# Presentation: 307247

## Review of Reported Adverse Events and Poisonings Associated with Cough and Cold Products in Young Children

**Joint Meeting of the Nonprescription Drugs Advisory Committee  and the Pediatric Advisory Committee **
**October 18, 2007**
**Silver Spring, Maryland**
**Gita Akhavan-Toyserkani, Pharm.D., MBA**
**Yoo Jung Chang, Pharm.D.**
**Syed Rizwanuddin Ahmad, M.D., MPH**
**Division of Drug Risk Evaluation**
**Office of Surveillance and Epidemiology**

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

## Outline

**Objectives **
**Adverse Event Reporting System (AERS) database**
**AERS review of pediatric deaths**
**AERS review of serious********* adverse events in children**
**Toxic Exposure Surveillance System (TESS) database**
**Database of the AAPCC**** **
**Overall Summary**
**Points to Consider**

*** Serious outcomes per regulatory definition includes death, hospitalization, life-threatening, disability, congenital anomaly, requiring intervention, and other.**

## Objectives

**Present AERS cases of serious adverse events, including deaths associated with cough/cold medications in children < 6 years of age **
**Discuss contribution of drug overdoses to serious adverse events**
**Show most AE cases were reported in age groups where there are no dosing recommendations on the OTC product label**

## Objectives

**Discuss association of single vs. multi-ingredient cough/cold products to serious adverse events**
**Discuss association of Rx vs. OTC cough/ cold products to serious adverse events**
**Review overdose and poisoning exposure cases in association with cough/cold products reported to the AAPCC**

## Voluntary, “spontaneous” reporting
Facilitated by the FDA MedWatch Program
Reports stored and retrieved via Adverse Event Reporting System (AERS) database

**Facilitated by the FDA MedWatch Program**
**Reports stored and retrieved via Adverse Event Reporting System (AERS) database**

**AERS: Spontaneous AE Reporting**** **

## AERS Strengths

**Includes all U.S. marketed products**
**Detection of events not seen in clinical trials**
**Especially good for events with **_**rare**_** background rate, short latency**

## AERS Limitations

**Extensive underreporting**
**New reporting requirements for OTC monograph products (effective December 22, 2007) **
**Quality of reports is variable**
**Reporting biases**
**Actual numerator & denominator not known**
**Causality of drug-event association often in question**

## AERS Review of Pediatric Deaths

## AERS Pediatric Deaths (1969 – September 2006)

**Search Criteria**
**AERS database:**
**Fatalities in children ****≤ ****6 years of age**
**Includes U.S. only, single/combination, and Rx/OTC products**
**Associated with the following ingredients:**

**Decongestants:**
- pseudoephedrine
- phenylephrine
- ephedrine** **

**Antihistamines:**
- diphenhydramine
- brompheniramine
- chlorpheniramine

## AERS Review of Pediatric Deaths: Decongestants

**Number of cases:**
**Pseudoephedrine (46)**
**Phenylephrine (4)**
**Ephedrine (4)**
**Majority (83%) of the decongestant cases were reported in children < 2 years of age**
**Drug overdose 72%**
**Rx (46%) and OTC (33%) cough/cold products were reported**
**Majority (83%; 24/28) of the cases with a reported postmortem blood level were above the adult therapeutic level**

## AERS Review of Pediatric Deaths

| Drug | Pseudoephedrine
(n=46) | Phenylephrine 
(n=4) | Ephedrine
(n=4) |
| --- | --- | --- | --- |
| Overdose | N=35: Use of multiple cough/cold preparations (7), medication error (10), accidental exposure (1), intentional overdose (2), drug interaction (1), opiate intoxication (2), unknown (12) | N=1: Intentional overdose (1) | N=3: Multiple drug intoxication (2), drug intoxication (1) |
| Reported Cause of Death | Drug intoxication/overdose (12), SIDS (7), apnea of prematurity (1), subarachnoid hemorrhage (1), cardiorespiratory arrest (2), head trauma (1), unknown (22) | Overdose (1), SIDS (1), unknown (2) | Drug intoxication (2), SIDS/ suspected drug intoxication (1), unknown (1) |

## AERS Review of Pediatric Deaths: Antihistamines

**Number of cases:**
**diphenhydramine (33)**
**brompheniramine (9)**
**chlorpheniramine (27)**
**Majority (59%) of the antihistamine cases were reported in children < 2 years of age**
**Drug overdose 65%**
**Rx (28%) and OTC (19%) cough/cold products were reported**
**Majority (64%;18/28) of the cases with a reported postmortem blood level were above the adult therapeutic level**

## AERS Review of Pediatric Deaths

| Drug | Diphenhydramine
(n=33) | Brompheniramine 
(n=9) | Chlorpheniramine
(n=27) |
| --- | --- | --- | --- |
| Drug Overdose | N=20: Intentional overdose (4), medication error (5), multi-drug intoxication (3), accidental exposure (3), unknown (5) | N=5: Intentional overdose (2) use of multiple cough/cold products (1), medication error (1), accidental exposure (1)  | N=20: Intentional overdose (4), medication error (5), multi-drug intoxication (3), accidental exposure (3), unknown (5) |
| Reported Cause of Death | Drug intoxication/ overdose(12), SIDS (1), ARDS (1), asphyxiation (2), septic shock (1), multi-organ failure (1), acute febrile illness (1), unknown (14) | Drug intoxication/ overdose (3), SIDS (1), viral pneumonia (1), apnea (1), head trauma (1), unknown (2)  | Drug intoxication/overdose (9), opiate intoxication (1), SIDS (1), subarachnoid hemorrhage (1), pulmonary edema (1), cardiopulmonary arrest (1), unknown (12)  |

## AERS Review of Serious* Adverse Events in Children

*** Serious  per regulatory definition includes death, hospitalization, life-threatening, disability, congenital anomaly, requiring intervention, and other.**

## AERS Serious AE in Children (January 1, 2002 – May 11, 2007)

**AERS database:**
**Serious adverse events in children ****< ****6 years **
**Includes U.S. only, single/combination, and Rx/OTC products**
**Associated with the following ingredients:**
**Decongestant: **pseudoephedrine
**Antitussive:** dextromethorphan
**Antihistamines: **chlorpheniramine, diphenhydramine

## AERS Serious AE in Children: Demographics

| Drug | Pseudo-ephedrine
(n=150) | Dextro-
methorphan
(n=105) | Chlorphen-iramine
(n=63) | Diphen-
hydramine
(n=83) |
| --- | --- | --- | --- | --- |
| Age:
 range
 median (month) | 
2 wks–5 yrs
18 | 
1 mo–5 yrs
18 | 
1 mo–5 yrs
24 | 
3 wks–5 yrs
24 |
|   0 – < 2 yrs
  2 – 5 yrs | 82 (55%)
65 (43%) | 57 (54%)
48 (46%) | 22 (35%)
41 (65%) | 39 (47%)
44 (53%) |
| Gender:
  female
  male
  unspecified | 
54
86
10 | 
43
56
6 | 
22
40
1 | 
35
44
4 |

## AERS Serious AE in Children: Dose and Onset

| Drug | Pseudo-ephedrine
(n=150) | Dextro-
methorphan
(n=105) | Chlorphen-iramine
(n=63) | Diphen-
hydramine
(n=83) |
| --- | --- | --- | --- | --- |
| Single Dose (mg) | 2.25 – 150
median: 15 (n=61) | <1 – 50
median: 5 (n=61) | 0.05 – 12
median: 1
(n=32) | 1 – 100
median: 12.5 (n=28) |
| Time to Onset

 | 1 dose–> 2 wks
median: 1 dose
(n=89) | 1 dose–> 2 wks
median: 1 dose
(n=55) | 1 dose–10 days
median: 1 dose
(n=36) | 1 dose– 2 wks
median: 1 dose
(n=29) |

**Recommended dosage for 2-6 years of age: pseudoephedrine  15 mg q4-6 hours; dextromethorphan 2.5 - 5 mg **
**q4 hours; chlorpheniramine 1 mg q4-6 hours; diphenhydramine 6.25 mg q4-6 hours**

## AERS Serious AE in Children:Product Classification

| Drug | Pseudo-ephedrine
(n=150) | Dextro-
methorphan
(n=105) | Chlorphen-iramine
(n=63) | Diphen-
hydramine
(n=83) |
| --- | --- | --- | --- | --- |
| Product Classification
  OTC
  Rx
  Unknown | 

106
19
25 | 

82
17
6 | 

35
20
8 | 

53
0
30 |
| Product Type
  SI*
  Combo**
  Unknown | 
15
113
22 | 
7
87
11 | 
0
55
8 | 
44
11
28 |

- SI*=single ingredient product, Combo**=combination/multiple ingredient product

## AERS Review of Serious AE: Drug Overdose

| Drug | Pseudo-ephedrine
(n=150) | Dextro-
methorphan
(n=105) | Chlorphen-iramine
(n=63) | Diphen-
hydramine
(n=83) |
| --- | --- | --- | --- | --- |
| Drug Overdose | 74
 (49%) | 41
 (39%) | 31 
(49%) | 46 
(55%) |
| Manner of Overdose:
  Accidental exposure
  Intentional overdose
  Medication error *
  Undetermined | 
32
2
13
27 | 
16
5
11
9 | 
12
5
10
4 | 
26
11
4
5 |

- * Medication errors to include prescribing errors, dispensing errors, administration errors, duplication of therapy, and wrong drug administration.

## AERS Serious AE in Children: By System Organ Class 

| Drug | Pseudo-ephedrine
(n=150) | Dextro-
methorphan
(n=105) | Chlorphen-iramine
(n=63) | Diphen-
hydramine
(n=83) |
| --- | --- | --- | --- | --- |
| Cardiac Disorders | 21 | 10 | 9 | 13 |
| Nervous System Disorders:
  Convulsion
  Depressed LOC | 

24
22 | 

22
24 | 

14
17 | 

7
27 |
| Respiratory Disorders | 14 | 15 | 18 | 20 |

- LOC=level of consciousness, AE=adverse events

## AERS Serious AE in Children:Overdoses vs. Non-Overdoses

- PSE=pseudoephedrine, CPM=chlorpheniramine, DPH=diphenhydramine, DXM=dextromethorphan, LOC=level of consciousness, AE=adverse events

## AERS Serious AE in Children:Children < 2 yrs vs. 2-5 yrs

- PSE=pseudoephedrine, CPM=chlorpheniramine, DPH=diphenhydramine, DXM=dextromethorphan, LOC=level of consciousness, AE=adverse events

## AERS Serious AE in Children:Hallucinations

| Drug | Pseudo-
ephedrine
(n=8) | Dextro-
methorphan 
(n=4) | Chlorphen-
iramine 
(n=3) | Diphen-
hydramine 
(n=9) |
| --- | --- | --- | --- | --- |
| Age
    < 2 | 1 | 1 | 1 | 1 |
| Age
  2 – 5 

≤ Therapeutic Dose 

> Therapeutic Dose  | 
7

5 

2 | 
3

2  

1 | 
2

2

0 | 
8

1 

7 |
| Time to Onset | 1 dose– 2 days
(n=6) | 1 dose–2 days
(n=4) | 1 dose–3 days
(n=3) | 1 dose–1 day 
(n=5) |
| Type of
Hallucination | Visual – 3 
Unknown – 5 | Visual – 2 
Unknown – 2 | Visual – 2 
Unknown – 1 | Visual – 4
Auditory  – 1
Unknown – 4 |

## AERS Serious AE in Children:Hallucinations

**Description of visual hallucinations:**
**“****bubbles” **
**“****snakes and frogs” **
**“****big creature” **
**“****snakes, spiders, and scorpions” **
**“****imaginary things” **
**“****spiders” **
**“****bugs everywhere, balls were coming after her, and raining in her room” **

## AERS Serious AE in Children:Postmortem Blood Levels

| Drug | Pseudo-ephedrine
(n=150) | Dextro-
methorphan
(n=105) | Chlorphen-iramine
(n=63) | Diphen-
hydramine
(n=83) |
| --- | --- | --- | --- | --- |
| Death | 43 | 28 | 20 | 26 |
| Postmortem blood levels

  median | <0.05 – 29.9 mg/L

2.75 mg/L
(n=33) | 9 – 1200 mcg/L

140 mcg/L (n=16) | 0.04 – 0.21 mg/L

0.07 mg/L
(n=6) | 0.07 – >10 mg/L

1.6 mg/L
(n=14) |

- Therapeutic blood concentrations: pseudoephedrine1 <1 mg/L, dextromethorphan2 2.4 – 207 mcg/L, chlorpheniramine1 0.01 – 0.02 mg/L, diphenhydramine1 0.1 – 1 mg/L
- 1Toxic Drug Concentrations. Office of the Chief Medical Examiner. Chapel Hill, NC 27713 Last revision: May 22, 2003.
- 2Gunn VL, et al. Toxicity of Over-the-Counter Cough and Cold Medications. Pediatrics. Sept 2001;108:3.

## Cardiac Case #1

**2 month old, female**
**Infant PediaCare Decongestant and Cough Concentrated Drops, recommended by a pharmacist**
**Indication, PMHx and concomitant meds unknown**
**1 hr after a single dose of 0.4 mL (pseudoephedrine 3.75 mg and dextromethorphan 1.25 mg)**
**heart rate of 240 bpm and was hospitalized**
**AEs resolved within 7 days **

## Cardiac Case #2

**2 week old, male**
**Infant PediaCare Decongestant Concentrated Drops (pseudoephedrine 9.375 mg/mL), recommended by a physician**
**to treat nasal congestion **
**no reported PMHx and no concurrent medications**
**immediately after 1****st**** dose (dose unspecified) **
**cardiac failure & supraventricular tachycardia **
**treated with digoxin and an unspecified medication**
**discharged after 2 weeks with events resolved**

## Convulsion Case

**5 year old, female**
**Triaminic Cough and Sore Throat**
**used for cough **
**1 dose (5 mL) of 15 mg of pseudoephedrine, 5 mg dextromethorphan, and 160 mg acetaminophen**
**seizures (lasted 10 sec) next morning**
**“****all vitals were fine” **
**outcome and interventions unknown **
**At 3 y/o age experienced same event with the same medication **
**on multivitamins**

## AERS Review of Serious AE in Children:Summary

**> 50% of pseudoephedrine and dextromethorphan cases occurred in children < 2 years of age**
**> 50% of chlorpheniramine and diphenhydramine cases occurred in children 2 – 5 years of age**
**Rx and OTC cold/cough products were reported; however, the majority were OTC (56 – 78%)**
**> 75% pseudoephedrine, chlorpheniramine, and dextromethorphan cases involved a multi-ingredient product**

## AERS Review of Serious AE in Children:Summary

**Deaths 30%**
**Overdoses 48%**
**Among all cases:**
**22% accidental exposures**
**6% intentional overdoses**
**9% medication errors**
**11% indeterminable**
**Serious adverse events related to the cardiac, nervous, and respiratory systems have been reported both in the setting of an overdose and outside of an overdose**
**Convulsions: more common outside of an overdose and appear more in children 2 – 5 years of age**
**Cardiac & respiratory events: more common in the setting of an overdose**

## TESS Review

## TESS Review

**TESS - Toxic Exposure Surveillance System is the poisoning surveillance database of the AAPCC**
**Reviewed reports from 2001-2005**
**Cases that listed cough/cold preparations or diphenhydramine**
**Caveat: Underreporting to TESS may be extensive **

## TESS Review – Cough/Cold

**In children < 6 yrs**
**Total # cases increased slightly from 59,949 in 2001 to 70,398 in 2005**
**Overall % of cases involving children **
**   ****< 6 yrs remained constant at about 61-62% in the 5-yr review period**
**For all ages, majority of these cases resulted from unintentional exposures **
**24% were treated in a health care facility**

## TESS Review - Diphenhydramine

**In children < 6 yrs**
**Total # of cases increased very slightly from 13,044 in 2001 to 13,445 in 2005**
**Overall % of cases involving children < 6 yrs remained constant at about 43-46% **
**For all ages, 45-75% of diphenhydramine cases resulted from unintentional exposure**
**42% required treatment in a health care facility**

## TESS Review - Fatalities

**In children < 6 yrs, 14 fatalities were reported in association with cough/cold and diphenhydramine products **
**Age range 2m-5yrs**
**Majority of deaths (N=8) occurred in children 12m or younger**
**Product**
**3 fatalities were noted in association with the use of single ingredient cough/cold or diphenhydramine products**
**11 fatalities noted with combination products or use of multiple products **

## TESS Review - Summary

**Data from poison control centers suggest substantial number of overdose and poisonings in association with cough/cold and diphenhydramine products**
**Both OTC and Rx products involved**
**Children < 6 years old make up 40% to 60% of all poisoning cases in association with cough/cold and diphenhydramine products **

## Overall Summary

**Use of OTC and Rx cough/cold medications in children < 6 years of age have been associated with serious adverse events, including death**
**Drug overdoses commonly contributed to serious adverse events and deaths**
**Manner of overdose was identified as:**
**accidental exposure, intentional overdose, and medication errors**

## Overall Summary

**Most occurred in age groups where there are no dosing recommendations on the OTC product label**
**Most involved multi-ingredient cough/cold products**
**Data from poison control centers suggest substantial number of overdose and poisonings cases reported with cough/cold and diphenhydramine products**

## Points to Consider

**An educational campaign directed towards healthcare providers and parents about the use of cough/cold products**
**The labeling of cough/cold products should include prominent language to describe the risk of overdose in children**
**Label should indicate that cough/cold products are not recommend in children under 2 years of age**
**Consider having only single ingredient cough/cold products for pediatric formulations**

## Acknowledgements

**Mark Avigan, M.D., C.M.**
**Allen Brinker, M.D., M.S.**
**Gerald Dal Pan, M.D., M.H.S**
**Rosemary Johann-Liang, M.D.**
**Lauren Lee, Pharm.D.**
**Ann McMahon, M.D., M.S. **
**Ellis Unger, M.D.**