Author) |
| --- | --- | --- | --- | --- |
| Sakchai-
nanont |  Antihistamines 
Rhinorrhea of 3 days | 143 | 1.5m-5y | No |
| Clemens | Antihistamine + Decongestant
Common cold | 59 | 6m - 5y
 | No
↑ sleep |
| Korrpi | Antitussive
Resp infection w/cough | 75 | 1y-10y | No |
| Taylor | Antitussive + Mucolytic/Cough | 49 | 18m-12y | No |
| Paul | Antitussive
Nocturnal cough & sleep | 100 | 2y-18y | No |
| Hutton
 | Combination Product Common cold | 96 | 6m - 5y | No |

## Limitations
& 
Challenges 

**& **
**Challenges **

**Published Clinical Studies:**

## Symptoms evaluated not related to the therapeutic effect of drug  
      - appetite, crankiness, fever (parental sleep)

Outcome measures not precise and/or not well-defined
  - measuring frequency of cough
    “very much” vs. “a lot” or “a little” vs. "occasional”

Treatment outcomes not measured at the time of expected efficacy of the drug 
  - evaluating symptoms after 24 or 48 hours

**      **- appetite, crankiness, fever (parental sleep)
**Outcome measures not precise and/or ****not well-defined**
-   - measuring frequency of cough
**    **“very much” vs. “a lot” or “a little” vs. "occasional”
**Treatment outcomes not measured at the time of expected efficacy of the drug **
-   - evaluating symptoms after 24 or 48 hours

**Published Clinical Studies: Limitations**** **

## Published Clinical Studies: Limitations (con’t.) 

**Symptoms not frequently measured**
**	****  **- assessment of symptoms more than
- 	    once a day may be necessary
**Inadequate dosing (amount, frequency) ****to elicit effect of drug**
**	****  **- for a drug given overnight, 2 doses may
-           be necessary in 8 to 10 hrs sleeping time

## Some studies conducted at least 50 yrs ago

No placebo arm in 2 studies claiming efficacy 

Randomization or blinding not clear 
Not adequately powered to show a difference between drug & placebo 

Concomitant use of other meds, such as antibiotics

**No placebo arm in 2 studies claiming efficacy **
**Randomization or blinding not clear**** **
**Not adequately powered to show a difference between drug & placebo **
**Concomitant use of other meds, ****such as antibiotics**

**Published Clinical**** Studies: Limitations **(con’t.)

## Clinical Studies: Challenges 

**Symptoms from common cold believed to be self-limiting, peak within a few days after infection**
**Congestion & rhinorrhea are very subjective outcome measures**
**Young children difficult to study: less verbal, need to rely on caregiver   **

## Adverse Events 
from 
Published Case Reports

**from **
**Published Case Reports**

## Adverse Events from Case Reports:Summary

| Author/Year | Cases Reported | Age  |
| --- | --- | --- |
| Clark        1990 | 1 | 19m |
| Joseph     1995 | 1 | 3y |
| Roberge   1999 | 1 | 2y |
| Gunn        2001 |  3                          13 month period | 9-36m |
| Boland      2003 | 1 | 2m |
| Marinetti   2005 | 10*                        8 month period | <12m |
| Wingert     2007 | 15                          6 year period                 | <16m |

- 8 cases had obvious underlying causes of death
-   e.g. sepsis, compressional asphyxia

## Adverse Events from Case Reports

**Had cough/cold symptoms or **
**	****were given cough/cold meds **
**Detectable or increased blood levels of cough/cold meds**** **
**Death or adverse event reported to be due to cough/cold meds**

## 9-month old, male
Persistent crying, fever (onset 6 days prior)
Nonconsolable x 1 wk
No sleep x 3 nights
Cough for several weeks, no rhinorrhea
Emesis 3x/day, no diarrhea
Mother reported giving ibuprofen 3⁄4 dropper
No mention of other meds in the history

**Persistent crying, fever **(onset 6 days prior)
**Nonconsolable x 1 wk**
**No sleep x 3 nights**
**Cough for several weeks, no rhinorrhea**
**Emesis 3x/day, no diarrhea**
**Mother reported giving ibuprofen 3⁄4 dropper**
**No mention of other meds in the history**

**Case Report  #1**Gunn (Pediatrics  2001)

## T= 39.5C (103.1°F)      P=208       RR=40screaming, tachycardic 
Evaluated for meningitis (CBC, CSF normal) 
Several hours later- 
alert, active, playful
tolerating oral liquids

IM ceftriaxone given & discharged 
Follow-up in ER the next day

**Evaluated for meningitis (CBC, CSF normal)**** **
**Several hours later- **
**alert, active, playful**
**tolerating oral liquids**
**IM ceftriaxone given & discharged**** **
**Follow-up in ER the next day**

***Gunn (Pediatrics  2001)***
***9-month old***

**Case Report  #1 **(con’t.)

## 12 hrs later - in cardiopulmonary arrest
ER: pronounced dead
Autopsy: no gross abnormality
Postmortem urine toxicology testing (+) for: 
acetaminophen
pseudoephedrine 
chlorpheniramine
dextromethorphan 
phenylpropanolamine 

**ER: pronounced dead**
**Autopsy: no gross abnormality**
**Postmortem *****urine *****toxicology testing (+) for: **
- acetaminophen
- pseudoephedrine
- chlorpheniramine
- dextromethorphan
- phenylpropanolamine

***9-month old                 ******Gunn (Pediatrics  2001)***

**Case Report  #1 **(con’t)

## Case Report  #1 (con’t) Drug Levels in the Blood

| Drug | Patient
Postmortem | Blood Concentration
at Therapeutic Doses |
| --- | --- | --- |
| PSE
Pseudoephedrine  | 10 mg/L | 0.18 - 0.5 mg/L |
| DM
Dextromethorphan  | 600 mcg/L
(0.6 mg/L) | 2.4 mcg/L - 207 mcg/L |
| PPA
Phenypropanolamine | 1.4 mg/L | 0.11 - 0.4 mg/L |

***9-month old                 ******Gunn, Pediatrics  2001***

**Pseudoephedrine is at least 20x higher than expected levels **

## Cause of death:  Mixed drug intoxication, unintentional 
Further investigation revealed: 
     Numerous doses of OTC cough & cold
     preparations given by caretakers 

Meds not intentionally given in toxic doses

**Further investigation revealed: **
**     **Numerous doses of OTC cough & cold
-      preparations given by caretakers
**Meds not intentionally given in toxic doses**

***9-month old                 ******Gunn, Pediatrics  2001***

**Case Report  #1**(con’t)

## Case Report #2Marinetti (J Anal Tox 2005)

**5-month old infant**** **
**History of ear infections & congestion**
**Given antibiotics & unknown OTC cold meds containing dextromethorphan**
**After taking OTC meds, **
**	****	****took nap on his belly at 9:30 am****	****at 12:30 pm, unresponsive, dead**
**Crib: no clutter or extra blankets**
**Autopsy: ear fluid, congested lungs**

## Cause of death: 
	  Acute multiple drug intoxication

Toxicology findings (+) in blood:
 - pseudoephedrine		- acetaminophen		
 - dextromethorphan   		- carbinoxamine
 - ephedrine			- metoclopramide 

Further investigation:
3 & 4 y/o siblings routinely given OTC cold meds for sedation 
   - siblings (+) dextromethorphan in urine & blood
   - siblings removed from home

**	****  ****Acute multiple drug intoxication**
**Toxicology findings (+) in blood:**
-  - pseudoephedrine		- acetaminophen
-  - dextromethorphan   		- carbinoxamine
-  - ephedrine			- metoclopramide** **
**Further investigation:**
**3 & 4 y/o siblings routinely given OTC cold meds for sedation **
**   ****- siblings (+) dextromethorphan in urine & blood**
**   ****- siblings removed from home**

***5-month old******	******                    Marinetti, J Anal Tox 2005***

**Case Report #2 **(con’t.)

## Case Report #3Boland (J Anal Tox 2003)

**2-month old, female**
**Cold symptoms, crying til 2:00 am**
**Mother fed infant w/ water and****	**** ****small amount of acetaminophen, ****infant fell asleep**
**4:30 am - infant woke up,**
**	****placed in prone position w/ head to side**
**7:30 am -  unresponsive, **
**	****pronounced dead in ER **

## At the scene: 
Infant prone
3 blankets underneath infant, 
   1 blanket covers back to shoulders
2 baby bottles: 1- small amt of formula
		                         1- pink tinted liquid
Meds received by Medical Examiner:
Infant pain reliever suspension drops
Children pain reliever 
Cough formula containing dextromethorphan 

**Infant prone**
**3 blankets underneath infant, **
**   ****1 blanket covers back to shoulders**
**2 baby bottles: 1- small amt of formula**
**	****	****                         ****1- pink tinted liquid**
**Meds received by Medical Examiner:**
**Infant pain reliever suspension drops**
**Children pain reliever **
**Cough formula containing dextromethorphan **

***2-month old******Boland, J Anal Tox 2003***

**Case Report #3** (con’t)

## Case Report #3 (con’t)

**2-month old**
**Boland, *****J Anal Tox 2003***

- Pseudoephedrine = 28x more than level at therapeutic doses.
- Brompheniramine  = 18x more than level at therapeutic doses.

**Case Report #3 **(con’t)

## Adverse Events from Case Reports: Summary 

**Most deaths had detectable or ****↑****blood level of cough/cold meds, mostly pseudoephedrine**** **
**Data on toxic levels in children limited for most cough/cold meds**** **
**In cases where drug levels were excessively elevated, the contribution of cough/cold meds   to death or serious adverse event should be  suspected despite confounding factors**** **
**Most deaths or serious adverse events confounded or limited clinical information **

## Adverse Events from Case Reports: Summary (con’t.)

**Deaths could have been due to other conditions such as SIDS, child abuse; administration of cough/cold meds  coincidental**** **
**Overdose mostly due to medication error **** **
**No info if physician consulted in children <2 y/o as stated in the label**

## Healthcare Professional OrganizationsGuidelines/Policy Statements

## American Academy of Pediatrics (AAP)

**On Use of Codeine & Dextromethorphan-Containing **_**Cough**_** Remedies in Children (1997): **
- No well-controlled studies support efficacy & safety of narcotics or dextromethorphan in children...
- Suppression of cough... may be hazardous
- Dosage...extrapolated from adults...imprecise for children. Further research  needed
- Educate parents about lack of proven efficacy
- 	antitussive effects & potential risks
**AAP Website: Parenting Corner**
- Never use cough/cold preparations in a child under 3 years of age unless prescribed by pediatrician

## American College of Chest Physicians (ACCP)

**Guidelines for Evaluating **
_**Chronic Cough**_** in Pediatrics (2006)**
- ACCP Evidence-Based Clinical Practice Guidelines
- “In children with cough, cough suppressants and other _OTC_ cough medicines should not be used... especially young children, may experience significant morbidity & mortality.”

## Overall Summary

## Overall Summary (con’t.)

**Published clinical studies in children ****did not establish efficacy of cough/cold meds when used to treat common cold symptoms, including cough. **** **
**Deficiencies in the design of the studies:**** **** **
**definition & timing of treatment outcomes**
**inadequate dose (amount, frequency)**
**studies may not be adequately powered**

## Overall Summary: (con’t.)

**There were no serious adverse events or deaths reported in any of the *****Published Clinical Studies*****  involving children.**

## Overall Summary: (con’t.)

**There were cases in which it was obvious that excessive levels of meds in the blood from patients (case reports) who died or had serious adverse events were mostly due to dosing and/or administration errors by caregivers.**** **
**In many cases, it is difficult to determine the exact contribution of these meds to the deaths or serious adverse events.**