Over‐the‐Counter Statin Therapy—Pros and Cons

A prescription drug typically becomes a candidate for over‐the‐counter (OTC) status if it is used for an intermittent condition that can be easily self‐diagnosed; moreover, an OTC compound should have low abuse potential under conditions of widespread availability. Statins in no way fit this description, since their use is for a chronic condition and, once therapy begins, there inevitably is not a prespecified end point. Thus, considerable debate both preceded and trailed the United Kingdom's Medicines and Healthcare Products Regulatory Agency's decision in May 2004 to reclassify simvastatin 10 mg (Zocor Heart‐Pro; Merck Manufacturing Division, Merck Sharp and Dohme Limited, Northumberland NE23 3JU, UK) as an OTC medication.

THE UNITED STATES' VIEW

Lovastatin was the first statin to be approved in the United States and has been available for 17 years. At the present time, there are over 27 million patient‐years of experience with this generically available statin. The history of attempts to bring statin therapy to OTC status in the United States dates back to 1999. At that time, an initial switch application to OTC status was separately submitted to the FDA for lovastatin 10 mg (Mevacor; Merck & Co., Inc., Whitehouse Station, NJ) and pravastatin 10 mg (Pravachol; Bristol‐Myers Squibb, New York, NY). In July 2000, the FDA's Advisory Committee suggested additional study of consumer behavior relative to purchase of an OTC statin and more definitive evidence of benefit in the proposed intermediate‐risk target population. ¹

Concrete evidence became available for intermediate‐risk patients based on the rather persuasive results of a primary prevention study—the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). ² This study included 6605 intermediate‐risk patients (10‐year risk for coronary heart disease of up to 20% and at least two atherosclerotic risk factors) treated with 20 mg and, if needed, titration to 40 mg/d of lovastatin. The entrance criteria for this study included cholesterol levels of 180–264 mg/dL, LDL cholesterol levels of 130–190 mg/dL, and HDL cholesterol levels of up to 45 mg/dL in men and up to 47 mg/dL in women. After a median of 5.2 years, the observed findings included a 37% relative risk reduction for a first major coronary event. There was no increase in noncardiac mortality with lovastatin compared with placebo, and the discontinuation rate was similar both in the lovastatin and placebo groups. ² The dose of lovastatin employed in AFCAPS/TexCAPS was one of several determining factors in the 2004 request for lovastatin OTC status to be at a 20 mg dose (originally the request was for approval of a 10 mg dose in 1999). ¹

The issue of consumer behavior was also addressed as an advised prerequisite to the rereview of OTC status for lovastatin. This was done by way of the Consumer Use of OTC Mevacor (CUSTOM) study, ³ which evaluated the ability of subjects to self‐manage elevated LDL cholesterol using a multifaceted cholesterol self‐management program, the Mevacor Over‐the‐Counter Self‐Management System (MOTC‐SMS). This 26‐week, all‐comers, multicenter observational study was conducted in naturalistic storefront settings that used the fully functional MOTC‐SMS to guide subjects' behavior. Of 3316 subjects who evaluated the product (evaluators), 1061 took at least one 20 mg tablet of Mevacor OTC (users). Eighty‐four percent of evaluators made appropriate initial‐use decisions. Most users demonstrated suitable ongoing‐use actions regarding treatment to goal, compliance/persistence, changes in health status, dietary patterns, and exercise habits. ³

FDA DELIBERATIONS

It is in the setting of prior approval for simvastatin in the United Kingdom as well as the AFCAPS/TexCAPS and CUSTOM studies that lovastatin was re‐reviewed at a 20 mg dose (Mevacor‐OTC) by the combined Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees in February 2005. The approval application switch from a 10 mg dose for OTC lovastatin to a 20 mg dose reflected an evolved understanding of the risk:benefit ratio of low‐dose statin therapy in the management of hypercholesterolemia. As a matter of record, the FDA routinely convenes such panels prior to making regulatory decisions. More often than not, the FDA adheres to the recommendations of such panels.

In the case of lovastatin 20 mg, the committee voted in a rather decided fashion (20 to 3) against a shift to OTC status. During the official vote, panel members agreed that 20 mg of lovastatin was quite effective in lowering LDL cholesterol. They unanimously agreed that concerns about muscle toxicity and liver function with lovastatin would not be sufficient to stop the compound from moving to OTC status.

During this meeting, the OTC experience with simvastatin in the United Kingdom was a frequent topic of discussion, since the regulatory bodies in the United Kingdom considered many of the same issues that the FDA advisory panel was being asked to consider. ⁴ , ⁵ Several panel members said that if they had the option of pharmacist control, they would have voted to recommend the OTC indication—but they were concerned that the sometimes aggressive nature of health marketing would shift the risk:benefit ratio too far toward patient risk if the patient were to make the decision to treat or not without any counseling.

THE PROCESS AT PLAY IN THE UNITED KINGDOM

Lovastatin 10 mg is available as Zocor Pro‐Heart for men over 45 years and women over 55 years of age who have other risk factors for cardiovascular disease (smoking, obesity, family history) and for all men over 55 years of age, regardless of risk. The pharmacist ideally assesses the patient's risk, which does not require the routine testing of cholesterol. The involvement of a pharmacist in this process is based on the UK's decision to classify simvastatin as a “pharmacy” product, wherein medications are placed behind the counter and distributed with a pharmacist's consultation—which is a third category not approved by US pharmaceutical law. Simvastatin is not in the “general sales list” category, which would be equivalent to OTC status in the United States.

The package insert for Zocor Heart‐Pro contains the following warnings as to when not to take this medication:

• 1)If you have liver disease or you have been told you have abnormal liver function blood tests;
• 2)If you drink more than 4 units of alcohol a day for men and 3 units of alcohol a day for women (one unit is 1/2 pint of lager, a pub measure of wine, or one shot);
• 3)If you have had an allergic reaction to this or similar medicines or to any of the ingredients in the past;
• 4)If you are already taking prescription drugs to lower your cholesterol;
• 5)If you become pregnant, are pregnant, plan to become pregnant, or are breast feeding;
• 6)If you discover you are pregnant while taking Zocor Heart‐Pro. In this case, you should stop taking these tablets immediately and contact your doctor;
• 7)If you have had muscle problems in the past after taking a cholesterol‐lowering medicine;
• 8)If you are taking one of the following medicines: oral antifungal medicines called itraconazole or ketoconazole; antibiotics called erythromycin, telithromycin, or clarithromycin; medicines for HIV infections called protease inhibitors (such as indinavir, nelfinavir, ritonavir, or saquinavir); or the antidepressant nefazodone;
• 9)If you have an underactive thyroid gland (hypothyroidism), kidney problems, a family history of muscle disorders, or are over age 70, you should check with your doctor before taking this product;
• 10)If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking Zocor Heart‐Pro, since this product contains lactose;
• 11)Zocor Heart‐Pro should not be used by children.

The label goes on to say that if you are in one of the following groups, you are at a higher risk of coronary heart disease. You should discuss your condition with your doctor since you are likely to need more than these tablets to reduce your risk.

• 1)You already have angina or have had a heart attack;
• 2)You have diabetes;
• 3)You have had a stroke;
• 4)You have disease of the arteries of your legs or neck; or
• 5)You have inherited (it runs in the family) very high blood cholesterol levels.

In the course of a recent visit to London, the opportunity arose to gain a better understanding of the process at play for the OTC purchase of simvastatin. As it turned out, I was able to purchase the product in one location with no qualifying assessment other than a question as to whether my cholesterol value was elevated. The price was approximately $1 per tablet of simvastatin when purchased as a 1‐month supply. Of note, in discussion with one pharmacist, she was quite frank in her concern about shifting responsibility to pharmacists to act as “gatekeeper” for those intermediate‐risk individuals in need of cholesterol lowering. ⁵ Obviously, one interview does not in any way generate a consensus—but it does point out that this model still has some growing pains.

CONCLUSIONS

Economic pressures in the United States will increasingly push certain medications toward an OTC status. This is particularly so if the medication in question follows the track of previously approved drugs for intermittent conditions such as hay fever or gastroesophageal reflux. OTC status for a medication in large measure transfers costs directly to the patient, because prescription plans will not cover the cost of medication acquired in this way. This amounts to a not‐so‐subtle method of cost diversion. In return for assuming fiscal responsibility, however, the patient is empowered to self‐medicate‐without the other health care costs that might follow from a physician encounter. ⁶

The OTC status for a statin differs from that of drugs being used for intermittent conditions. Accordingly, we will have to carefully rethink the economic implications of this form of therapy. Nonetheless, the cost–benefit ratio for an OTC approach to managing hypercholesterolemia in intermediate‐risk patients seems to fall more on the side of benefit, but is still in need of some fine‐tuning. ⁷ The denial of OTC status for lovastatin should not be viewed as an immutable decision. A greater public realization of the unmet need for cholesterol reduction in intermediate‐risk patients, a less guarded approach to this type of therapy on the part of physicians, and a greater role for pharmacists in the implementation process should result in a more favorable future review on the part of advisory panels and, ultimately, the FDA. ⁸