Sobre la seguridad de los medicamentos antitusivos y antigripales de venta libre, en Pediatría. Definitivamente, NO deben usarse.

1. http://cpj.sagepub.com/
Clinical Pediatrics
http://cpj.sagepub.com/content/53/4/326
The online version of this article can be found at:
DOI: 10.1177/0009922813507998
2014 53: 326 originally published online 6 November 2013CLIN PEDIATR
Michele Yang and Tsz-Yin So
Revisiting the Safety of Over-the-Counter Cough and Cold Medications in the Pediatric Population
Published by:
http://www.sagepublications.com
can be found at:Clinical PediatricsAdditional services and information for
http://cpj.sagepub.com/cgi/alertsEmail Alerts:
http://cpj.sagepub.com/subscriptionsSubscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
What is This?
- Nov 6, 2013OnlineFirst Version of Record
- Mar 5, 2014Version of Record>>
at FUDAN UNIV LIB on March 18, 2014cpj.sagepub.comDownloaded from at FUDAN UNIV LIB on March 18, 2014cpj.sagepub.comDownloaded from

2. Clinical Pediatrics
2014, Vol. 53(4) 326­–330
© The Author(s) 2013
Reprints and permissions:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0009922813507998
cpj.sagepub.com
Article
Introduction
Cough and cold symptoms represent a significant cause
of morbidity in pediatric patients. With the average child
suffering from 6 to 10 colds per year, with durations of
up to 14 days, it is not surprising that the use of non-
prescription cough and cold medications (CCMs) is
widespread.1
According to a survey investigating the
prevalence and patterns of CCMs use, approximately 1
in 10 US children or just more than 7 million individuals
are exposed to these medications in a given week.2
CCMs typically include antitussive, decongestants,
expectorants, and antihistamines and are often formu-
lated in combinations. Although cough and cold prepa-
rations are regarded generally safe, strong evidence of
efficacy within the pediatric population has not been
demonstrated. Concerns over potential severe toxicities
and deaths associated with CCMs use have prompted
re-evaluations of its role in the management of cough
and cold symptoms in the pediatric population.
Efficacy of Cough and Cold
Medications in the Pediatric
Population
Efficacy within this age-group has historically been
based on extrapolated data involving adult studies.3
These notions of efficacy have largely been challenged
and the limited available data does not support its use
among children. A 2008 Cochrane review of
25 placebo-controlled, randomized trials, 8 of which
involved 616 pediatric patients, assessed the efficacy
of over-the-counter (OTC) products for acute cough.4
The primary outcomes were based on frequency, sever-
ity, amount of sputum, improvement in cough symp-
toms, cough counts, patient questionnaires, and
physical assessments. Significant adverse effects were
measured as secondary outcomes. Within the pediatric
trials, the age ranged from 6 months to 18 years. This
review found 7 trials that showed CCMs to be no more
effective than placebo using the following prepara-
tions: dextromethorphan, dextromethorphan/codeine,
dextromethorphan/salbutamol, brompheniramine/
phenylpropanolamine, bromphineramine/phenyleph-
rine/propanolamine, clemastine, chlorpheniramine, and
diphenhydramine.4
Only 1 trial demonstrated benefits
over placebo using mucolytic letosteine (P < .01). In the
507998CPJXXX10.1177/0009922813507998Clinical PediatricsYang and So
research-article2013
1
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2
Moses H. Cone Memorial Hospital, Greensboro, NC, USA
Corresponding Author:
Tsz-Yin So, Department of Pharmacy, Moses H. Cone Memorial
Hospital, 1200 North Elm Street, Greensboro, NC 27401-1020, USA.
Email: jeremy.so@conehealth.com
Revisiting the Safety of Over-the-Counter
Cough and Cold Medications in the
Pediatric Population
Michele Yang, PharmD Candidate1
and Tsz-Yin So, PharmD, BCPS2
Abstract
Increased reports of serious adverse events in young children have led to numerous investigations of its therapeutic
role in the pediatric population. A review of the literature has shown limited support of its use in young children,
with the majority of randomized controlled trials showing no difference in endpoints when compared to placebo.
Because of the recent recommended changes to pediatric cough and cold medication use, studies have suggested
a decline in ingestion misuses, health care referrals, and reports of adverse events. While these patterns of use
are reassuring, clinicians should continue to educate and provide caregivers guidance in managing cough and cold
symptoms. Although a tremendous improvement in frequency of therapeutic error ingestions in children younger
than 2 years was shown in these studies, the same magnitude of improvement was not seen in children 2 to 12 years.
Therefore, future research is necessary to investigate its role in children younger than 12 years.
Keywords
over-the-counter medications, cough and cold medications, pediatrics, clinical practitioner
at FUDAN UNIV LIB on March 18, 2014cpj.sagepub.comDownloaded from

3. Yang and So 327
trial using brompheniramine/phenylpropanolamine, a
higher proportion of children was reported asleep in the
active treatment group (46.6%) versus placebo (26.5%),
although no statistical significance was demonstrated
(P = .53).4
Because of the unclear outcome measures,
the authors concluded that clinically relevant benefits
could not be determined from these positive results.4
This systematic review confirms the limited available
evidence in supporting the recommendation of using
OTC CCMs in children.
Patterns of Use and Safety
Despite the lack of demonstrated benefit among chil-
dren, CCMs are widely used in children for the treat-
ment of coughs, colds, and allergies. Therefore, it is
necessary to assess the risks posed by this subset of
patients given its limited utility. While the Cochrane
review mentioned earlier reported a low incidence of
side effects in its evaluation of the OTC products, an
important limitation of the randomized controlled trials
evaluated can be attributed to the numbers of patients
enrolled, which were insufficient to detect serious tox-
icities and less common adverse effects.4
CCM misuse
has been linked to respiratory depression, neurological
impairments, cardiovascular instability, and death
occurring most frequently among young children.3
According to a recent study, there are more than 7000
annual pediatric emergency department visits related to
CCMs.5
The predominant age of these patients was 2 to
6 years. Between 2004 and 2005, the Centers for Disease
Control and Prevention reported more than 1500 emer-
gency department cases of children suffering from
adverse effects attributed to CCMs. Severe toxicities
and deaths primarily involved children younger than
2 years.6
In light of these alarming emergency depart-
ment reports, many studies concentrated efforts to eluci-
date patterns of use, frequencies, and key contributing
factors. These studies include a survey conducted from
1999 to 2006 of 4267 children, which found that expo-
sure was highest to decongestants and first-generation
antihistamines.2
The study revealed that 64.2% of the
cough and cold preparations used in these patients con-
tained multiple ingredients. In an evaluation of 189
pediatric fatality cases associated with CCMs, the
majority of cases involved supratherapeutic doses and
children younger than 2 years. Contributing factors were
identified as administration of duplicative active ingre-
dients, failure to use a measuring device, product mis-
identification, multiple caregivers administering CCMs,
and intents to induce sedation.7
Toxicities Related to Cough and
Cold Medications
Modes of toxicities may vary for the different cough
and cold agents. Pseudoephedrine, which stimulates
α-adrenergic receptors on vascular smooth muscles
may present with central nervous system (CNS) stimu-
lation, hypertension, and tachycardia.3
Consequent to
CNS stimulation, extreme agitation, restlessness,
insomnia, and psychosis may be manifested. Serious
complications have been reported with cases of sei-
zures, dysrhythmias, stroke, and cerebral hemorrhage
after pseudoephedrine ingestion.3
Adverse effects due
to antihistamines are characterized by varying degrees
of CNS toxicity and anticholinergic side effects.
Reports of tachycardia, blurred vision, agitation, hyper-
activity, toxic psychoses, and seizures have been
described especially after first-generation antihistamine
use.3
Severe toxicity may manifest in the form of dys-
rhythmias, including torsades de pointes. Toxic side
effects of dextromethorphan, an antitussive, have been
associated with lethargy, stupor, hyperexcitability,
ataxia, and coma.8
While it is difficult to definitively
prove the cause of the observed toxicities, the resolu-
tion of symptoms have often correlated with adverse
effects from the drug and the timing of its metabolism.3
In the analysis of postmortem blood of a 9-month-old
child, who was presumed to have suffered a dysrhyth-
mia prior to death, showed marked levels of pseudo-
ephedrine, dextromethorphan, acetaminophen, and
chlorpheniramine.3
Table 1 lists the common ingredi-
ents in CCMs, their normal pediatric dosages, and
potential side effects and toxicities.
Regulation of Cough and Cold
Medications
In response to these concerns with CCMs use in
young children, the Food and Drug Administration
(FDA) conducted a review of the safety and efficacy
of these drugs. In October 2008, the FDA issued
warning against the use of CCMs in children younger
than 2 years with a final decision pending for children
aged 2 to 11 years.10
The Consumer Healthcare
Products Association, which represents most of the
manufacturers of CCMs, extended the recommenda-
tion that such products should not be used in children
younger than 4 years.11
Many products marketed for
children younger than 2 years were withdrawn from
the market and new labeling changes have reflected
these recommendations.
at FUDAN UNIV LIB on March 18, 2014cpj.sagepub.comDownloaded from

4. 328 Clinical Pediatrics 53(4)
Recent studies evaluating the impact of industry and
FDA initiatives have shown a decline in reports of inges-
tions, health care facility referral, and adverse medical
outcomes in the target population of children younger
than 2 years. A retrospective study of 57 US Poison
Centers assessed data involving ingestions occurring in
children younger than 13 years for exposure reasons of
therapeutic error or unintentional error.12
Therapeutic
errors were defined as a deviation from the proper thera-
peutic regimen involving administration errors, whereas
unintentional errors were exposures due to abuse, envi-
ronmental, occupational, or unknown purposes. The
study showed an overall decline of 33.4% in uninten-
tional ingestions of CCMs (P < .0001) and 46% in thera-
peutic errors (P < .0001) in children younger than 12
years following a year after the highly publicized CCM
labeling changes.12
Additionally, a decline of 59.2% in
health care referral in children younger than 2 years due
to therapeutic errors was also demonstrated in these stud-
ies (P < .0001). In the unintentional ingestions arm, mod-
erate and severe adverse outcomes decreased by 32.4%
in children younger than 2 years and 21.3% in the 2- to
5-year-old group (P < .0001).12
The authors concluded a
need to expand the labeling warnings to all children
younger than 6 years because of the high frequency of
use in this age-group. Another study comparing the pre-
and postwithdrawal period confirmed a statistically sig-
nificant difference in the frequency of therapeutic errors
inchildrenyoungerthan2years(P<.001).13
Furthermore,
the fear that the impact of withdrawing pediatric medica-
tions would increase misuse as a result of caregivers
administering products intended for older children have
not been demonstrated in these studies.12,13
Warnings of CCM use in pediatric patients have also
been issued in other countries. The Medicines and
Healthcare Products Regulatory Agency in the United
Kingdom has advised against the use of CCMs in chil-
dren younger than 6 years, stating that no evidence dem-
onstrate its safe use.14
In addition, the Marketed
Pharmaceuticals and Medical Devices Bureau of Health
Canada mandated that OTC cough and cold products
should not be labeled for use in children younger than
6 years.15
Canadian relabeling of these medications were
also completed in late 2009.
Table 1. Common Active Ingredients in Pediatric Over-the-Counter Cough and Cold Products.9
Active Ingredient Drug Class Usual Pediatric Doses Side Effect and Toxicity
Dextromethorphan Antitussive 2-6 y: 2.5-7.5 mg Q4-8H
7-12 y: 5-10 mg Q4-8H
Confusion, dysarthria, stupor, nystagmus, dystonia,
coma, hallucinations, tachycardia, seizures, respiratory
depression
Guaifenesin Expectorant ≥2 y: 12 mg/kg/day
divided into 6 doses
2-5 y: 50-100 mg Q4H
6-11 y: 100-200 mg Q4H
Nausea, vomiting, diarrhea, abdominal pain, nephrolithiasis
Phenylephrine HCl Decongestant 4-6 y: 2.5 mg Q4H prn
>6-12 y: 5 mg Q4H prn
Hypertension, angina, precordial pain, reflex sever
bradycardia, peripheral vasoconstriction, arrhythmias,
respiratory depression, hallucinations
Pseudoephedrine Decongestant <4 y: 1 mg/kg/dose Q6H
4-5 y: 15 mg Q4-6H
6-12 y: 30 mg Q4-6H
Arrhythmias, palpitations, tachycardia, bradycardia, nausea,
insomnia, dizziness, psychosis, rash, urticaria
Diphenhydramine Antihistamine 2-5 y: 6.25 mg Q4H
6-11 y: 12.5 mg Q4H
Hypertension, tachycardia, chest pain, confusion,
constipation, diarrhea, paresthesia
Loratadine Antihistamine 2-5 y: 5 mg
≥6 y: 10 mg
Hypotension, hypertension, palpitations, tachycardia,
hallucinations
Brompheniramine Antihistamine 2-6 y: 1 mg Q4-6H prn
7-12 y: 2-4 mg Q6-8H prn
Palpitations, paradoxical, anxiety, circulatory collapse, rash,
diplopia
Chlorpheniramine
maleate
Antihistamine 2-5 y: 1 mg Q4-6H
6-11 y: 2 mg Q4-6H
Hypotension, tachycardia, palpitations, sedations, confusion,
depression, hemolytic anemia, nausea, diarrhea,
constipation
Clemastine Antihistamine <6 y: 0.335-0.67 mg/day
divided into 2 doses
6-12 y: 0.67-1.34 mg BID
Sedation, dizziness, disturbed coordination, epigastric
distress, difficult urination, hemolytic anemia, wheezing
Abbreviations: Q4-8H, every 4 to 8 hours; Q4H, every 4 hours; Q6H, every 6 hours; Q4-6H every 4 to 6 hours; prn, pro re nata (as needed).
at FUDAN UNIV LIB on March 18, 2014cpj.sagepub.comDownloaded from

5. Yang and So 329
Clinical Practitioner’s Role
Nonpharmacologic supportive care is the mainstay of
managing cough and cold symptoms in pediatric
patients. Clinicians should aim efforts at educating care-
givers regarding the safe use of CCMs in order to reduce
inappropriate exposure and minimize risks to targeted
children. Clinicians play an integral role in ensuring the
continuum of care by identifying the appropriateness of
self-care and when referral to primary care provider is
necessary. When the use of OTC cough and cold prepa-
rations is deemed appropriate, clinicians should ensure
dosing instructions of the specific recommended prod-
uct are given in milliliters with a measuring device. In
addition, clinicians should remind caregivers to always
check drug labels to confirm that duplicative active
ingredients are not mistakenly administered. It is also
important to educate caregivers the self-limiting nature
of the common cold disease. CCMs only treat symp-
toms, do not shorten the illness’ length of time, and
importantly, are not benign when used inappropriately.
The removal of dosing recommendations on CCM
labels for young children has been speculated to possibly
increase caregivers to seek assistance in choosing appro-
priate therapy.16
This would create an opportunity for
clinicians to ensure safe use of CCMs and minimize the
use of unnecessary products for the child. A survey
assessing pharmacists’ attitudes toward pediatric cough
and cold products showed that a majority of pharmacists
felt comfortable recommending CCMs.17
Additionally,
most pharmacists endorsed placing pediatric CCMs
behind the counter in order to encourage caretakers to
seek professional advice.
Conclusions
Although the absolute magnitude of risk may be small,
the important clinical question is whether any serious
risk is justified in light of its limited efficacy within the
pediatric population. It has become increasingly diffi-
cult for clinicians to provide pharmacologic options to
pediatric patients as a result of the recent recommenda-
tion changes. CCMs should not be recommended in
children younger than 2 years and continued research is
necessary to investigate its role in children younger than
12 years. When CCM use is identified as appropriate,
clinicians should follow current recommendations and
monitor patients closely.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
References
1. Pappas DE, Hayden GF, Hendley JO. Treating colds:
keep it simple. Contemp Pediatr. 1999;16:108-118.
2. VernacchioL,KellyJP,KaurmanDW,MitchellAA.Cough
and cold medication use by US children, 1999-2006: results
from the Slone survey. Pediatrics. 2008;122:e323-e329.
3. Gunn VL, Taha SH, Liebelt EL, Serwint JR. Toxicity of
over-the-counter cough and cold medications. Pediatrics.
2001;108:e52.
4. Smith SM, Schroeder K, Fahey T. Over-the-counter
medications for acute cough in children and adults in
ambulatory settings. Cochrane Database Syst Rev.
2008;(1):CD001831.
5. Schaefer MK, Shehab N, Cohen AL, Budnitz DS. Adverse
events from cough and cold medications in children.
Pediatrics. 2008;121:783-787.
6. Centers for Disease Control and Prevention. Infant deaths
associated with cough and cold medications—two states,
2005. MMWR Morbid Mortal Wkly Rep. 2007;56:1-4.
7. Dart RC, Paul IM, Bond GR, et al. Pediatric fatali-
ties associated with over the counter (nonprescription)
cough and cold medications. Ann Emerg Med. 2009;53:
411-417.
8. Pender ES, Parks BR. Toxicity with dextromethorphan con-
taining preparations: A literature review and report of two
additional cases. Pediatr Emerg Care. 1991;7:163-165.
9. Lexi-Comp Online, Pediatric & Neonatal Lexi-Drugs
Online. Hudson, OH: Lexi-Comp. http://webstore.lexi.
com/Pediatric-Lexi-Drugs-Lexi-Interact. Accessed July
21, 2013.
10. US Food and Drug Administration. News & Events. FDA
releases recommendations regarding use of over-the-
counter cough and cold products. Products should not be
used in children under 2 years of age; evaluation continues
in older populations. http://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/2008/ucm116839.htm.
Accessed July 11, 2013.
11. US Food and Drug Administration. Using over-the-
counter cough and cold products in children. October 22,
2012. http://www.fda.gov/downloads/ForConsumers/
ConsumerUpdates/ucm048524.pdf. Accessed July 11, 2013.
12. Mazer-Amirshahi M, Reid N, van Den Anker J,
Litovitz T. Effect of cough and cold medication restric-
tion and label changes on pediatric ingestions reported to
United States Poison Centers [published online June 12,
2013]. J Pediatr. doi: 10.1016/j.jpeds.2013.04.054.
13. Klein-Schwartz W, Sorkin JD, Doyon S. Impact of the
voluntary withdrawal of over-the-counter cough and cold
medications on pediatric ingestions reported to poison
centers. Pharmacoepidemiol Drug Saf. 2010;19:819-824.
14. Medicines and Healthcare Products Regulatory Agency.
Children’s over-the-counter cough and cold medicines:
new advice. November 10, 2010. http://www.mhra.gov.
at FUDAN UNIV LIB on March 18, 2014cpj.sagepub.comDownloaded from

6. 330 Clinical Pediatrics 53(4)
uk/Safetyinformation/Safetywarningsalertsandrecalls/
Safetywarningsandmessagesformedicines/CON038908.
Accessed July 16, 2013.
15. Health Canada. Drug and health products: cough and cold
medicine for children. December 11, 2008. http://www.
hc-sc.gc.ca/dhp-mps/medeff/res/cough-toux-video-eng.
php. Accessed July 18, 2013.
16. Condren M. Safe use of over-the-counter cough and
cold products. J Pediatr Pharmacol Ther. 2009;14:
124-126.
17. Huston SA, Porter KB, Clements T, Shepherd G.
Pharmacists’ attitudes towards pediatric cough and
cold products and behind the counter status. J Pediatr
Pharmacol Ther. 2010;15:126-137.
at FUDAN UNIV LIB on March 18, 2014cpj.sagepub.comDownloaded from