Basic and Clinical Pharmacology, 13th Ed.

Therapeutic & Toxic Potential of Over-the-Counter Agents

Robin L. Corelli, PharmD

CASE STUDY

A 66-year-old man presents to his primary care provider for worsening shortness of breath, chest congestion, and symptoms of a severe cold (cough, rhinorrhea, nasal congestion, drowsiness) over the past week. His past medical history is significant for heart failure, hypertension, and hyperlipidemia. His current medications include metoprolol succinate 50 mg daily, lisinopril 20 mg daily, atorvastatin 20 mg daily, furosemide 40 mg daily, and potassium chloride 20 mEq daily. The patient reports excellent compliance with his prescribed medications but admits to taking several over-the-counter (OTC) medications over the past 5 days for his recent cold symptoms, including Alka-Seltzer Plus Cold Formula (2 tablets every 4 hours during the day), Sudafed (60 mg every 6 hours), and Advil PM (2 tablets at bedtime). His social history is significant for alcohol use (3–4 beers/night). His vital signs include the following: afebrile, blood pressure 172/94 mm Hg, pulse 84 bpm, respiratory rate 16/min. On physical examination an S3 gallop is heard; 3+ pitting edema is noted in his lower extremities, and a chest examination reveals inspiratory rales bilaterally. What medications do OTC “cold” preparations typically contain? Which of the OTC medications might have contributed to the patient’s current hypertension? Are any of these preparations implicated in the signs of heart failure?

In the USA, medications are divided by law into two classes: those restricted to sale by prescription only and those for which directions for safe use by the public can be written. The latter category constitutes the nonprescription or over-the-counter (OTC) medications. This category does not include supplements (vitamins, minerals, herbals, and botanicals), which are subject to different regulatory requirements (see Chapter 64). In 2013, the American public spent approximately 33.1 billion on OTC products to medicate themselves for ailments ranging from acne to warts. These products contain approximately 800 active ingredients in various forms and combinations.

It is apparent that many OTC medications are no more than “me too” products advertised to the public in ways that suggest significant differences between them. For example, there are over 100 different systemic analgesic products, almost all of which contain aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, or a combination of these agents as primary ingredients. They are made different from one another by the addition of questionable ingredients such as caffeine or antihistamines; by brand names chosen to suggest a specific use or strength (“women’s,” “migraine,” “arthritis,” “maximum”); or by special dosage formulations (enteric-coated tablets, geltabs, liquids, orally disintegrating strips and tablets, sustained-release products, powders, seltzers). There is a price attached to all of these features, and in most cases a less expensive generic product can be equally effective. It is probably safe to assume that the public is generally overwhelmed and confused by the wide array of products presented and will probably use those that are most heavily advertised.

Over the past four decades the FDA has been engaged in a methodical review of OTC ingredients for both safety and efficacy. There have been two major outcomes of this review: (1) Ingredients designated as ineffective or unsafe for their claimed therapeutic use are being eliminated from OTC product formulations (eg, antimuscarinic agents have been eliminated from OTC sleep aids, attapulgite and polycarbophil can no longer be marketed as OTC antidiarrheal products); and (2) agents previously available by prescription only have been made available for OTC use because they were judged by the review panel to be generally safe and effective for consumer use without medical supervision (Table 63–1). The prescription-to-OTC switch process has significantly enhanced and expanded self-care options for US consumers. Indeed, more than 100 OTC active ingredients or dosages are on the market today that were available only by prescription less than 40 years ago. Some agents such as docosanol and the nicotine polacrilex lozenge have bypassed the prescription route altogether and have been released directly to the OTC market. Other OTC ingredients previously available in low doses only are now available in higher-strength or original prescription strength formulations. Examples of other prescription medications with the potential for future OTC reclassification include oral contraceptives, nicotine replacement therapy (oral inhaler, nasal spray) for smoking cessation, proton-pump inhibitors (pantoprazole) for heartburn, and second-generation nonsedating antihistamines (desloratadine, levocetirizine) for relief of allergy and cold symptoms. The frequency of prescription-to-OTC switches, while commonplace in the mid-1990s, has largely declined over the past decade. The prescription-to-OTC reclassification process is both costly and rigorous and fewer prescription medications are appropriate candidates for a switch (eg, a consumer can self-diagnose and safely treat the condition). For example, the cholesterol-lowering agents lovastatin and pravastatin were denied OTC status on the basis that these agents could not be used safely and effectively in an OTC setting. The nonprescription drug advisory committee believed that diagnosis and ongoing management by a health care professional was necessary for the management of hyperlipidemia, a chronic, asymptomatic condition with potentially life-threatening consequences. In a similar recommendation, oral acyclovir for OTC use in the treatment of recurrent genital herpes was not approved because of concerns about misdiagnosis and inappropriate use leading to increased viral resistance.

TABLE 63–1 Selected agents switched from prescription to OTC status by the Food and Drug Administration.

image

There are three reasons why it is essential for clinicians to be familiar with the OTC class of products. First, many OTC medications are effective in treating common ailments, and it is important to be able to help the patient select a safe, effective product. Because managed-care practices encourage clinicians to reduce costs, many will recommend effective OTC treatments to their patients, since these medications are rarely paid for by health plans (Table 63–2). Second, many of the active ingredients contained in OTC medications may worsen existing medical conditions or interact with prescription medications. (See Chapter 66, Important Drug Interactions & Their Mechanisms.) Finally, the misuse or abuse of OTC products may actually produce significant medical complications. Phenylpropanolamine, for example, a sympathomimetic previously found in many cold, allergy, and weight control products, was withdrawn from the US market by the FDA based on reports that the drug increased the risk of hemorrhagic stroke. Dextromethorphan, an antitussive found in many cough and cold preparations, has been increasingly abused in high doses (eg, > 5–10 times the recommended antitussive dose) by adolescents as a hallucinogen. Although severe complications associated with dextromethorphan as a single agent in overdose are uncommon, many dextromethorphan-containing products are formulated with other ingredients (acetaminophen, antihistamines, and sympathomimetics) that can be fatal in overdose. Additionally, pseudoephedrine, a decongestant contained in numerous OTC cold preparations, has been used in the illicit manufacture of methamphetamine. A general awareness of these products and their formulations will enable clinicians to more fully appreciate the potential for OTC medication-related problems in their patients.

TABLE 63–2 Ingredients of known efficacy for selected OTC classes.

image

image

image

image

image

Table 63–2 lists examples of OTC products that may be used effectively to treat common medical problems. The selection of one ingredient over another may be important in patients with certain medical conditions or in patients taking other medications. These are discussed in detail in other chapters. The recommendations listed in Table 63–2 are based on the efficacy of the ingredients and on the principles set forth in the following paragraphs.

1.Select the product that is simplest in formulation with regard to ingredients and dosage form. In general, single-ingredient products are preferred. Although some combination products contain effective doses of all ingredients, others contain therapeutic doses of some ingredients and subtherapeutic doses of others. Furthermore, there may be differing durations of action among the ingredients, and there is always a possibility that the clinician or patient is unaware of the presence of certain active ingredients in the product. Acetaminophen, for example, is in many cough and cold preparations; a patient unaware of this may take separate doses of analgesic in addition to that contained in the cold preparation, potentially leading to hepatotoxicity.

2.Select a product that contains a therapeutically effective dose.

3.Consumers and providers should carefully read the “Drug Facts” label to determine which ingredients are appropriate based on the patient’s symptoms, underlying health conditions, and whatever is known about the medications the patient is already taking. This is critical because many products with the same brand name contain different ingredients that are labeled for different uses. For example, multiple products (with different active ingredients) carry the Allegra name including Allegra Allergy (fexofenadine), Allegra-D (fexofenadine and pseudoephedrine), and Allegra Anti-Itch Cream (allantoin and diphenhydramine). This marketing practice of “extending a brand name” across product lines, while legal, is confusing and can lead to medication errors.

4.Recommend a generic product if one is available.

5.Be wary of “gimmicks” or advertising claims of specific superiority over similar products.

6.For children, the dose, dosage form, and palatability of the product are prime considerations.

Certain ingredients in OTC products should be avoided or used with caution in selected patients because they may exacerbate existing medical problems or interact with other medications the patient is taking. Many of the more potent OTC ingredients are hidden in products where their presence would not ordinarily be expected (Table 63–3). Although OTC medications have standardized label formatting and content requirements that specify the indications for use, dosage, warnings, and active and inactive ingredients contained in the product, many consumers do not carefully read or comprehend this information. Lack of awareness of the ingredients in OTC products and the belief by many providers that OTC products are ineffective and harmless may cause diagnostic confusion and perhaps interfere with therapy. For example, innumerable OTC products, including analgesics and allergy, cough, and cold preparations, contain sympathomimetics. These agents should be avoided or used cautiously by type 1 diabetics and patients with hypertension, angina, or hyperthyroidism. Aspirin should not be used in children and adolescents for viral infections (with or without fever) because of an increased risk of Reye’s syndrome. Aspirin and other NSAIDs should be avoided by individuals with active peptic ulcer disease, certain platelet disorders, and patients taking oral anticoagulants. Cimetidine, an H2-receptor antagonist, is a well-known inhibitor of hepatic drug metabolism and can increase the blood levels and toxicity of agents such as phenytoin, theophylline, and warfarin.

Overuse or misuse of OTC products may induce significant medical problems. A prime example is rebound congestion from the regular use of decongestant nasal sprays for more than 3 days. The improper and long-term use of some antacids (eg, aluminum hydroxide) may cause constipation and even impaction in elderly people, as well as hypophosphatemia. Laxative abuse can result in abdominal cramping and fluid and electrolyte disturbances. Insomnia, nervousness, and restlessness can result from the use of sympathomimetics or caffeine hidden in many OTC products (Table 63–3). The long-term use of some analgesics containing large amounts of caffeine may produce rebound headaches, and long-term use of analgesics has been associated with interstitial nephritis. OTC products containing aspirin, other salicylates, acetaminophen, ibuprofen, or naproxen may increase the risk of hepatotoxicity and gastrointestinal hemorrhage in individuals who consume three or more alcoholic drinks daily. Recent evidence suggests the long-term use of certain NSAIDs may increase the risk of heart attack or stroke. Furthermore, acute ingestion of large amounts of acetaminophen by adults or children can cause serious, and often fatal, hepatotoxicity. Antihistamines may cause sedation or drowsiness, especially when taken concurrently with sedative-hypnotics, tranquilizers, alcohol, or other central nervous system depressants. Antihistamines and other substances contained in OTC topical and vaginal products may induce allergic reactions.

TABLE 63–3 Hidden ingredients in OTC products.

image

Finally, use of OTC cough and cold preparations in the pediatric population has been under scrutiny by the FDA based on a lack of efficacy data in children less than 12 years of age and reports of serious toxicity in children. Following a thorough review, the FDA recommends that OTC cough and cold agents (eg, products containing antitussives, expectorants, decongestants, and antihistamines) not be used in infants and children younger than 2 years due to serious and potentially life-threatening adverse events associated with accidental overdose including arrhythmias, hallucinations, and encephalopathy. Further safety reviews by the FDA regarding the use of these agents in children between the ages of 2 and 11 years are ongoing.

There are three major drug information sources for OTC products. Handbook of Nonprescription Drugs is the most comprehensive resource for OTC medications; it evaluates ingredients contained in major OTC drug classes and lists the ingredients included in many OTC products. Nonprescription Drug Therapy is an online reference that is updated monthly; it provides detailed OTC product information and patient counseling instructions. Physicians’ Desk Reference for Nonprescription Drugs, a compendium of manufacturers’ information regarding OTC products, is published annually but is somewhat incomplete with regard to the number of products included. Any health care provider who seeks more specific information regarding OTC products may find useful the references listed below.

REFERENCES

Conca AJ, Worthen DR: Nonprescription drug abuse. J Pharm Pract 2012;25:13.

Consumer Healthcare Products Association website: http://www.chpa.org/.

Handbook of Nonprescription Drugs, 17th ed. American Pharmacists Association, 2011.

Nonprescription Drug Therapy. Facts and Comparisons Clinical eAnswers (online). Wolters Kluwer Health, 2014.

Physicians’ Desk Reference for Nonprescription Drugs, 35th ed. Thomson Healthcare, 2014.

US Food and Drug Administration website. FDA Approved Drug Products: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

CASE STUDY ANSWER

OTC cold medications typically contain antihistamines (eg, brompheniramine, chlorpheniramine, diphenhydramine), antitussives (eg, dextromethorphan), expectorants (eg, guaifenesin), and nasal decongestants (eg, phenylephrine, pseudoephedrine). Systemic nasal decongestants (contained in Alka-Seltzer and Sudafed) stimulate α1-adrenoceptors and may raise blood pressure through direct vasoconstrictor effects. Additionally, NSAIDs (such as ibuprofen, contained in Advil PM) increase blood pressure and may reduce the effectiveness of antihypertensive agents. NSAIDs may also exacerbate heart failure through increased fluid retention and elevated blood pressure. Alka-Seltzer cold preparations should be avoided in patients with heart failure due to the high sodium content, which can lead to fluid retention. The sodium content in one dose of Alka-Seltzer Plus cold medicine (948 mg/dose) provides more than half of the maximum recommended daily sodium allowance for patients with heart failure.