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 DOI: 10.1177/0009922813507998

2014 53: 326 originally published online 6 November 2013CLIN PEDIATRMichele Yang and Tsz-Yin So

Revisiting the Safety of Over-the-Counter Cough and Cold Medications in the Pediatric Population  

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Clinical Pediatrics2014, Vol. 53(4) 326 –330© The Author(s) 2013Reprints and permissions: sagepub.com/journalsPermissions.navDOI: 10.1177/0009922813507998cpj.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

507998 CPJXXX10.1177/0009922813507998Clinical PediatricsYang and Soresearch-article2013

1University of North Carolina at Chapel Hill, Chapel Hill, NC, USA2Moses 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

AbstractIncreased 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.

Keywordsover-the-counter medications, cough and cold medications, pediatrics, clinical practitioner

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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.

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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 in children younger than 2 years (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 Q4-8H7-12 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 Q4H6-11 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 Q6H4-5 y: 15 mg Q4-6H6-12 y: 30 mg Q4-6H

Arrhythmias, palpitations, tachycardia, bradycardia, nausea, insomnia, dizziness, psychosis, rash, urticaria

Diphenhydramine Antihistamine 2-5 y: 6.25 mg Q4H6-11 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 prn7-12 y: 2-4 mg Q6-8H prn

Palpitations, paradoxical, anxiety, circulatory collapse, rash, diplopia

Chlorpheniramine maleate

Antihistamine 2-5 y: 1 mg Q4-6H6-11 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).

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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.

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