Transcript Document 7249404

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
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Outline
• Published Clinical Studies in Children
• Adverse Events from Case Reports
• Guidelines/Policy Statements from
Healthcare Professional Organizations
• Overall Summary
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Published
Clinical Studies
in Children
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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
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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)
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*Common Active Ingredients Found in OTC
Cough/Cold Products Used in Children
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Summary of Published Studies in Children
(1951-1984)
Author
Drug Class/Indication
N
Age
Efficacy
(Author)
Fisher
1951-1966
Antihistamine/Common Cold
74
9y-16y
No
McGovern
Antihistamine/Nasal allergy
485 2m-14y
Yes*
Lipschutz Decongestant ± Antihistamine 200 4m-17y
Allergy & non-allergy sx
Combination Product /Cough 64 2m-12y
Reece
(Decong + Antihistamine +
Antitussive)
Yes
Yes
1984
Weipple
Combination Product/
Cough & cold symptoms
56
≥ 4y
Yes*
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*No placebo arm
Summary of Published Studies in Children
(1990-2004)
Author
Drugs/Indication
Sakchainanont
Antihistamines
Rhinorrhea of 3 days
Clemens
N
Age
Efficacy
(Author)
143 1.5m-5y
No
Antihistamine + Decongestant
Common cold
59
No
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
6m - 5y
↑ sleep
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Published Clinical Studies:
Limitations
&
Challenges
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Published Clinical Studies: Limitations
•
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
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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
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Published Clinical Studies: Limitations
(con’t.)
•
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
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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
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Adverse Events
from
Published Case Reports
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Adverse Events from Case Reports:Summary
Author/Year
Cases Reported
Age
1990
1995
1
1
19m
3y
Roberge 1999
Gunn
2001
1
2y
9-36m
Clark
Joseph
3
13 month period
Boland
2003
Marinetti 2005
1
10*
2m
<12m
8 month period
Wingert
2007
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<16m
6 year period
•8 cases had obvious underlying causes of death
e.g. sepsis, compressional asphyxia
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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
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Case Report #1
Gunn (Pediatrics 2001)
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
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Case Report #1 (con’t.)
• T= 39.5C (103.1°F)
P=208
screaming, tachycardic
RR=40
• 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
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Gunn (Pediatrics 2001)
9-month old
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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
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9-month old
Gunn (Pediatrics 2001)
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Case Report #1 (con’t)
Drug Levels in the Blood
Drug
PSE
Blood Concentration
Patient
Postmortem at Therapeutic Doses
10 mg/L
0.18 - 0.5 mg/L
Pseudoephedrine
DM
Dextromethorphan
PPA
600 mcg/L
(0.6 mg/L)
1.4 mg/L
2.4 mcg/L - 207 mcg/L
0.11 - 0.4 mg/L
Phenypropanolamine
Pseudoephedrine is at least 20x higher than expected levels
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9-month old
Gunn, Pediatrics 2001
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Case Report #1(con’t)
• 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
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9-month old
Gunn, Pediatrics 2001
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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
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Case Report #2 (con’t.)
• Cause of death:
Acute multiple drug intoxication
• Toxicology findings (+) in blood:
- pseudoephedrine
- dextromethorphan
- ephedrine
- acetaminophen
- carbinoxamine
- metoclopramide
• Further investigation:
– 3 & 4 y/o siblings routinely given OTC cold meds
for sedation
- siblings (+) dextromethorphan in urine & blood
- siblings removed from home
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5-month old
Marinetti, J Anal Tox 2005
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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
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Case Report #3 (con’t)
• 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
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2-month old
Boland, J Anal Tox 2003
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Case Report #3 (con’t)
Pseudoephedrine = 28x more than level at therapeutic doses.
Brompheniramine = 18x more than level at therapeutic doses.
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2-month old
Boland, J Anal Tox 2003
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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
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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
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Healthcare Professional
Organizations
Guidelines/
Policy Statements
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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
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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.”
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Overall Summary
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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
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Overall Summary: (con’t.)
• There were no serious adverse
events or deaths reported in any of
the Published Clinical Studies
involving children.
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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.
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