1. 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 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

2. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 2 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 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.

3. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 3ObjectivesObjectives 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 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

4. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 4 ObjectivesObjectives 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 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

5. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 5 Voluntary, “spontaneous” reporting Facilitated by the FDA MedWatch Program Reports stored and retrieved via Adverse Event Reporting System (AERS) database Voluntary, “spontaneous” reporting Facilitated by the FDA MedWatch Program Reports stored and retrieved via Adverse Event Reporting System (AERS) database AERS: Spontaneous AE Reporting

6. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 6 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 Includes all U.S. marketed products Detection of events not seen in clinical trials Especially good for events with rare background rate, short latency

7. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 7 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 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

8. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 8 AERS Review of Pediatric Deaths

9. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 9 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: 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: 1.pseudoephedrine 2.phenylephrine 3.ephedrine Decongestants: 1.pseudoephedrine 2.phenylephrine 3.ephedrine Antihistamines: 1.diphenhydramine 2.brompheniramine 3.chlorpheniramine Antihistamines: 1.diphenhydramine 2.brompheniramine 3.chlorpheniramine

10. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 10 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 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

11. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 11 AERS Review of Pediatric Deaths DrugPseudoephedrine (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)

12. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 12 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 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

13. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 13 AERS Review of Pediatric Deaths DrugDiphenhydramine (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)

14. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 14 AERS Review of Serious* Adverse Events in Children * Serious per regulatory definition includes death, hospitalization, life-threatening, disability, congenital anomaly, requiring intervention, and other.

15. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 15 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 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

16. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 16 AERS Serious AE in Children: Demographics DrugPseudo- 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

17. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 17 AERS Serious AE in Children: Dose and Onset DrugPseudo- 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 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

18. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 18 AERS Serious AE in Children: Product Classification DrugPseudo- 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

19. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 19 AERS Review of Serious AE: Drug Overdose DrugPseudo- ephedrine (n=150) Dextro- methorphan (n=105) Chlorphen- iramine (n=63) Diphen- hydramine (n=83) Drug Overdose74 (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.

20. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 20 AERS Serious AE in Children: By System Organ Class DrugPseudo- ephedrine (n=150) Dextro- methorphan (n=105) Chlorphen- iramine (n=63) Diphen- hydramine (n=83) Cardiac Disorders2110913 Nervous System Disorders: Convulsion Depressed LOC 24 22 24 14 17 7 27 Respiratory Disorders 14151820 LOC=level of consciousness, AE=adverse events

21. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 21 AERS Serious AE in Children: Overdoses vs. Non-Overdoses PSE=pseudoephedrine, CPM=chlorpheniramine, DPH=diphenhydramine, DXM=dextromethorphan, LOC=level of consciousness, AE=adverse events

22. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 22 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

23. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 23 AERS Serious AE in Children: Hallucinations DrugPseudo- ephedrine (n=8) Dextro- methorphan (n=4) Chlorphen- iramine (n=3) Diphen- hydramine (n=9) Age < 2 1111 Age 2 – 5 ≤ Therapeutic Dose > Therapeutic Dose 752752 321321 220220 817817 Time to Onset1 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

24. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 24 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” 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”

25. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 25 AERS Serious AE in Children: Postmortem Blood Levels DrugPseudo- ephedrine (n=150) Dextro- methorphan (n=105) Chlorphen- iramine (n=63) Diphen- hydramine (n=83) Death43282026 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: pseudoephedrine 1 <1 mg/L, dextromethorphan 2 2.4 – 207 mcg/L, chlorpheniramine 1 0.01 – 0.02 mg/L, diphenhydramine 1 0.1 – 1 mg/L 1 Toxic Drug Concentrations. Office of the Chief Medical Examiner. Chapel Hill, NC 27713 Last revision: May 22, 2003. 2 Gunn VL, et al. Toxicity of Over-the-Counter Cough and Cold Medications. Pediatrics. Sept 2001;108:3.

26. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 26 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 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

27. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 27 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 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

28. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 28 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 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

29. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 29 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 > 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

30. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 30 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 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

31. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 31 TESS Review

32. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 32 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 - 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

33. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 33 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 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

34. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 34 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 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

35. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 35 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 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

36. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 36 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 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

37. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 37 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 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

38. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 38 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 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

39. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 39 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 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

40. Joint meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee October 18 & 19, 2007 40 AcknowledgementsAcknowledgements 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. 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.