Perspective
Statins and Over-the-Counter Availability
N Engl J Med 2005; 352:1403-1405April 7, 2005
- Article
Approximately 1000 active ingredients are currently in use in more than 100,000 over-the-counter medications in the United States, with combined annual sales exceeding $17 billion. Many drugs have recently been switched from prescription to over-the-counter status; other such switches have been proposed and rejected, in decisions that have sometimes been controversial. Drugs that have been approved by the Food and Drug Administration (FDA) for shifts to over-the-counter status include some nonsteroidal antiinflammatory drugs (such as ibuprofen, naproxen, and ketoprofen), histamine2-receptor blockers (such as cimetidine, ranitidine, and famotidine), topical antifungal agents, and nicotine-based smoking-cessation products. Recent controversial decisions include those regarding nonsedating antihistamines (switched by the FDA despite objections by the manufacturers), hormonal postcoital pregnancy-prevention drugs (i.e., the “morning-after pill,” which was denied over-the-counter status), and statins, for which a proposed status change was rejected (see Table 1
Selected Drugs Switched by the Food and Drug Administration from Prescription to Over-the-Counter Status, 1995 to 2003.).Over-the-counter status offers some clear potential advantages over prescription status. The medication becomes easier to obtain, and access to it broadens. The price of the drug often drops, and patients avoid both the cost and the delay of a visit to a prescribing physician. Patients' ability to choose their own medications increases their autonomy, and patients benefit from educating themselves about their options. There are also benefits for the manufacturer, which gains a new opportunity for profits after its patent has expired and competitors have entered the market, since patent protection is frequently extended when such a switch is made.
Of course, there are a number of potential disadvantages as well, including risks related to self-treatment by patients — risks of misdiagnosis, delays in obtaining a correct diagnosis, adverse interactions with other medications, reduced opportunities to receive counseling about possible lifestyle therapies (such as exercise and diet), poorer compliance (by patients who view over-the-counter drugs as different from “real” medications), use by patients who are unlikely to benefit from the drug but will nevertheless be exposed to its risks, and patterns of taking medications inappropriately (e.g., “if one is good, two are better”). In addition, patients with insurance that covers medications face the paradox of increased, rather than reduced, costs for their medications, because insurers ordinarily do not cover over-the-counter drugs, prices of which may exceed the amount of patients' copayments for the prescription versions. Finally, over-the-counter use renders it more difficult to study a drug's effects, since prescription databases can no longer be used for that purpose.
Generally, drugs are eligible for over-the-counter status if they can be used safely and effectively and have a label that is easily understood by the average person in order to permit self-treatment. Although determining whether a drug meets this standard is ultimately a matter of judgment, there are some generally accepted criteria that may be useful in guiding that judgment. Typically, the condition treated by the medication can be self-diagnosed by consumers, the success of the therapy monitored by patients, and the condition expected to be short-lived, so that consumers can be directed to visit a physician if it continues or worsens. Furthermore, the condition and its other treatments need to be sufficiently understandable to consumers that they can choose whether to initiate treatment, as well as which drug to use and at what dose and frequency to take it. It is also useful if the condition being treated is sufficiently innocuous that symptomatic treatment will not prove counterproductive by delaying definitive treatment.
In addition, the drug might be assessed according to certain criteria. Generally, it would have established efficacy for the treatment of a self-diagnosed condition, consumers would be able to determine whether they had any contraindications to its use, and any complications would be self-diagnosable and self-treatable. Furthermore, the drug should have a large safety margin, at high doses, that has been proved in large numbers of patients, and it should be established enough that doctors and patients are aware of its serious adverse effects. It should have a low potential for misuse and abuse and should have no or few adverse interactions with other drugs. Treatment with it should not have the capacity to mask serious illness. Its efficacy and safety should not depend critically on the precise dose or frequency of administration, and it should be possible to label it in lay terminology for proper use. Finally, it should be safe even when used by consumers other than those for whom it is recommended on the label — pregnant women, for instance, and people outside the recommended age range.
Given these considerations, it is relatively easy to see why an FDA advisory committee, faced with a second proposal to grant over-the-counter status to statins, recently recommended against doing so. Proponents of over-the-counter access for this class of drugs cite their dramatic efficacy, relative safety, and underuse, stating that many people in the United States would benefit from more aggressive efforts to lower levels of cholesterol. Moreover, serious illness is unlikely to be masked by this therapy, and there is precedent in the United Kingdom, where some statins are no longer restricted to prescription access.
The experience in the United Kingdom, however, is largely irrelevant, since the drugs there are available not over the counter but, rather, “behind the counter” (a third option that is not used in the United States), meaning that an intervention by a pharmacist is still required. More important, statins fail to meet many of the other criteria for a switch to over-the-counter status.
Hypercholesterolemia, the indication for statin use, is not self-diagnosable. Treatment is long-term. The efficacy of statins is dose-related, and monitoring is required for titration. Over-the-counter drugs are typically formulated at a lower dose than are prescription drugs, to address concerns about the safety margin, but access to lower-dose statin therapy may delay or prevent patients from receiving higher-dose (albeit not curative) therapy under a physician's direction. Furthermore, patients might conflate hypercholesterolemia with its complications (e.g., coronary artery disease) and might purchase statins rather than visit their physician when they have angina. Other consumers, despite having normal cholesterol levels, might treat themselves for peace of mind — which would significantly affect the therapy's risk–benefit balance.
Statins have not been proved effective for a self-diagnosed condition, and their contraindications and complications, such as liver disease, are unlikely to be self-diagnosed. It is true that statins have a large safety margin and have been used in many patients, but whereas the potential for abuse is clearly low, the potential for misuse is not. For example, some patients may self-medicate irrationally (“I ate a hamburger, so I'll take an extra pill”), increasing the risk of dose-related adverse effects (such as rhabdomyolysis), and the risk of serious toxic effects increases when these drugs interact with other medications.
The label on prescription statins recommends monitoring of liver function at baseline, at 12 weeks, after any increase in dose, and periodically thereafter. Some physicians also monitor patients for toxic effects on muscle. The efficacy of these agents is sensitive to the proper choice of dose, frequency, and with some statins, whether the medication is taken with meals.
Compliance is known to be woefully inadequate among many recipients of prescription statins. Studies show that patients need one to two years of continuous therapy for benefit to be achieved; even with a physician's supervision, such a course of treatment is not completed by a large proportion of patients. Would patients follow directions better with over-the-counter statins? Furthermore, given that insured patients would need to pay for the drugs out of their own pockets, it is unclear that their use would increase.
Finally, safety in special populations, especially pregnant women, is uncertain. Indeed, on the basis of studies in animals, statins have been classified as category X drugs, which are contraindicated during pregnancy.
The motivation for making statins available over the counter is understandable: to increase access to an effective and underused therapy. But it is unclear that such a switch would help to achieve that goal. Although statins are great prescription drugs, these considerations suggest that they would make poor over-the-counter drugs.
Dr. Strom reports having received consulting fees or funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, Novartis, and Pfizer and having provided legal testimony in cases involving Bayer, Bristol-Myers Squibb, and Pfizer.
Source Information
Dr. Strom is a professor of biostatistics and epidemiology at the University of Pennsylvania School of Medicine, Philadelphia.
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Alan M. Weiss. (2009) Cardiovascular Disease in Women. Primary Care: Clinics in Office Practice 36:1, 73-102
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Pertti J Neuvonen, Janne T Backman, Mikko Niemi. (2008) Pharmacokinetic Comparison of the Potential Over-the-Counter Statins Simvastatin, Lovastatin, Fluvastatin and Pravastatin. Clinical Pharmacokinetics 47:7, 463-474
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Valentin Fuster. (2007) A New Perspective on Nonprescription Statins: An Opportunity for Patient Education and Involvement. The American Journal of Cardiology 100:5, 907-910
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Shirya Rashid. (2007) Should cholesterol-lowering medications be available in Canada without a prescription?. Canadian Journal of Cardiology 23:3, 189-193
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Simon W. Beaven, Peter Tontonoz. (2006) Nuclear Receptors in Lipid Metabolism: Targeting the Heart of Dyslipidemia. Annual Review of Medicine 57:1, 313-329
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Hawk, Ernest, Viner, Jaye L., . (2005) Statins and Cancer — Beyond the “One Drug, One Disease” Model. New England Journal of Medicine 352:21, 2238-2239
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