US Pharm. 2008;33(3)(OTC suppl):4-7.
Asthma is a pulmonary disease characterized by reversible airflow obstruction and bronchial hyperresponsiveness. The central feature of asthma is inflammation, which leads to recurrent episodes of wheezing, coughing, shortness of breath, and chest tightness.1,2 The goal of therapy is to gain control of the disease in order to maintain a normal quality of life.
The burden of asthma has been steadily increasing over the past three decades. In 1970, approximately 3% of the population had asthma, compared with 5.5% and 7.7% in 1995 and 2005, respectively.3 The latter estimate equates to approximately 22.2 million Americans.2,3 With an increase in the prevalence of this disease in the United States, morbidity and mortality due to asthma are also increasing. Attributed to asthma in 2004 were 1.8 million emergency-department visits, 497,000 hospitalizations, and 4,055 deaths.3
Treatment Based on Asthma Control
The National Asthma Education and Prevention Program (NAEPP), a division of the National Heart, Lung, and Blood Institute, publishes Guidelines for the Diagnosis and Management of Asthma , most recently updated in 2007.2 The guidelines classify asthma severity as intermittent or persistent based on symptoms and frequency of use of quick-relief medications. Individuals with intermittent asthma have infrequent symptoms, consequently infrequent use of quick-relief medication, and no interference with normal activity. If the asthma is less controlled, then the asthma severity is classified as persistent (see TABLE 1).
The guidelines describe the cornerstones of asthma management as self-management education, the use of quick-relief medications, and the use of long-term control medications in individuals with persistent asthma. Health care providers offering self-management education should instruct patients to identify and avoid asthma triggers when possible, use pharmacologic therapies properly, and devise an asthma action plan. Quick-relief medication should be initiated for all patients diagnosed with asthma and may be used as monotherapy in individuals with intermittent asthma; individuals diagnosed with persistent asthma, however, should have one or more long-term control medications added to their regimen. Long-term control medications include inhaled corticosteroids, leukotriene modifiers, long-acting beta-agonists, and theophylline (see TABLE 2).
The guidelines also note that approximately 30% of the U.S. population uses complementary and alternative medications and interventions. At present, however, insufficient evidence exists to recommend these treatment modalities for asthma. The guidelines advise against the use of herbal remedies to treat asthma based on the lack of safety and efficacy data.
Nonprescription Asthma Products and Their Regulation
Nonprescription asthma products have been
available since the 1950s, although some of the active ingredients have
changed considerably over the years. Currently available nonprescription
active ingredients are ephedrine--with or without guaifenesin--and epinephrine.
Theophylline and phenobarbital previously were active ingredients in
nonprescription asthma products; however, both are now classified as
For the past three decades, the FDA has taken actions regarding the regulation of nonprescription treatments for asthma. In 1976, the FDA concluded that inhaled epinephrine provided quick and effective relief in mild to moderate asthma. In 1982, it again concluded in a tentative final monograph: "Epinephrine, epinephrine bitartrate, and epinephrine hydrochloride (racemic; since renamed racepinephrine hydrochloride) in pressurized metered-dose inhalation aerosol dosage forms can be generally recognized as safe and effective for OTC use at dosage for adults and children 4 years of age and older of 1 to 2 inhalations of a metered-dose equivalent to 0.16 to 0.25 mg epinephrine per inhalation not more often than every 3 hours."5,6
In 1986, the FDA reviewed ephedrine products for bronchodilation and approved this active ingredient as generally recognized as safe and effective for nonprescription use. In that year, the FDA decided that data were insufficient to limit inhaled epinephrine to prescription use only and that the benefits of nonprescription availability outweighed the risks. The FDA concluded that expanded and revised labeling would benefit consumers.5,6
After reports of life-threatening events and deaths attributable to nonprescription combination products containing theophylline, the FDA issued a final ruling in 1995 that these products were not safe or effective.7 Thus, products containing a combination of ephedrine and theophylline were discontinued and some were reformulated to contain ephedrine and guaifenesin. Also in 1995, the FDA proposed to remove ephedrine from the nonprescription market due to its role in the manufacture of methamphetamine and methcathinone and its misuse for weight control and muscle enhancement.7
In 1996, the FDA amended the 1986 final monograph to remove monograph status for OTC bronchodilators.6 Instead, manufacturers of any new nonprescription metered-dose inhaler are required to submit an approved application that contains information not found in the monograph.6 Currently marketed nonprescription bronchodilators were not affected by this amendment.
Despite the FDA's proposal to remove ephedrine from the nonprescription market because of its use as a base element in methamphetamine production, the product remains available nonprescription. Instead, the Combat Methamphetamine Epidemic Act of 2005, incorporated into the Patriot Act in 2006, conferred behind-the-counter status on ephedrine-containing nonprescription products.8 Consumers wishing to purchase products containing ephedrine now must present government-issued photo identification at a pharmacy, as these products are no longer legally sold in convenience stores or warehouse stores without a registered pharmacy.
As part of global public-health protection, an international agreement was formed to reduce and eventually eliminate products that contain ozone-depleting substances (ODSs) such as chlorofluorocarbons (CFCs) found in metered-dose inhalers (MDIs). This agreement gave rise to the 1987 Montreal Protocol and subsequently the 1990 Clean Air Act Amendments.9-11 The agreement provides an exemption for the use of CFCs in MDIs used for asthma treatment if use of the product is determined to be essential by the FDA.12 Nonprescription asthma medications have remained under the essential-use designation. However, in 2007 the FDA announced a proposal to remove the essential-use designation for inhaled epinephrine effective December 31, 2010.13 The FDA used the following criteria, found in 21 CFR 2.125(g)(2), to review the essential-use designation for inhaled epinephrine: "(i): Substantial technical barriers exist to formulating the product without ODSs; (ii): The product will provide an unavailable important public health benefit; and (iii): Use of the product does not release cumulatively significant amounts of ODSs into the atmosphere or the release is warranted in view of the unavailable important public health benefit."13 The FDA is currently receiving comments on this matter prior to their final ruling.
Safety and Efficacy of Nonprescription Products
As evidenced by the various proposals made and
actions taken by the FDA regarding the nonprescription status of asthma
products, the past few decades have seen much debate regarding the safety and
efficacy of the active ingredients in these products. Although these products
are not actively promoted, their availability means that their safety and
efficacy are critically important for consumers.
Ephedrine: Single-ingredient ephedrine products for use as bronchodilators have been considered generally recognized as safe and effective by the FDA since 1986.14 Ephedrine releases epinephrine from tissues, which triggers alpha-adrenergic and nonselective beta-adrenergic receptor activity. The effectiveness of ephedrine for bronchodilation has been demonstrated in studies dating to the 1950s. Properties that make ephedrine less desirable as a bronchodilator include a slower onset of action than inhaled products (15 minutes to one hour) and nonselectivity of beta stimulation, which could contribute to cardiovascular adverse events (AEs).15-17 However, studies have demonstrated conflicting results regarding cardiovascular adverse events attributable to ephedrine use at labeled doses of 12.5 to 25 mg.16
Epinephrine: Epinephrine exhibits the same alpha- and beta-adrenergic receptor activity as ephedrine; therefore the same concerns exist as to the possibility of cardiovascular AEs. The onset of action of inhaled epinephrine (15 sec) is much more rapid than that of oral ephedrine, making it a more appropriate choice for immediate relief from an acute asthma exacerbation.6 Its short duration of action (23 min), however, may necessitate that the patient use the product repeatedly for continued relief rather than following the label instructions of no more than two inhalations within three hours.6 Nonprescription epinephrine inhalers appear to be safe and effective for patients with mild, intermittent asthma when used as labeled.5 This remains a source of controversy, however, as many health care providers are concerned that patients who rely on nonprescription inhalers may not be receiving appropriate disease management from a health care team, possibly leading to severe repercussions.
Guaifenesin: Guaifenesin is used in combination with ephedrine for asthma treatment and is recognized as safe and effective when the product is labeled for cough associated with asthma.14 Although guaifenesin is an FDA-approved mucolytic, it does not possess bronchodilatory effects. Thus, it contributes no additional benefit to the ephedrine product for an acute exacerbation.17
Use of Nonprescription Asthma Products
A Wyeth Consumer Healthcare (WCH) survey conducted in 1999 found that roughly six million (30%) individuals with asthma use epinephrine inhalers.6 Respondents' self-reports suggest that about 20% of these six million would be classified as having mild-to-moderate persistent asthma, which is not in the labeled use for this product.5 The NAEPP guidelines promote the use of short-acting beta agonists at least as needed by all individuals suffering from asthma; the guidelines do not specifically mention inhaled epinephrine as a treatment choice, however.
In 2005, WCH conducted an Internet survey of 330 individuals regarding the use of nonprescription bronchodilators for treatment of their symptoms. WCH determined that, of nonprescription-only users, 92% had been diagnosed with asthma, 91% used inhaled epinephrine only when experiencing an acute asthma exacerbation, 31% had no medical insurance, and 38% had no prescription insurance.6 WCH extrapolated these results to estimate that approximately 5% to 10% of individuals with asthma use nonprescription bronchodilators as monotherapy.6 The primary reasons given for nonprescription use--ease of access and lower cost--directly correlate with health care providers' concerns that individuals using nonprescription asthma products may not be receiving appropriate disease management.6
The properties desirable in acute asthma treatment include effectiveness as a bronchodilator, safeness when taken as labeled, fast onset of action, and long duration of action. Both inhaled epinephrine and oral ephedrine have demonstrated efficacy in trials for decades. Given the mixed cardiovascular results in clinical trials, however, the safety of nonprescription bronchodilator use by individuals who may not be followed medically is a major concern of health care providers. Inhaled epinephrine has a faster onset of action than oral ephedrine, but its short duration of action may limit its effectiveness.
The availability of oral ephedrine has been limited since 2006 by its behind-the-counter status. The availability of inhaled epinephrine hinges on the FDA's decision regarding whether this formulation will maintain its essential-use designation. No nonprescription alternatives exist for currently marketed CFC-containing nonprescription bronchodilators.12 One manufacturer tried to reformulate its nonprescription inhaled-epinephrine product with a hydrofluoroalkane propellant, with undesirable effects for the user; it has partnered with another pharmaceutical firm for reformulation in anticipation of filing with the FDA by 2011.6 Key concerns regarding alternative propellants include the need for effective delivery of epinephrine and safety and efficacy data for the new product as a result of the changes.18
In determining whether to remove the essential-use designation for inhaled epinephrine, the FDA is not examining the safety or efficacy of the currently marketed CFC-containing products; rather, it is examining the impact on public health should the designation be removed. In letters from the National Association of Chain Drug Stores and the American Pharmacists Association to the FDA on the proposal to remove the essential-use designation, the primary concern was the potential negative impact on current users of nonprescription inhalers if the products became unavailable.19,20 The FDA has stated that if the proposed rule to remove the essential-use designation becomes final and nonprescription alternatives do not exist, it will be necessary for consumers to obtain a prescription for an alternative product.12 Many consumers using inhaled epinephrine may choose to forego asthma treatment or seek alternative nonprescription therapy.
It is imperative that the medical community make the public aware of the seriousness of the consequences of uncontrolled asthma and that any person who experiences difficulty breathing should see a health care provider for diagnosis and treatment. A patient who chooses to use nonprescription bronchodilators should be advised to inform his or her health care provider; the patient also should be counseled on the difference in label instructions between nonprescription and prescription inhalers. The current continued accessibility of nonprescription bronchodilators necessitates the informed counseling of patients to prevent improper use of these products and subsequent adverse effects.
1. Moorman JE, Rudd RS, Johnson CA, et al. National Surveillance for Asthma--United States, 1980–2004. MMWR. Oct 19, 2007;56:1-14, 18-54.
2. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 2007.
3. Akinbami L. Asthma prevalence, health care use and mortality: United States, 2003-05. National Center for Health Statistics. www.cdc.gov/nchs/products/pubs
/pubd/hestats/ashtma03-05/asthma03-05.htm. Accessed December 10, 2007.
4. W. Steven Pray. OTCproducts and asthma therapy. US Pharm. 1997;22(7):18-22.
5. Dickinson BD, Altman RD, Deitchman SD, Champion HC. Safety of over-the-counter inhalers for asthma: report of the Council on Scientific Affairs. Chest. 2000;118:522-526.
6. Wyeth ConsumerHealthcare. 2005N–0374. Use of ozone-depleting substance: essential-use determination of over-the-counter (OTC) epinephrine metered dose inhalers. Briefing document. December 19, 2005. www.fda.gov/ohrms/dockets/ac
/06/briefing/2006-4200B1_01_01-Wyeth-Backgrounder.pdf. Accessed December 30, 2007.
7. Kupec IF. Theophylline-containing bronchodilators and ephedrine drug products. Answers T95-40. July 27, 1995. www.fda.gov/bbs/topics/ANSWERS/ANS00675.html. Accessed December 10, 2007.
8. Drug Enforcement Administration. General information regarding the Combat Methamphetamine Epidemic Act of 2005 [Title VII of Public Law 109-177]. May 2006. www.deadiversion.usdoj.gov/meth/cma2005_general_info.pdf. Accessed February 4, 2008.
9. Jarabek AM, Fisher JW, Rubenstein R, et al. Mechanistic insights aid the search for CFC substitutes: risk assessment of HCFC-123 as an example. Risk Anal. 1994;14:231-250.
10. DeCanio SJ, Norman CS. Economics of "essential use exemptions" for metered-dose inhalers under the Montreal Protocol. J Environ Manage.2007;85:1-8.
11. D'Souza S. The Montreal Protocol and essential use exemptions. J Aerosol Med. 1995;8(suppl 1):S13-S17.
12. Food and Drug Administration. FDA News. FDA proposing phase out of CFCs in metered-dose inhalers for epinephrine. www.fda.gov/bbs/topics/NEWS
/2007/NEW01706.html. Accessed December 10, 2007.
13. Food and Drug Administration. Code of Federal Regulation 21 CFR part 2 2007N-0262. www.fda.gov/ohrms/dockets/98fr/cd0612.pdf. Accessed February 6, 2008.
14. Whitehall-Robins. RE: docket no. 98N-0148; Fed. Reg. 13258, international drug scheduling; Convention on Psychotropic Substances. April 16, 1998. www.fda.gov/ohrms/dockets/dockets/98n0148/c000010.pdf. Accessed December 30, 2007.
15. Lexi-Comp Online. www.crlonline.com. Accessed December 28, 2007.
16. Tashkin DP, Meth R, Simmons DH, Lee YE. Double-blind comparison of acute bronchial and cardiovascular effects of oral terbutaline and ephedrine. Chest. 1975;68:155-161.
17. Dulfano MJ. The new oral bronchodilators [editorial]. Chest.1975;68:133-134.
18. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; amendment of monograph for OTC bronchodilator drug products. Fed Regist. 1996; 61:25142-25147.
19. National Association of Chain Drug Stores. Subject: use of ozone-depleting propellants; removal of essential use designation for over-the-counter epinephrine metered-dose inhalers (MDIs). January 6, 2006. www.fda.gov/ohrms/dockets/dockets/05n0374/05n-0374-EC6-Attach-1.pdf. Accessed February 6, 2008.
20. Statement of the American Pharmacists
Association (APhA) to the Food and Drug Administration's Nonprescription Drugs
Advisory Committee and the Pulmonary-Allergy Drugs Advisory Committee. Use of
ozone-depleting substance: essential-use determination of OTC epinephrine
metered dose inhalers. January 24, 2006.
February 6, 2008.
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