U.S. Prescribing Information for Simvastatin Revised to Include New Limits on the Use of the Highest Dose -- 80 mg -- and

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)-- Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced changes to the prescribing information in the United States for the highest dose of simvastatin, 80 mg, and the use of simvastatin with certain other medicines. Simvastatin is a cholesterol-lowering medicine developed by Merck (marketed as ZOCOR®) that is now widely available in generic form; simvastatin is also a component of VYTORIN® (ezetimibe/simvastatin), another cholesterol-lowering medicine from Merck. The revised U.S. prescribing information for ZOCOR and VYTORIN reflecting the changes regarding the 80 mg dose of simvastatin and the drug interaction updates are posted at www.merck.com (see direct links below).

The changes follow a U.S. Food and Drug Administration (FDA) review, announced by the agency in March 2010, of the risk of muscle injury (called myopathy, including its most serious form, rhabdomyolysis) with the highest dose of simvastatin. Merck has updated the U.S. prescribing information:

  • To limit the use of the high dose of simvastatin, 80 mg, which is taken by approximately 12 percent of U.S. simvastatin users, to patients who have been taking that prescribed amount chronically (e.g., for 12 months or more) without evidence of muscle toxicity; and, in addition,
  • To contraindicate and/or limit the dose of simvastatin when used with certain drugs where the combined use may increase the risk of myopathy and rhabdomyolysis.

These updates are described further below.

"Nothing is more important to Merck than the safety of our medicines and the well-being of the patients who take them," said Michael Rosenblatt, M.D., chief medical officer for Merck. "We are proud of the role that simvastatin plays along with a healthy diet for patients with high cholesterol and those at high risk for heart attacks and strokes. Many people who take simvastatin will not be affected by these label updates. We encourage those who think these changes might affect them to talk to their doctor. Patients should talk with their doctor before they stop taking any of their medicines. We are committed to communicating these changes to help physicians and their patients understand the updated recommendations for use of this important medicine."

As part of that commitment, Merck has launched a new website, www.simvastatininfocenter.com, with information for patients on these updates.

Prescribing information for ZOCOR has included information about the risk of myopathy and rhabdomyolysis since the initial approval of the medicine in 1991 and has described the dose-related nature of this risk since 2002. The FDA's review concluded that there is an increased risk of myopathy, including rhabdomyolysis, with simvastatin 80 mg compared with other statin therapies that can provide similar or greater reduction in LDL cholesterol and compared with lower doses of simvastatin. This increased risk is highest during the first year of treatment and then notably decreases.

In addition to limiting use of the 80 mg dose, the updated U.S. prescribing information modifies limitations on concomitant use of simvastatin with certain drugs:

  • the use of simvastatin is contraindicated with certain azole antifungals and antibiotics, with HIV protease inhibitors, and with the drugs nefazodone, gemfibrozil, cyclosporine, and danazol; and
  • the maximum recommended doses of simvastatin have been revised when used with amiodarone, ranolazine, and the calcium channel blockers verapamil, diltiazem and amlodipine.

Merck will be communicating to physicians about the changes, and also will communicate with managed care organizations and others to support efforts to implement the revised recommendations for use.

Simvastatin was approved by the FDA under the brand name ZOCOR in 1991. The highest dose, 80 mg, was approved in 1998. In studies, more than 40,000 patients have been treated with simvastatin, and more than 12,000 of these patients received simvastatin 80 mg. Simvastatin has been available generically since 2006 and it is estimated that the vast majority of patients taking simvastatin are taking a generic formulation of the drug.

The FDA's review was based on final data from a Merck-funded clinical study called SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) that compared simvastatin 80 mg to simvastatin 20 mg, and on data from other sources. In 2005, Merck voluntarily updated the labeling for ZOCOR to incorporate the myopathy/rhabdomyolysis rates observed in earlier years of SEARCH. Since the final results of SEARCH became available in 2009, Merck has worked with regulatory agencies around the world to incorporate them into labeling.

Besides the website, people seeking additional information about these label changes may also contact Merck at 1-800-235-1434.

Additional information about simvastatin

Simvastatin is indicated, in addition to diet, when diet and other nondrug therapy are not enough, to reduce elevated total cholesterol, LDL cholesterol, Apo B, and triglycerides and to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and combined hyperlipidemia (Fredrickson Types IIa and IIb). Simvastatin also is indicated, along with diet, to reduce the risk of total mortality (by reducing CHD deaths), nonfatal MI, and stroke; and to reduce the need for coronary and noncoronary revascularization procedures in patients at high risk of coronary events because of existing CHD, diabetes, peripheral vascular disease, or history of stroke or other cerebrovascular disease.

Simvastatin should not be taken with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone); with gemfibrozil, cyclosporine, or danazol; by anyone with active liver disease, unexplained persistent elevations of serum transaminases, or hypersensitivity to the product; or by women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant.

The use of simvastatin and the insights from Merck's studies of simvastatin have contributed to the reduction in deaths from heart attacks and strokes in patients at high cardiovascular risk over the last two decades. Merck's landmark 1994 4S study of simvastatin was the first large outcomes study to definitively establish the role of lowering LDL with a statin along with diet in helping to save lives by reducing heart attacks.

Selected cautionary information about simvastatin

Muscle pain, tenderness, or weakness in people taking simvastatin should be reported to a doctor promptly because these could be signs of a serious side effect. Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness, or weakness with creatine phosphokinase (CK) levels above 10 × ULN. Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have occurred. The risk of myopathy, including rhabdomyolysis, is dose related. Predisposing factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Therapy with simvastatin should be discontinued immediately if myopathy is diagnosed or suspected.

The risk of myopathy, including rhabdomyolysis, is greater in patients taking simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy, and with lower doses of simvastatin. Patients using 80 mg should be advised of this increased risk. Use of the 80 mg dose is restricted.

Because of the increased risk of myopathy/rhabdomyolysis, particularly at higher doses of simvastatin, concomitant use is contraindicated with drugs that are strong CYP3A4 inhibitors or with gemfibrozil, cyclosporine or danazol, and large quantities of grapefruit juice (>1 quart daily) should be avoided. Use caution when prescribing simvastatin with other fibrates or colchicine. The dose of simvastatin should not exceed 10 mg daily in patients receiving concomitant therapy with amiodarone, verapamil or diltiazem, and 20 mg daily in patients receiving amlodipine or ranolazine. The use of simvastatin with these drugs, or with lipid-lowering doses of niacin, should be carefully weighed against the potential risk of myopathy/rhabdomyolysis with these combinations. Chinese patients should not receive simvastatin 80 mg daily with niacin (≥1 g/day), and caution should be used when Chinese patients taking niacin are co-administered simvastatin doses exceeding 20 mg/day. Adjustment of the simvastatin dose may be needed when used with voriconazole. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking simvastatin.

Doctors should perform blood tests to check for liver problems before treatment with simvastatin and thereafter when clinically indicated. If an increase in serum transaminases persists at or above 3 times the upper limit of normal (ULN), discontinue the drug. Persistent increases (>3 times ULN) in serum transaminases have occurred in approximately 1% of patients who received simvastatin in clinical trials.

In clinical trials of simvastatin, the most commonly reported side effects, regardless of cause, included upper respiratory infections (9.0%), headache (7.4%), abdominal pain (7.3%), constipation (6.6%), and nausea (5.4%).

Selected dosage and administration information about simvastatin

The recommended usual starting dose of simvastatin is 10 or 20 mg once a day in the evening. For patients at high risk of a CHD event due to existing CHD, diabetes, peripheral vascular disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day. The usual dosage range is 5 to 40 mg/day. Use of the 80 mg dose is restricted and patients should not be titrated to that dose; see Dosage and Administration section of Prescribing Information for additional information. No dosage adjustment is necessary in patients with mild or moderate renal impairment. Caution should be used when simvastatin is administered to patients with severe renal impairment; such patients should be started at 5 mg/day and be closely monitored.

Additional important information about VYTORIN (ezetimibe/simvastatin)

VYTORIN contains 2 active ingredients: ezetimibe and simvastatin. VYTORIN is indicated as adjunctive therapy to diet for the reduction of total cholesterol, LDL cholesterol, Apo B, triglycerides, and non–HDL cholesterol and to increase HDL-C in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed hyperlipidemia. No incremental benefit of VYTORIN on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established.

VYTORIN is available as tablets containing 10 mg of ezetimibe combined with 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40, or 10/80 mg, respectively). The recommended usual starting dose is 10/10 mg/day or 10/20 mg/day. Patients who require a larger reduction in LDL-C (greater than 55%) may be started at 10/40 mg/day. The usual dosage range is 10/10 mg/day to 10/40 mg/day. Because the 10/80 mg dose of VYTORIN contains 80 mg of simvastatin, use of the 10/80 mg dose is restricted and patients should not be titrated to that dose; see Dosage and Administration section of Prescribing Information for additional information. Patients with severe renal insufficiency should not receive VYTORIN unless they already have tolerated treatment with simvastatin.

The use of fibrates with VYTORIN is not recommended (and as with simvastatin, gemfibrozil is contraindicated).

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, VYTORIN is not recommended in these patients.

As with simvastatin, doctors should perform blood tests to check for liver problems. In three placebo-controlled, 12 week trials, the incidence of consecutive elevations (≥3 × ULN) in serum transaminases was 1.7 percent overall and appeared to be dose related, with an incidence of 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly treated and previously treated patients, the incidence of consecutive elevations (≥3 × ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with 10/80 mg. These elevations were generally asymptomatic, not associated with cholestasis, and reversible whether treatment was maintained or discontinued.

In clinical trials of VYTORIN, the most commonly reported side effects, regardless of cause, included headache (5.8%), increased ALT (3.7%), myalgia (3.6%), upper respiratory tract infection (3.6%), and diarrhea (2.8%).

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the United States and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2010 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Please see Prescribing Information for ZOCOR (simvastatin) at www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf.

Please see Prescribing Information for VYTORIN (ezetimibe/simvastatin) at www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdf and Patient Information for VYTORIN at www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_ppi.pdf.

ZOCOR® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

VYTORIN® is a registered trademark of MSP Singapore Company, LLC.



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