1. 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 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 Center for Drug Evaluation and Research

2. Joint Advisory Committee Meeting 2 Literature Review: Safety & Efficacy of OTC Cough & Cold Drug Products in Pediatric Patients Safety & Efficacy of OTC Cough & Cold Drug Products in Pediatric Patients

3. Joint Advisory Committee Meeting 3 OutlineOutline Published Clinical Studies in Children Adverse Events from Case Reports Guidelines/Policy Statements from Healthcare Professional Organizations Overall Summary Published Clinical Studies in Children Adverse Events from Case Reports Guidelines/Policy Statements from Healthcare Professional Organizations Overall Summary

4. Joint Advisory Committee Meeting 4 Published Clinical Studies in Children Published Clinical Studies in Children

5. Joint Advisory Committee Meeting 5 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 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

6. Joint Advisory Committee Meeting 6 Published Studies in Children: Active Ingredients Included in the Studies Antihistamine – brompheniramine maleate* – chlorpheniramine maleate* – diphenhydramine* – clemastine fumarate – tripelennamine – azatadine maleate – pheniramine maleate – pyrilamine maleate – triprolidine Antitussive –dextromethorphan* –diphenhydramine* Nasal Decongestant –pseudoephedrine* –phenylephrine* Expectorant –guaifenesin* (glyceryl guaicolate) Antihistamine – brompheniramine maleate* – chlorpheniramine maleate* – diphenhydramine* – clemastine fumarate – tripelennamine – 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

7. Joint Advisory Committee Meeting 7 Summary of Published Studies in Children (1951-1984) AuthorDrug Class/IndicationNAgeEfficacy (Author) 1951-1966 Fisher Antihistamine/Common Cold 749y-16yNo McGovern Antihistamine/Nasal allergy 4852m-14yYes* Lipschutz Decongestant ± Antihistamine Allergy & non-allergy sx 2004m-17yYes Reece Combination Product /Cough (Decong + Antihistamine + Antitussive) 642m-12yYes 1984 WeippleCombination Product/ Cough & cold symptoms 56≥ 4yYes* *No placebo arm

8. Joint Advisory Committee Meeting 8 990-2004) Summary of Published Studies in Children (1990-2004) AuthorDrugs/IndicationNAgeEfficacy (Author) Sakchai- nanont Antihistamines Rhinorrhea of 3 days 1431.5m-5yNo ClemensAntihistamine + Decongestant Common cold 596m - 5yNo ↑ sleep KorrpiAntitussive Resp infection w/cough 751y-10yNo TaylorAntitussive + Mucolytic/Cough4918m-12yNo PaulAntitussive Nocturnal cough & sleep 1002y-18yNo HuttonCombination Product Common cold 966m - 5yNo

9. Joint Advisory Committee Meeting 9 Limitations & Challenges Limitations & Challenges Published Clinical Studies:

10. Joint Advisory Committee Meeting 10 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 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 Published Clinical Studies: Limitations

11. Joint Advisory Committee Meeting 11 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 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

12. Joint Advisory Committee Meeting 12 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 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 Studies: Limitations (con’t.) Published Clinical Studies: Limitations (con’t.)

13. Joint Advisory Committee Meeting 13 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 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

14. Joint Advisory Committee Meeting 14 Adverse Events from Published Case Reports Adverse Events from Published Case Reports

15. Joint Advisory Committee Meeting 15 Adverse Events from Case Reports:Summary Author/YearCases ReportedAge Clark 1990119m Joseph 199513y Roberge 1999 1 2y Gunn 2001 3 13 month period 9-36m Boland 200312m Marinetti 200510* 8 month period <12m Wingert 2007 15 6 year period <16m 8 cases had obvious underlying causes of death e.g. sepsis, compressional asphyxia

16. Joint Advisory Committee Meeting 16 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 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

17. Joint Advisory Committee Meeting 17 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 ¾ dropper No mention of other meds in the history 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 ¾ dropper No mention of other meds in the history Case Report #1 Gunn (Pediatrics 2001)

18. Joint Advisory Committee Meeting 18 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 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 Gunn (Pediatrics 2001) 9-month old Case Report #1 (con’t.)

19. Joint Advisory Committee Meeting 19 12 hrs later - in cardiopulmonary arrest ER: pronounced dead Autopsy: no gross abnormality Postmortem urine toxicology testing (+) for: –acetaminophen –pseudoephedrine –chlorpheniramine –dextromethorphan –phenylpropanolamine 12 hrs later - in cardiopulmonary arrest 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)

20. Joint Advisory Committee Meeting 20 Case Report #1 (con’t) Drug Levels in the Blood DrugPatient Postmortem Blood Concentration at Therapeutic Doses PSE Pseudoephedrine 10 mg/L0.18 - 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/L0.11 - 0.4 mg/L 9-month old Gunn, Pediatrics 2001 Pseudoephedrine is at least 20x higher than expected levels

21. Joint Advisory Committee Meeting 21 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 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 9-month old 9-month old Gunn, Pediatrics 2001 Case Report #1 (con’t)

22. Joint Advisory Committee Meeting 22 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 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

23. Joint Advisory Committee Meeting 23 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 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 5-month old Marinetti, J Anal Tox 2005 Case Report #2 (con’t.)

24. Joint Advisory Committee Meeting 24 Case Report #3 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 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

25. Joint Advisory Committee Meeting 25 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 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 2-month old 2-month old Boland, J Anal Tox 2003 Case Report #3 (con’t)

26. Joint Advisory Committee Meeting 26 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)

27. Joint Advisory Committee Meeting 27 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 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

28. Joint Advisory Committee Meeting 28 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 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

29. Joint Advisory Committee Meeting 29 Healthcare Professional Organizations Guidelines/ Policy Statements

30. Joint Advisory Committee Meeting 30 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 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

31. Joint Advisory Committee Meeting 31 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.” 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.”

32. Joint Advisory Committee Meeting 32 Overall Summary

33. Joint Advisory Committee Meeting 33 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 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

34. Joint Advisory Committee Meeting 34 Overall Summary: (con’t.) There were no serious adverse events or deaths reported in any of the Published Clinical Studies involving children.

35. Joint Advisory Committee Meeting 35 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. 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.