- *Section of Clinical Toxicology, Division of Clinical Pharmacology, Toxicology and Therapeutic Innovations, Children’s Mercy Hospital, Department of Pediatrics, University of Missouri – School of Medicine, Kansas City, MO.
- †Pediatric Clinical Pharmacology, Division of Clinical Pharmacology, Toxicology and Therapeutic Innovations, Children’s Mercy Hospital, Departments of Pediatrics and Pharmacology, University of Missouri-Kansas City, Kansas City, MO.
Drs Lowry and Leeder have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.
Although there are benefits to the availability of over-the-counter products (eg, rapid access to effective medications, decreased utilization of the health care system, and patient autonomy), there also are risks to their use that clinicians should know and discuss with their patients and families. These include delay in seeking advice from a health care professional, increased drug-drug interactions, potential for misuse and abuse, and increased adverse effects when not used properly.
After completing this article, readers should be able to:
Recognize that over-the-counter (OTC) cough and cold preparations have not been adequately studied in children younger than 6 years of age and that they are not recommended for treating the common cold.
Recognize the systemic effects of oral decongestants and antihistamines in infants and young children.
Recognize the signs and symptoms of acetaminophen and aspirin toxicity and know the management of overdose of these agents.
Be aware of potentially harmful additives in OTC medications.
Over-the-counter (OTC) medications are widely marketed and frequently used to treat most health problems in adults and children. The use of symptomatic treatments, such as OTC medications for the common cold, is controversial. Children often receive analgesics, decongestants, antihistamines, expectorants, and cough suppressants during the course of their illnesses. However, these OTC products have not been proven to be safe and effective in young children. In addition, their common use puts children at risk for poisonings. Published data show no efficacy (no benefit) of OTC cough and cold preparations when compared to placebo for most ingredients in these products. After much review, the U.S. Food and Drug Administration (FDA) and the Consumer Healthcare Products Association issued a warning against the use of OTC cough and cold products in children younger than 4 years of age. This has led to decreased unintentional ingestions reported to U.S. Poison Control Centers. Nonetheless, unintentional effects can occur, and pediatricians should understand the signs and symptoms of these adverse reactions and overdoses of medications and additives.
The Common Cold
The common cold (or inflammation of the nasal passages) is a frequent manifestation of upper respiratory tract infections caused by respiratory viruses. Most of these viruses are rhinoviruses, but infection with other viruses (eg, coronavirus, respiratory syncytial virus, influenza virus, parainfluenza virus, and adenovirus) can result in similar symptoms. However, determining the virus responsible for the cold is unnecessary because a “tincture of time” results in infection resolution. Colds occur year-round, with most seen between September and May. Younger children have an average of six to eight colds annually, which decrease in number as children age and exposures to the viruses decrease. Viruses spread by aerosolization and direct contact.
The onset of symptoms usually occurs within 1 to 3 days of contact with the virus. Often, the first symptom is a sore or scratchy throat, followed by nasal congestion and rhinorrhea. By the third day of the symptoms, nasal congestion dominates. Cough may be associated with approximately 30% of common cold symptoms. Depending on the virus, fever may be present. Symptoms usually persist for 7 to 10 days; a few may last up to 2 weeks.
Management of the common cold is primarily symptomatic and supportive. Antiviral therapy is approved for respiratory syncytial virus and influenza. Antimicrobial therapy is not effective in treating viral illnesses. The use of symptomatic treatments is controversial. Efficacy may be established in adults, but this is not the case in children. However, because caregivers feel that doing something is better than doing nothing, children often receive antipyretics, analgesics, decongestants, antihistamines, expectorants, and cough suppressants during the course of the illness. For example, parents frequently treat a fever rather than focusing on a child’s symptoms. Fever is a natural response to inflammation and infection but does not need to be treated unless the child appears ill. Many OTC products have not been proven to be safe and effective in young children. Further, their common use puts children at risk for poisonings because children act fast when their parents’ backs are turned.
Published data show no efficacy (no benefit) of OTC cough and cold preparations when compared to placebo in children for brompheniramine, diphenhydramine, chlorpheniramine, guaifenesin, clemastine, phenylephrine, codeine, phenylpropanolamine, dextromethorphan, or salbutamol (oral). (1) Only one study in children found benefit from pseudoephedrine administration, but placebo controls were not included.
A prospective randomized, double-blind, placebo-controlled trial (n=59; ages 6 months to 6 years) assessed common cold symptoms after receiving a combination product (brompheniramine and phenylephrine) at “standard” doses and placebo. (2) Using a seven-point Likert scale, patients/parents were asked to assess symptoms of runny nose, nasal congestion, cough, and sleep. No statistical difference was seen in symptoms except for higher sleep scale scores with the combination drug product. These findings are similar to other previously reported studies.
The efficacies of dextromethorphan and diphenhydramine were assessed in a single-dose night-time study (n=100; ages 2 to 16.5 years) in which patients received a fixed dose per age. (3) Using a seven-point Likert scale, no statistically significant differences were seen in symptoms assessed (cough frequency, cough severity, child or parental sleep).
A 2008 Cochrane review of 25 placebo-controlled, randomized trials assessed the efficacy of OTC products for the symptomatic treatment of cough. (4) Frequency, severity, amount of sputum, improvement in cough symptoms, patient questionnaires, and physical examination changes were assessed. Adverse effects were noted as a secondary outcome. Seven trials within the review found cough and cold medications (dextromethorphan, dextromethorphan/codeine, dextromethorphan/salbutamol, brompheniramine/phenylpropanolamine, brompheniramine/ phenylephrine/propanolamine, clemastine, chlorpheniramine, and diphenhydramine) had no more efficacy than placebo. One trial of letosteine (a mucolytic) demonstrated benefit compared to placebo (P < 0.01). Given the unclear outcomes and limited evidence, the review concluded that there was no support for the use of OTC cough and cold medications for cough in children.
The Durham Humphrey Amendment of 1951 authorized the FDA to classify certain drugs as available by prescription only. OTC drugs refer to “nonprescription” drugs or those that do not require a prescription. Marketing of OTC drugs is regulated by the Office of Nonprescription Products (ONP) in the Center for Drug Evaluation and Review at the FDA., When the FDA developed a comprehensive review of OTC products, the OTC Drug Review, in 1972, an estimated 100,000 to 500,000 OTC drug products containing approximately 200 OTC active ingredients and approximately 26 OTC drug categories were being marketed.
The OTC Drug Review led to an OTC Monograph three-step rulemaking process. The first step was an Advance Notice of Proposed Rulemaking (ANPR), followed by a Tentative Final Monograph, and finally publication of the Final Monograph. The ANPR to establish a monograph for OTC cough, cold, allergy, bronchodilator, and antiasthmatic drug products along with recommendations of the advisory panel established to evaluate the products were published in the Federal Register of September 9, 1976 (41 FR 38312). Final rules for each type of product were published over a 10-year period between November 1985 (anticholinergics) and August 1994 (nasal decongestants). The advisory panel recommended against marketing of cough and cold preparations to children younger than 2 years of age due to negligible or nonexistent pediatric data and extrapolation of doses from adults to older children.
Final rules for antitussives, expectorants, and antihistamines were published on August 12, 1987 (52 FR 30042), February 28, 1989 (54 FR 8494), and December 9, 1992 (57 FR 58356), respectively, but the suitability of the marketed products for pediatric use was not revisited until a Citizen's Petition was filed by Joshua Sharfstein, then Commissioner of Health for Baltimore, and 15 other petitioners on March 1, 2007. Major manufacturers of OTC cough and cold products voluntarily recalled preparations for children younger than 2 years of age 10 days before a joint meeting of the Pediatric Committee and the Nonprescription Drug Advisory Committee (October 18–19, 2007) at which committee members concluded that there was no evidence that OTC medications eased cold symptoms in children younger than 12 years of age. A public hearing was held on October 2, 2008, with presentations by representatives from academia, industry, and regulatory agencies. On October 7, 2008, the Consumer Healthcare Products Association, a trade group for OTC manufacturers, announced that its members would be adding a warning against the use of OTC cough and cold products in children younger than age 4 years on product labels. This was followed the next day by a statement from the FDA supporting the industry's voluntary effort.
These changes have led to a decrease in unintentional ingestions reported to U.S. Poison Control Centers. A retrospective review of pre- and postintervention periods documented a significant decline in unintentional ingestions, therapeutic errors, health care facility referrals, and serious medical outcomes in children younger than 2 years of age. (5) Additionally, ingestions in 2- to 5-year-old children declined (Table 1).
Common Ingredients and Formulations
The ONP regulates the marketing of OTC medications. For products to be considered OTC, they must be regulated under a New Drug Application or the OTC drug monograph process (http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm106368.htm), which provides marketing regulations and mandates that the drug is “generally recognized as safe and effective” (GRASE). Under GRASE conditions, the product must list active ingredients, including dosage strength and form. Additional labeling requirements include the drug’s indications, warnings, and directions. At times, final formulation testing is required.
The active ingredients targeted by these recommendations and labeling changes are decongestants, antitussives, expectorants, and antihistamines. Many OTC cough and cold products contain more than one of these ingredients, and similar brand names may contain varying numbers and types of active ingredients. Similarly, products with different brand names may contain the same ingredients. Common generic active ingredients are listed in Table 2.
The ideal drug should be effective, well-tolerated, stable, affordable, and (especially for children) palatable. Accordingly, in addition to active ingredients, excipients are added to OTC medications to help with formulation and palatability. These may include bulk fillers, sweeteners and flavoring agents, coloring agents, preservatives, surfactants, thickeners or suspending agents, or other miscellaneous products such as antioxidants and lubricants.
Not all excipients are inert substances; some have been shown to be potential toxicants. The Federal Food, Drug, and Cosmetic Act of 1938 was enacted after the tragedy of sulfanilamide elixir in 1937 in which an untested excipient (diethylene glycol) was responsible for the deaths of many children who consumed the pharmaceutical. The Act required manufacturers to perform safety testing of pharmaceuticals. Since that time, the FDA has become aware that certain other excipients can cause serious toxicities in OTC drug products.
Products under the OTC drug monographs (21 CFR 330.1(e)) are required to contain “only suitable inactive ingredients which are safe in the amounts administered and do not interfere with the effectiveness of the preparation or with suitable tests or assays to determine if the product meets its professed standards of identity, strength, quality, and purity. Color additives may be used only in accordance with section 721 of the act and subchapter A.” However, these regulations do not account for hypersensitivity reactions to the excipients or the harm that can occur in overdoses (eg, ethanol in mouthwash).
One of the principal determinants of oral drug administration in children is the ability to actually get the drug into the body. Medications are often rejected by children because of poor taste and texture. This is a significant issue, especially when considering that taste sensation differs as a consequence of development and on an interindividual basis. Solid formulations such as tablets and capsules are not easily administered to most infants and children because of their inability to swallow them easily and safely. Finally, solid formulations limit the ability for dose titration and dosing flexibility.
With regard to dosing accuracy with oral formulations, liquids (eg, drops, solutions, syrups, suspensions, elixirs) are preferred for infants and young children. The utility of these formulations is often limited by palatability when the taste of the active ingredient(s) cannot be masked effectively. In the case of suspension formulations, improper reconstitution or resuspension before dose administration can introduce problems related to dosing accuracy. Other potential limitations of liquid drug formulations (including those that may be extemporaneously compounded by the pharmacist from drug powder or from solid dosage forms of a given drug) are related to possible problems related to drug stability, contamination (chemical or bacterial), portability, and the need for refrigeration of some products to ensure drug stability.
Administration of liquid medications can be associated with risk if the administration device is not appropriate (eg, use of a kitchen teaspoon or dosing cup rather than a 5.0-mL dosing spoon) or the dose for the patient’s age or weight is inappropriate. The low cost and convenience of oral syringes has prompted many physicians and pharmacists to dispense them with liquid medications. However, these are not available with OTC medications, and often parents rely on the dosage cup that accompanies the liquid medication, resulting in inaccurate dosing.
Adverse Reactions and Toxicity
Diphenhydramine and other first-generation antihistamines (eg, chlorpheniramine, doxylamine, brompheniramine) antagonize histamine-induced responses at histamine-1 receptors. They are commonly used in the management of allergic disorders, motion sickness, vertigo, pruritus associated with skin disorders, and nausea as well as for sedation. They can prevent, but not reverse, histamine peripheral effects, such as urticaria, pruritus, and wheal-and-flare responses. Overdose of these medications is common.
The typical therapeutic dose of a sedating antihistamine may produce adverse effects in a susceptible individual and can cause delirium during topical or oral therapy. The acute toxicity of oral antihistamines is dose-dependent. Mild symptoms (somnolence, anticholinergic signs, tachycardia, nausea, vomiting) occur in 60% of patients. These are usually seen at doses less than 300 mg for diphenhydramine. Moderate symptoms (isolated and spontaneously resolving agitation, confusion, hallucinations, and electrocardiographic [ECG] disturbances) develop in 25% of patients, usually at doses between 300 and 1000 mg. Severe symptoms (delirium, psychosis, seizures, and coma) occur with larger doses (generally > 1 g ingested).
Most serum concentrations of oral antihistamines peak in 1 in 4 hours, but the peak may be prolonged in overdoses because the anticholinergic effects can decrease gastrointestinal (GI) motility and prolong the absorption phase. Antihistamines are metabolized by the liver with extensive first-pass metabolism. The half-life in therapeutic doses is 2.4 to9.3 hours, which may be prolonged in overdoses.
Neither diagnostic tests specific to determining the ingestion of antihistamines nor specific drug measurements are readily available. Two types of urine drug screens can be used to detect the presence of antihistamines: immunoassay and gas chromatography-mass spectrometry (GC-MS). Immunoassays, which use antibodies to detect the presence of specific drugs or metabolites, are the most commonly used initial screening processes. Advantages of immunoassays include large-scale screening through automation and rapid detection. The primary disadvantage is the potential for false-positive results when detection of a drug in the same class requires a second test for confirmation. Results of immunoassays are always considered presumptive until confirmed by a laboratory-based test for the specific drug (eg, GC-MS or high-performance liquid chromatography). Tricyclic antidepressants (TCAs) are commonly found as a false-positive result on immunoassay.
Most patients experiencing antihistamine overdose only require symptomatic and supportive care. Treatment focuses on controlling agitation, maintaining the airway, reversing hyperthermia, and supporting hemodynamic function. GI decontamination is not essential, but if it is used, it should be undertaken within 1 to 2 hours of the ingestion. In view of the potential cardiac toxicity, observation for dysrhythmias is warranted. Agitation and hallucinations are typically treated with a benzodiazepine or antipsychotic medication. Fluids followed by vasopressors can be used to treat hypotension, but hypertension is more typical. If hypertension occurs, benzodiazepines (to control agitation) or antihypertensives may be indicated. The addition of sodium bicarbonate to the treatment may be indicated because, as with TCA overdoses, the QRS can be prolonged and place the patient at risk for serious dysrhythmias. Hemoperfusion and hemodialysis are of limited use.
Physostigmine is indicated in the presence of peripheral or central anticholinergic manifestations without evidence of significant QRS or QT prolongation. This approach is controversial because of documented adverse events with physostigmine use in patients who have ingested TCAs. In those patients, physostigmine may augment vagal effects, contributing to decreased cardiac output and conduction defects. However, in cases of pure anticholinergic overdose, physostigmine is clearly beneficial. A shorter time to recovery following agitation has been seen in patients receiving the antidote. The dose is 1 to 2 mg in adults and 0.02 mg/kg (maximum, 0.5 mg) in children administered intravenously over at least 5 minutes. The onset of action is within minutes. The dose can be repeated after 10 to 15 minutes if an adequate response is not achieved and muscarinic (eg, salivation, lacrimation, vomiting, sweating) effects are not noted. The onset of action is up to 1 hour and repeat doses may be needed. However, care must be exercised to avoid cholinergic symptoms.
Nonsedating (second-generation) antihistamines (eg, loratadine, desloratadine, cetirizine) are long-acting selective histamine-1-receptor antagonists used in the treatment of allergic rhinitis. Somnolence, tachycardia, and headache have been reported in adult overdoses (range, 40 to 180 mg). Sinus tachycardia (150 beats/min) and respiratory alkalosis were reported in an adult following an ingestion of 300 mg, but the patient recovered completely. Extrapyramidal signs and palpitations have been reported in children following doses of greater than 10 mg. A 6-year-old child who ingested 300 mg of loratadine developed mild elevations in heart rate and blood pressure with no permanent sequelae. Sinus tachycardia has been reported in overdoses with minimal hemodynamic instability. Dysrhythmias are a rare event.
The time to peak concentration is approximately 2 hours following a single dose of the once-daily and twice-daily combination tablet formulation. Loratadine is 97% protein bound; cetirizine has minimal protein binding. Cetirizine is minimally metabolized, and loratadine is extensively metabolized in the liver. Evidence suggests that loratadine is preferentially metabolized by the cytochrome P450 isoenzyme CYP3A4 to its active metabolite. It can also be metabolized by CYP2D6 in the presence of inhibitors of CYP3A4. Desloratadine is rapidly metabolized via hydroxylation. Mean elimination half-life in normal adults for most second-generation antihistamines is 8 hours (range, 3–20 hours). The mean elimination half-life of desloratadine is 27 hours.
Treatment of overdoses is symptomatic and supportive. Significant toxicity has not been reported in patients ingesting second-generation antihistamines. There is no known antidote for these agents. Tachycardia has been reported in overdose but does not usually require intervention unless hemodynamic compromise is present. The heart rate should be monitored, and a baseline ECG may be indicated and repeated as necessary. Continuous cardiac monitoring should be instituted as needed. No routine laboratory studies are necessary, unless otherwise clinically indicated. Neurologic status also should be monitored because limited reports suggest that somnolence may develop following overdose.
Children experience an average of six to eight colds per year that may result in significant congestion. Parents and physicians often use decongestants (oral or topical) to help alleviate the symptoms. Because these treatments are available without a prescription, they are commonly used. Previous studies have shown that the use of decongestants in children can result in significant adverse reactions. A recent Cochrane Review failed to find any trials that proved efficacy for their use in children. Accordingly, they should not be used routinely in children.
Phenylephrine is the primary decongestant used in oral OTC products in the United States. It is a sympathomimetic agent, differing from epinephrine only in lacking a hydroxyl group in the 4 position on the benzene ring. It is a powerful postsynaptic alpha-receptor stimulant with little effect on beta-receptors in the heart. Peripheral resistance increases considerably due to constriction of most vascular beds, and both systolic and diastolic blood pressures increase. Phenylephrine is used orally as a decongestant even though evidence of its effectiveness in reducing nasal congestion is inconclusive.
Phenylephrine has 38% oral bioavailability. It is extensively metabolized in the intestinal wall and liver after oral dosing. It is renally excreted, with 2.6% eliminated as the parent compound in the urine after 48 hours. The elimination half-life is 2 to 3 hours in most patients.
With mild-to-moderate overdoses, most patients experience tachycardia, hypertension, mydriasis, insomnia, headache, and agitation. Large overdoses and severe toxicity may cause seizures, hallucinations, agitated delirium, and tachydysrhythmias, including supraventricular tachycardia and ventricular tachycardia. Vasospasm can lead to myocardial ischemia or focal cerebrovascular deficits. Severe hypertension may also result in intracranial hemorrhage or renal insufficiency. Reflex bradycardia due to significant hypertension is possible. Prolonged agitation can lead to rhabdomyolysis and hyperthermia.
Treatment is largely symptomatic and supportive. A 12-lead ECG should be obtained in all symptomatic patients. Patients with moderate-to-severe toxicity should be admitted until symptoms improve. Those with mild tachycardia, hypertension, and agitation can be treated with benzodiazepines and observed until symptoms and vital signs normalize.
Oral Decongestants of the Past
In 2000, the FDA requested a voluntary recall of phenylpropanolamine (PPA) from all manufacturers and issued a public health warning about the increased risk for hemorrhagic stroke associated with its use, particularly among women. In a case-control study, the adjusted odds ratio was 1.49 for an association between hemorrhagic stroke and PPA use within 3 days in all patients. The adjusted odds ratio increased to 1.98 in women. A similar study found an adjusted odds ratio of 16.58 (95% confidence interval 1.51 to 182.21) in women. (6) Case reports have documented similar clinical findings in children ingesting PPA overdoses.
Although pseudoephedrine is considered a safe and effective oral nasal decongestant, its use as a precursor in the manufacturing of methamphetamine has resulted in legislation to restrict its availability (2005 Combat Methamphetamine Epidemic Act). Epidemiologic data have shown that pseudoephedrine exposures in children are common, especially among those younger than 2 years of age. Because most pseudoephedrine products are in combination products, many of the exposures resulted from taking more than one combination product or use for extended periods of time. Pseudoephedrine has sympathomimetic properties, and clinical effects and toxicity are expected to be similar to those seen with phenylephrine.
Imidazoline topical decongestants are commonly used in adults for the immediate and temporary treatment of nasal congestion. However, they are not approved by the FDA for use in children younger than age 6 years. Topical imidazolines are found in many OTC eye and nose decongestants. Products with imidazoline components are numerous and include: tetrahydrozoline, naphazoline, oxymetazoline, and xylometazoline. Imidazolines have central and peripheral alpha-2 agonist activity. However, unlike other alpha-2 agonists, they are designed to stimulate peripheral alpha-2 receptors on local vessels to achieve the intended clinical effect of vasoconstriction. Both topical and oral imidazolines have a rapid onset of action that is often prolonged.
Use of topical imidazolines in infants and inappropriate use in children and adults has had important consequences. Administration of intranasal tetrahydrozoline, especially in larger-than-recommended doses in adults and children, may cause drowsiness, hypertension, bradycardia, rebound hypotension, and possibly arrhythmias due to coronary vasoconstriction. Rebound congestion frequently occurs with prolonged use of these solutions and may prompt overuse of the drug. Unfortunately, exposures are not specific to topical applications, and significant morbidity (hypotension and bradycardia) and mortality has resulted from tetrahydrozoline ingestions in young children that necessitated intensive care management.
Cough is a normal response to irritation (eg, mechanical, chemical, or inflammatory) to the tracheobronchial tree mediated by neural reflexes from the brainstem. Cough can be the result of many process, including infection, asthma, foreign body, or other inflammatory processes. However, because of the symptomatology and the interference with daily life, children are often given cough suppressants that may adversely affect their health. Dextromethorphan and codeine are often chosen as OTC agents for their cough suppression properties, but their efficacy has not been established in children. In fact, use of these medications may be harmful in overdoses. In addition, both medications are commonly used as drugs of abuse.
Dextromethorphan is an antitussive agent commonly used in OTC cough and cold preparations. It is the D-isomer of the codeine analog of levorphanol but has little analgesic or addictive properties. However, it does act on the cough center in the medulla oblongata by elevating the threshold for coughing. In usual doses, the drug can cause pupillary dilation but without significant reduction of respiratory rate. Dextromethorphan may cause slight elevations in blood pressure. After ingestion, the initial response occurs within 15 to 30 minutes, with an duration of effect of 5 to 6 hours. The time to peak concentration is 2 to 2.5 hours.
Dextromethorphan undergoes extensive hepatic oxidative biotransformation via cytochrome P450 2D6 (CYP2D6). The CYP2D6 gene locus is highly polymorphic, with more than 70 allelic variants (and additional subvariants) identified. The proteins encoded by these alleles may have full, reduced, or no function, conveying a wide range of activity from none to ultrarapid metabolism. In patients who are genetically deficient in CYP2D6 activity, clearance of dextromethorphan is reduced 150-fold and can result in symptoms of toxicity.
Ingestion of less than 10 mg/kg of dextromethorphan is unlikely to produce toxicity in a child. Overdose may result in symptoms from the parent compound and active metabolites. Central nervous system (CNS) effects are most prevalent and include stupor, ataxia, nystagmus, hyperexcitability, dystonia, coma, toxic psychosis, and changes in muscle reflexes. Among other effects are respiratory depression, tachycardia, increased baseline seizure activity, and nausea and vomiting. Anecdotal reports suggest that the CNS and respiratory depressant effects of dextromethorphan can be reversed. Otherwise, treatment is symptomatic and supportive. Agitation and seizures may be treated with benzodiazepines.
Codeine is an opiate receptor agonist that binds to the mu receptor. It is commonly used as an analgesic, with a mechanism that is speculated to stem from its conversion by CYP2D6 to morphine. In prodrugs like codeine, however, increased formation of pharmacologically active metabolites may lead to an increased incidence of adverse effects or, in extreme cases, overt toxicity. In addition, the antitussive effects of codeine may result from direct depression of the cough reflex in the medulla. In adults, studies have shown a linear relationship between codeine dose and the decrease in frequency of chronic cough. The dosing in these studies ranged from 7.5 to 60 mg/day. However, even at the highest dose, complete cough suppression was not achieved. Although codeine is a scheduled drug in all states, it has been present in OTC cough suppressants in the past. However, the available concentrations were very low, resulting in much lower efficacy.
Studies assessing the pharmacokinetic properties of codeine in children are lacking. Published recommendations suggest a dose of 1 mg/kg per day in four divided doses (not to exceed 60 mg/day), but no studies have confirmed the safety and efficacy of this dose. Codeine is absorbed within the GI tract and food has no effect on its absorption. It undergoes metabolism in the liver by CYP2D6, CYP3A4, and glucuronidation. The active metabolite of codeine is morphine, which is a product of the CYP2D6 pathway. As mentioned previously, CYP2D6 is polymorphic, which can lead to problems with codeine efficacy and safety if patients are poor metabolizers or ultrarapid metabolizers , respectively. The elimination half-life is approximately 3 hours.
Adverse reactions can occur at therapeutic doses and overdoses, depending on the pharmacogenetics. The most common adverse effects at therapeutic doses are dizziness, somnolence, nausea, and vomiting. In mild-to-moderate overdoses, euphoria, drowsiness, constipation, bradycardia, hypotension, and miosis may occur. Severe overdoses can result in respiratory depression leading to apnea, hypoxia, worsening bradycardia, and coma. Treatment is symptomatic and supportive, but the toxicity is generally responsive to naloxone unless the codeine is ingested with other CNS depressants. Naloxone is an opioid antagonist that may be administered intravascularly, intramuscularly, subcutaneously, intranasally, or endotracheally. In children, the usual dose is 0.4 to 2 mg. In adolescents and adults, care must be exercised when administering naloxone because its use may precipitate withdrawal symptoms if the patients being treated are chronic users of opiates. A continuous infusion of naloxone can be considered if frequent boluses are required to maintain mental status and airway.
Guaifenesin is commonly used alone or in combination products as an expectorant. It is believed to act by irritating the gastric mucosa, resulting in stimulation of respiratory tract secretions. However, a recently conducted clinical trial failed to show measurable effect on sputum volume or viscosity, suggesting that the drug is unlikely to be an efficacious expectorant or mucolytic when used to treat acute respiratory tract infections.
Guaifenesin is generally well absorbed. It is hydrolyzed in the blood to an inactive metabolite, beta-2-methoxyphenoxy-lactic acid. The elimination half-life of the parent drug is approximately 1 hour.
The most common adverse effects are nausea, vomiting, and GI discomfort. Excessive doses of guaifenesin have resulted in renal stones containing the metabolite. This has usually occurred in patients who have intentionally ingested combination products with the purpose of using them as drugs of abuse.
Many OTC cough and cold preparations are combination products that include an analgesic/antipyretic such as acetaminophen, ibuprofen, or aspirin. Parents may fail to recognize the individual medications in these products and choose to supplement cough and cold preparations with stand-alone antipyretics. This places children at great risk for toxicity. Clinicians should educate parents on the risks associated with combined products.
An acute acetaminophen (APAP) overdose in children younger than 6 years of age occurs when more than 200 mg/kg is ingested in one period or if more than 200 mg/kg or 10 g (whichever is less) is ingested in children older than 6 years of age. Absorption is generally complete within 4 hours, and the Rumack-Matthew nomogram (Figure) may be used to assess the need for treatment. The nomogram is conservative because it is overly sensitive and lacks specificity to allow a safety net. Plasma concentrations of greater than 150 mcg/mL at 4 hours postingestion are considered “possibly toxic.”
Clinical manifestations of APAP toxicity occur in three stages. Typical early signs and symptoms within the first 24 hours are anorexia, nausea, vomiting, malaise, pallor, and sweating. Hepatotoxicity has not yet occurred, so the patient may be asymptomatic and laboratory test results should be normal. The next 24 hours reveal the onset of liver injury, and other organ system effects may occur, most commonly approximately 24 hours after ingestion but nearly universally by 36 hours. Aspartate aminotransferase abnormalities are the most sensitive, occurring before evidence of actual liver dysfunction. GI distress, tenderness of the right upper quadrant of the abdomen, worsening of liver function laboratory results, worsening of coagulopathy, and possible renal effects occur due to hepatotoxicity. The third phase occurs 3 to 5 days after ingestion when liver enzymes usually peak. Signs and symptoms vary with severity of injury, ranging from asymptomatic to fulminant hepatic failure with encephalopathy, coma, and hemorrhage. Aspartate aminotransferase/alanine aminotransferase commonly measure more than 10,000 U/L (167 µkat/L) and may continue to rise until 7 to 8 days after ingestion. Fatalities generally occur between days 3 and 5, typically due to multiorgan failure, with hemorrhage, acute respiratory distress syndrome, sepsis, and cerebral edema, but if the patient survives the acute stage, hepatic failure may not occur for 8 to 10 days. Notably, a decrease in liver enzymes after 7 to 8 days may indicate hepatic cellular death rather than improvement. Thus, it is imperative to examine liver function (eg, bilirubin, glucose, bleeding time) concurrently with the falling enzyme concentrations.
Up to 90% of acetaminophen normally undergoes hepatic glucuronide and sulfate conjugation to form active, harmless metabolites that are eliminated in urine. Approximately 5% to 15% is oxidized by the CYP2E1 pathway of the P450 mixed-function oxidase system, resulting in the formation of a highly reactive electrophile, N-acetyl-p-benzoquinoneimine (NAPQI). Toxicity is the result of glutathione depletion and formation of the NAPQI metabolite that instantly binds to cysteine-containing cellular macromolecules, especially in the liver and kidneys. This covalent binding causes hepatocellular damage that can lead to necrosis and fulminant liver failure. In as many as 46% of cases with significant hepatic enzyme elevation, clinically evident renal injury may also occur. Renal P450 formation of NAPQI is the likely cause of acute proximal renal tubular necrosis after acute overdose. Cases of significant toxicity after a single acute overdose generally involve doses greater than 250 mg/kg or 15 g.
Patients either recover or develop fulminant hepatic failure, which may require liver transplantation. All survivors have 100% regeneration of the liver with no toxic sequelae. Abnormal laboratory values may resolve within days to weeks. Renal failure is reversible. Bleeding time and other coagulopathies should not be abnormal without significant hepatotoxicity. This is an important point because N-acetylcysteine (NAC) (especially intravenous NAC and the loading dose) may cause prolonged prothrombin time, which is not significant in nontoxic cases.
NAC is a glutathione precursor and aids in the conversion of NAPQI to a nontoxic metabolite. It is available in oral and intravenous form. No clear difference has been shown between oral and intravenous NAC when the antidote is administered within 10 hours. NAC should be administered intravenously to patients with vomiting or to those whose condition precludes enteral use. NAC therapy initiated within 8 to 10 hours of ingestion has almost a 100% (94%–97%) chance of preventing toxicity. Treatment after 10 hours is associated with lessening chances of preventing toxicity (eg, 64%–70% within 10–16 hours and 42%–59% within 16–24 hours). Treatment after 24 hours may not help the liver but may aid other organs such as lungs, brain, and kidneys. Young children recover better than adults. Patients with glutathione deficiency due to illness or poor diet or chronic alcoholics do worse and are especially susceptible to hepatotoxicity. Prognostic indicators of severe toxicity include an arterial pH less than 7.3, encephalopathy, prothrombin time greater than 100 seconds, and serum creatinine greater than 2.3 mg/dL (203.3 µmol/L). Delay in treatment time is also a significant risk factor for children.
Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for fever and pain control. These include the combined COX-1/COX-2 inhibitors (eg, ibuprofen, naproxen, ketorolac) and selective COX-2 inhibitors (eg, celecoxib, piroxicam). OTC NSAIDs include ibuprofen and naproxen. The toxicity is primarily the result of COX-1 and COX-2 inhibition and the resultant diminished prostaglandin synthesis. There may be a direct mucosal effect as well.
There are no established lethal doses, but overall NSAID toxicity is low. Toxicity is dose-related. Children ingesting less than 200 mg/kg ibuprofen generally are asymptomatic or have mild effects. Ingestions of 400 mg/kg in children have been associated with severe toxicity. In adults, 3 g has been reported to cause mild CNS depression. Renal injury has been reported with ingestions of more than 6 g.
Depending on the amount ingested, a patient may present with effects ranging from no symptoms to CNS depression with severe metabolic acidosis. The risk of major toxicity increases with dose. CNS effects are relatively common and include changes in mood and cognition, seizures, headaches, and hallucinations. Acute renal insufficiency is rare and usually reversible after acute ingestions.
No specific diagnostic tests establish the diagnosis of NSAID exposure or toxicity. Baseline laboratory studies should include a complete blood cell count, coagulation studies that include an international normalized ratio, serum electrolytes, glucose, blood urea nitrogen, creatinine, urinalysis, liver function tests, and ECG as clinically appropriate. Asymptomatic children who have accidentally ingested more than 400 mg/kg may merit a baseline assessment of electrolytes, blood urea nitrogen, and creatinine.
Treatment is symptomatic and supportive; there is no antidote. Intravenous fluids may be necessary if the patient is volume-depleted. GI ulcers are usually not problematic in the acute overdose, and medications to address them are generally not necessary.
Salicylates are absorbed variably from the GI tract and absorption is largely dose-dependent (and prolonged in overdoses). They are distributed widely through the body and may be seen in increased concentrations in the CNS in toxic ingestions. They are metabolized in the liver by esterases and conjugation and undergo Michaelis-Menton elimination. As the salicylate concentration increases after an overdose, pathways for elimination become saturable and change from first-order elimination to zero-order elimination. Thus, with higher concentrations, the half-life is markedly increased. In addition, elimination is strongly dependent on urinary pH.
The mechanism of action for salicylate toxicity is uncoupling oxidative phosphorylation resulting in increased oxygen consumption and carbon dioxide production. The agent also inhibits the Kreb cycle dehydrogenases, leading to decreased production of adenosine triphosphate and increased lactate production. Ultimately, ketosis and a wide anion gap metabolic acidosis occur. Stimulation of the CNS respiratory center in the medulla leads to hyperventilation and respiratory alkalosis. Although many associate metabolic acidosis with salicylate poisoning, respiratory alkalosis predominates initially. In children, the respiratory alkalosis may be transient, and metabolic acidosis becomes significant very early in the course. Other potential effects include hypoglycemia, pulmonary edema, hypoprothrombinemia, platelet dysfunction, GI effects, cerebral edema, and tinnitus. Lethargy, agitation, and confusion may be early findings in patients with severe toxicity, with coma and seizures possibly developing subsequently. Cerebral edema and evidence of increased intracranial pressure (papilledema, nuchal rigidity) may develop in severe cases. Cerebral edema was present on autopsy in 9 of 13 children who died after acute and chronic salicylate intoxication.
Except in certain situations, salicylate toxicity correlates poorly with serum levels. The Done nomogram is not effective in predicting toxicity and should not be used to guide treatment. Careful observation of the patient, correlation of the serum salicylate values with blood pH values, and repeat evaluation of serum salicylate concentrations every 2 to 4 hours are essential until the patient is clinically improving and has a low salicylate value in the presence of a normal or high blood pH. A concurrent blood pH should be determined when a blood salicylate is obtained because more salicylic acid leaves the blood in the presence of acidemia and enters the CSF and other tissues, increasing the toxicity. Therefore, meaningful interpretation of serum salicylate levels must take into account the effect of the blood pH on salicylate distribution. A falling serum salicylate value accompanied by a falling or low blood pH should be presumed to reflect a serious or worsening situation, not a benign or improving one.
Treatment is largely symptomatic and supportive. Laboratory studies should be obtained at least every 4 hours and include a salicylate concentration, electrolytes, glucose, and blood gas until the salicylate value is consistently falling and acid/base abnormalities are improving. Complete blood cell count and coagulopathy studies should be monitored routinely in patients with moderate-to-severe effects. Patients undergoing alkalinization may require large amounts of potassium supplementation due to renal wasting. Alkalinization is recommended to “ion trap” the salicylate ion in the kidneys and increase its elimination rather than having it reabsorbed into the body. Alkalinization can be achieved using a 1- to 2-mEq/kg bolus of sodium bicarbonate followed by maintenance fluids, with the addition of sodium bicarbonate to keep the urine pH at 7 to 8.
Activated charcoal is usually reserved for presentations within 1 hour of the ingestion, but certain circumstances may require its use later. Some medications undergo hepatic recirculation (eg, dapsone, theophylline, phenobarbital, carbamazepine, quinine); others, such as valproic acid and aspirin, may benefit from later use of charcoal. This is especially true when concentrations are rising from a presumed bezoar.
Hemodialysis is recommended for patients with high serum salicylate values (> 80 mg/dL after acute overdose, 50 to 60 mg/dL with chronic intoxication), refractory acidosis, inability to maintain appropriate respiratory alkalosis, acidemia, evidence of CNS toxicity (seizures, mental status depression, persistent confusion, coma, cerebral edema), progressive clinical deterioration despite appropriate fluid therapy and attempted urinary alkalinization, acute lung injury, inability to tolerate sodium bicarbonate (eg, renal insufficiency, pulmonary edema), refractory/profound electrolyte disturbances, or renal failure. The patient’s clinical condition is more important than the serum salicylate concentration in determining the need for hemodialysis, especially in patients with chronic toxicity or delayed presentation after acute overdose. For those presenting early after acute overdose, serum concentrations approaching 100 mg/dL warrant consideration for dialysis, even with mild or moderate clinical manifestations of toxicity.
Administration and Absorption: The Role of Excipients
Excipients (or additives) are used to increase the ease of administration and absorption of medications. For children, the oral administration route is preferable. Although solid forms of dosing are preferable to parents, younger children are unable to swallow tablets. Liquid preparations are easier to adjust for dosing per bodyweight. However, even after completion of a clinical trial, efficacy cannot be achieved if the child refuses to take a medication, which is why excipients (or additives) are used.
As mentioned previously, products must contain only inactive ingredients that are safe in the amounts administered and do not interfere with the clinical effectiveness. Common additives include ethanol, artificial colors, artificial sweeteners, minerals, and other agents to help with solubility and taste. OTC products that contain the inactive ingredients alcohol, calcium, magnesium, potassium, sodium, and FD&C Yellow #6 require special warning statements. In addition, alcohol must be expressed as a percent absolute alcohol per volume of product (%v/v) and be declared on the label in quantity, type, and proportion.
In 2012, the FDA reissued a final rule limiting the concentration limit for alcohol as an inactive ingredient in OTC products intended for ingestion. These included 0.5% alcohol for children younger than 6 years, 5% alcohol for children 6 to 12 years, and 10% for those older than 12 years. Other inactive ingredients must be listed to ensure that consumers can avoid those that may result in adverse reactions. Ethanol may also be found in other OTC products, including perfumes, colognes, mouthwash, food flavorings, and hand sanitizers.
Ethanol is rapidly and almost completely (80%–90%) absorbed from the stomach and small intestine. Its peak plasma level occurs between 30 minutes and 2 hours after ingestion but may be prolonged in large overdoses. Metabolism occurs in the liver via alcohol dehydrogenase to acetaldehyde and then to acetic acid. Rather than following first-order kinetics (concentration per unit time), it follows Michaelis-Menten kinetics that involves zero-order kinetics (amount per unit time) at high concentrations. An average adult decreases ethanol by 15 to 20 mg/dL per hour. Children may metabolize ethanol more rapidly.
Mild-to-moderate toxicity can result in intoxication, ataxia, altered mental status, nausea, vomiting, and tachycardia. These symptoms may be difficult to discern, and ethanol can be the cause if taken in overdose with an OTC medication such as a cough syrup containing dextromethorphan. Large overdoses of ethanol are rare if the only source is the OTC medication, but such overdoses may result in coma, respiratory depression, hypoglycemia, and hypothermia. Children are more prone to the hypoglycemic effects due to decreased glucose reserves.
Treatment is largely symptomatic and supportive. Obtaining an ethanol value can help discern the cause of the altered sensorium if the source is an OTC product. A bedside glucose assessment should be obtained in all children and in symptomatic adolescents. Serum chemistries should be monitored. Decontamination with activated charcoal is not effective. Depending on the degree of CNS depression, patients may need airway assistance or intubation. When nausea, vomiting, or hypoglycemia is present, fluid replacement with glucose supplementation may be necessary.
Although small amounts of calcium offer no therapeutic value, even nontherapeutic doses can change the bioavailability of drugs. Calcium salts are contraindicated in some medical conditions, such as nephrocalcinosis and metabolic conditions (eg, hypercalcemia from milk-alkali syndrome) because even small amounts can change the physiologic nature of a disease.
Sodium and Potassium
Similar to calcium, small amounts of these metals should have no clinical significance except in rare cases. Hypernatremia, hypokalemia, or systemic alkalosis has occurred with sodium or potassium bicarbonates at large therapeutic doses.
Artificial Colors and Sweeteners
Artificial colors and sweeteners are used as additives in foods, beverages, and medications for added palatability. Since 1950, the number of artificial food colors that the FDA has certified has increased more than fivefold. In addition, studies in the last few decades have found a dose association with the use of artificial colors and behavioral reactions such as hyperactivity. (7)
Based on strong research evidence, over-the-counter (OTC) medications are used frequently to treat most health problems in adults and children, especially with cough and cold symptoms. (1,4) (Evidence Quality A)
Based on research evidence as well as consensus from the U.S. Food and Drug Administration, the potential for misuse and abuse and increased adverse effects when not used properly has resulted in changes to recommended ages and dosing of OTC medications when used in children. (6)(8)(9) (Evidence Quality B)
Adverse reactions to OTC medications are not uncommon in the pediatric age group, but observational studies using poison control center data show that the recommended changes have resulted in decreased reactions and risk to children. (5) (Evidence Quality C)
Despite these findings, consistent evidence suggests that unintentional effects can occur, and pediatricians should understand the signs and symptoms of these adverse reactions and overdoses to medications and additives for appropriate diagnosis and treatment. (7)(8) (Evidence Quality B)
Parent Resources from the AAP at HealthyChildren.org
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