Merck, BMS Prepare To Seek FDA Reversal On OTC Cholesterol Drugs

Merck and Bristol-Myers Squibb are aiming to switch the lowest dosage levels of their respective Rx cholesterol-lowering drugs, Mevacor (lovastatin) and Pravachol (pravastatin), to OTC status. The firms have filed NDAs for approval of OTC 10 mg daily doses.

FDA's Nonprescription Drugs and Endocrinologic & Metabolic Drugs Advisory Committees will evaluate whether the two statin drugs should be available OTC. The committees are scheduled to meet jointly July 13 to consider the Mevacor NDA, filed Dec. 10; Pravachol's switch potential will be taken up by the committees July 14. A July 12 NDAC meeting also is scheduled, but an agenda has not been announced.

The proposed OTC indication for both drugs is to treat individuals with total cholesterol levels of 200- 240 mg/dL and low density lipoprotein levels over 130 mg/dL. Mevacor's indication is limited to men over 40 and postmenopausal women with no established cardiovascular disease or diabetes. Pravachol's indication also applies to individuals without CVD or diabetes but is not age- or gender-specific.

If approved, OTC Mevacor would be marketed by J&J/Merck Consumer Pharmaceuticals. It is expected both Mevacor and Pravachol would continue to be available in prescription strengths for previously approved Rx indications.

In attempting to switch Mevacor OTC, Merck is seeking to build upon a recently expanded indication for a lower risk population, as well as create new sales potential and marketing exclusivity for a drug whose patent expires June 15, 2001.

In March 1999, Mevacor received FDA approval for the primary prevention of coronary heart disease in patients without symptomatic CVD who have average to moderately elevated total and LDL cholesterol, and below-average HDL cholesterol. Marketing exclusivity for the condition expires March 11, 2002.

Approval of the indication was thought to help bolster the firm's case for an Rx-to-OTC switch. Previous indications for Mevacor, the first statin drug introduced, were for the reduction of elevated total and LDL cholesterol levels in patients with primary hypercholesterolemia when response to nonpharmacological measures alone has been inadequate, and to slow progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower total and LDL cholesterol levels.

As Mevacor's patent expiration looms, Merck is managing down sales. First quarter 2000 sales were $125 mil., down 36%, while 1999 U.S. sales totaled $480 mil.; worldwide sales were $600 mil.

Mevacor's usual recommended starting dose is 20 mg once a day with the evening meal. The recommended dosing range is 10-80 mg/day. The drug is available in 10 mg, 20 mg and 40 mg tablets.

Pravachol is indicated for primary prevention of coronary events in hypercholesterolemia patients without clinically evident coronary heart disease. It is indicated to slow progression of coronary atherosclerosis and reduce the risk of acute coronary events in patients with high cholesterol and clinical evidence of heart disease.

In March 1998, FDA approved a supplemental indication for use in patients with previous myocardial infarction and normal cholesterol levels to reduce the risk of recurrent MI, myocardial revascularization and cerebrovascular disease.

With no patent expiration until October 2005, Bristol is attempting an OTC switch earlier in the patent life than is typical for Rx drugs, possibly to establish an early presence in the nonprescription market if and when FDA gives the go ahead for OTC treatment of hypercholesterolemia. Rx Pravachol's recommended starting dose is 10 mg, 20 mg or 40 mg once daily, any time of the day with or without food.

Pravachol's 1999 worldwide sales totaled $1.7 bil. As Bristol's top-selling product, the statin posted worldwide sales of $461 mil. during the first quarter, a 5% decline despite a U.S. price increase.

Bristol is considering a DTC program for the statin - a move that would increase public recognition of the drug in preparation for an OTC switch. BMS has focused its Pravachol promotional efforts on medical education and professional venues in the past year.

Liver dysfunction tops the listed warnings for both statin drugs. "Marked persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials," Mevacor prescribing information states.

Bristol warns: "Increases of serum transaminase values to more than 3 times the upper limit of normal occurring on 2 or more...occasions have been reported in 1.3% of patients treated with pravastatin in the U.S. over an average period of 18 months."

Pravachol's testing requirements in this area may give it an OTC edge over Mevacor. Liver function tests for Pravachol are recommended prior to and at 12 weeks following initiation of therapy or elevation of dose. With Mevacor, liver function tests should be performed "before the initiation of treatment, at 6 and 12 weeks after initiation of therapy or elevation of dose, and periodically thereafter (e.g. semiannually)."

Both drugs also contain warnings about rhabdomyolysis and myopathy, and both are contraindicated in pregnant and nursing women.

In addition to overcoming liver testing requirement obstacles in an OTC setting, Merck and Bristol also will have to face issues that led to BMS' failed switch attempt for the cholesterol drug Questran (cholestyramine) in 1997. Questran advisory committee members expressed concerns about adequate monitoring of consumers using the drug and their ability to self-treat. Drug interactions, side effects, poor compliance and OTC drug costs also were cited.

Extensive consumer and physician education efforts supporting OTC status likely will be outlined by both Merck and Bristol, following a trend toward greater emphasis on consumer educational materials for Rx-to-OTC products, such as audiotapes and user guides sold with smoking cessation products.

In attempting to switch Questran, Bristol proposed separate educational materials for physicians and consumers, with consumer kits containing a booklet, recipes and an offer for instructional audiotapes.

One avenue FDA could take to address concerns about physician monitoring and consumer self-treatment is the creation of a new class of nonprescription "behind the counter" drugs similar to that found in other countries. Although FDA has long resisted the idea, it is seeking public comment on the adequacy of the U.S. OTC marketing structure and other switch-related issues at a June 28-29 meeting (¹ (Also see "Rx-To-OTC Switch Flips On With June Public Forum, July NDAC Meeting" - Pink Sheet, 1 May, 2000.)).

In reexamining the issue of OTC cholesterol treatment, FDA has signaled it may be open to softening its firm stance, announced in a 1997 guidance, against over-the-counter use of cholesterol-lowering drugs.

The July 13 and 14 advisory committee meetings will be held at the Holiday Inn in Bethesda, Md. The open public portion will begin at 8 a.m. July 13. The deadline for written submissions is July 6.