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ASCEND LABORATO
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67877049000

ezetimibe 10 mg tablet (generic zetia)

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Uses

Dyslipidemias

Ezetimibe is used alone or in combination with other antilipemic agents (i.e., a hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor [statin], fenofibrate) as an adjunct to dietary therapy in the treatment of primary hyperlipidemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, and/or homozygous familial sitosterolemia. Efficacy of ezetimibe, alone or in fixed combination with simvastatin, in patients with Fredrickson type I, III, IV, or V dyslipidemias has not been established.

Effects of ezetimibe on cardiovascular morbidity and mortality have not been established.

The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated.For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., ezetimibe) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. However, nonstatin drugs may be useful as adjuncts to statin therapy in high-risk patients (e.g., patients with ASCVD, low-density lipoprotein [LDL]-cholesterol concentrations of at least 190 mg/dL, or diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy, particularly when there is evidence from randomized controlled studies suggesting that the nonstatin drug further reduces ASCVD events when added to statin therapy. When a nonstatin drug is required, selection of the nonstatin drug should be based on a favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects and drug interactions) and patient preferences. For additional details on prevention of ASCVD, see and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

Primary Hyperlipidemia and Mixed Dyslipidemia

Ezetimibe is used alone or in combination with a statin as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apolipoprotein B (apo B), and non-high-density lipoprotein (non-HDL)-cholesterol concentrations in the treatment of primary (heterozygous familial and nonfamilial) hyperlipidemia. Ezetimibe in fixed combination with simvastatin (Vytorin) is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hyperlipidemia or mixed dyslipidemia. Ezetimibe also is used in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia.

Efficacy and safety of ezetimibe monotherapy in the management of primary hyperlipidemia were established in 2 multicenter, randomized, double-blind, placebo-controlled studies of 12 weeks' duration in approximately 1700 patients with primary hyperlipidemia. In these studies, patients who received ezetimibe (10 mg daily) had mean reductions of approximately 12-13% in total cholesterol, 18% in LDL-cholesterol, 15-16% in apo B, 16% in non-HDL-cholesterol, and 7-9% in triglyceride concentrations; increases in high-density lipoprotein (HDL)-cholesterol concentrations in patients receiving ezetimibe were negligible (1%). In most patients with primary hyperlipidemia, maximal or near-maximal reductions in serum lipoprotein and apolipoprotein concentrations are achieved within 2 weeks and maintained during continued therapy. Reductions in LDL-cholesterol concentrations appear to be consistent across age, gender, and baseline LDL-cholesterol concentrations.

Data from several multicenter, randomized, double-blind, placebo-controlled studies indicate that concomitant therapy with ezetimibe and a statin may produce additive antilipemic effects. In a study in patients with primary hyperlipidemia and either multiple cardiovascular risk factors or documented coronary heart disease (CHD) who had not achieved their target LDL-cholesterol goal with diet and statin monotherapy, addition of ezetimibe (10 mg daily) to existing statin therapy reduced total cholesterol, LDL-cholesterol, apo B, non-HDL-cholesterol, and triglyceride concentrations by an additional 17, 25, 19, 23, and 14%, respectively, at 8 weeks and increased HDL-cholesterol concentrations by an additional 3% compared with statin monotherapy. For patients whose LDL-cholesterol levels were above the target levels recommended by the Second Report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel [ATP] II), approximately 72% of patients receiving combination therapy achieved their target LDL-cholesterol goal compared with 19% of those receiving statin monotherapy. In 4 multicenter, randomized, double-blind, placebo-controlled studies in hyperlipidemic patients, combination therapy with ezetimibe (10 mg daily) and a statin (i.e., atorvastatin 10-80 mg daily, lovastatin 10-40 mg daily, pravastatin 10-40 mg daily, or simvastatin 10-80 mg daily), initiated concurrently and continued for 12 weeks, reduced total cholesterol, LDL-cholesterol, apo B, non-HDL-cholesterol, and triglyceride concentrations and, except for the combination of ezetimibe and pravastatin, increased HDL-cholesterol concentrations compared with monotherapy with the corresponding statin. Following combination therapy with ezetimibe and either atorvastatin, simvastatin, pravastatin, or lovastatin, total reductions in LDL-cholesterol concentrations averaged 53-61, 46-58%, 34-42, or 34-46, respectively, compared with reductions of 37-54, 27-45, 21-31, or 20-30% with atorvastatin, simvastatin, pravastatin, or lovastatin monotherapy, respectively. Results of one study in patients with known CHD or CHD risk equivalents indicated that reductions in LDL-cholesterol concentrations achieved with the combination of ezetimibe 10 mg and simvastatin 10 mg (47%) were greater than those achieved with simvastatin 20 mg alone (38%).

Similar additive antilipemic effects were observed following therapy with the fixed-combination preparation containing ezetimibe and simvastatin. Data from several randomized, double-blind studies in patients with primary hyperlipidemia indicated that reductions in LDL-cholesterol concentrations achieved with pooled doses of the fixed-combination preparation were greater than those achieved with pooled doses of atorvastatin, rosuvastatin, or simvastatin monotherapy. In one study, LDL-cholesterol concentrations were reduced by 47-59% following therapy with the fixed-combination preparation containing ezetimibe (10 mg) and simvastatin (10-80 mg) and by 36-53% following monotherapy with atorvastatin (10-80 mg daily). In another study, LDL-cholesterol concentrations were reduced by 52-61% following therapy with the fixed-combination preparation containing ezetimibe (10 mg) and simvastatin (20-80 mg) and by 46-57% following monotherapy with rosuvastatin (10-40 mg daily). In the third study, LDL-cholesterol concentrations were reduced by 45-60% following therapy with the fixed-combination preparation containing ezetimibe (10 mg) and simvastatin (10-80 mg) and by 33-49% following monotherapy with simvastatin (10-80 mg daily).

Despite its additive effects on LDL-cholesterol reduction, early findings from a randomized, double-blind, active-controlled study (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression [ENHANCE]) in patients with heterozygous familial hypercholesterolemia indicated that the fixed-combination preparation containing ezetimibe and simvastatin (10 and 80 mg daily, respectively) was not superior to simvastatin monotherapy (80 mg daily) in reducing carotid intimal-medial wall thickness (cIMT). In this study, treatment with the fixed-combination preparation for 2 years resulted in a change in cIMT (increase of 0.011 mm) that was not statistically different from the change in cIMT observed with simvastatin monotherapy (increase of 0.006 mm). However, reductions in LDL-cholesterol concentrations achieved with the fixed-combination preparation (56%) were substantially greater than those achieved with simvastatin monotherapy (39%). Although the greater reductions in LDL-cholesterol concentrations did not translate into substantial improvement in cIMT in the ENHANCE study, the cardiovascular benefits of reducing LDL-cholesterol concentrations are well established and have been demonstrated in other studies.

The addition of ezetimibe to simvastatin therapy resulted in further LDL-cholesterol lowering and improved cardiovascular outcomes in the Improved Reduction of Outcomes: Vytorin Efficacy International (IMPROVE-IT) study. IMPROVE-IT was a large randomized, double-blind study in 18,144 patients who had been hospitalized for an acute coronary syndrome in the preceding 10 days and had baseline LDL-cholesterol concentrations of 50-125 mg/dL (or 50-100 mg/dL if they were receiving lipid-lowering therapy). Patients were randomized to receive the fixed-combination preparation containing ezetimibe and simvastatin (10 and 40 mg daily, respectively) or simvastatin monotherapy (40 mg daily). After a median duration of follow-up of 6 years, the fixed-combination preparation produced a 24% further reduction in mean LDL-cholesterol concentration and also reduced the rate of the primary end point (composite of cardiovascular death, nonfatal myocardial infarction [MI], unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke) compared with simvastatin monotherapy; the absolute risk reduction for the primary composite outcome was 2% over 7 years. The treatment benefit of combined simvastatin/ezetimibe therapy began to emerge after 1 year and appeared to be particularly pronounced in patients with diabetes mellitus and geriatric patients (75 years of age or older).

The combination of ezetimibe and fenofibrate has been shown to reduce total and LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in patients with mixed dyslipidemia. In a randomized, double-blind, placebo-controlled study in patients with mixed dyslipidemia, combination therapy with ezetimibe and fenofibrate (160 mg daily) was superior to fenofibrate monotherapy in reducing total cholesterol (22 versus 11%), LDL-cholesterol (20 versus 6%), apo B (26 versus 15%), and non-HDL-cholesterol (30 versus 16%) concentrations at 12 weeks. Effects on triglyceride and HDL-cholesterol concentrations in patients receiving combination therapy were comparable to those in patients receiving fenofibrate monotherapy. Following an additional 48 weeks of combination therapy or monotherapy, changes in lipoprotein concentrations were consistent with those observed at 12 weeks of therapy. The manufacturer states that efficacy and safety of ezetimibe in combination with a fibric acid derivative other than fenofibrate have not been studied and currently is not recommended.(See Fibric Acid Derivatives under Drug Interactions: Antilipemic Agents.)

Patients with Chronic Kidney Disease

In the Study of Heart and Renal Protection (SHARP), the fixed-combination preparation containing ezetimibe and simvastatin was shown to reduce the risk of major vascular and atherosclerotic events in patients with chronic kidney disease, a population known to be at increased risk of cardiovascular disease. More than 9000 patients with moderate to severe chronic kidney disease (33% receiving dialysis) and no known history of MI or coronary revascularization were initially randomized in a 4:4:1 ratio to receive the fixed-combination preparation containing ezetimibe and simvastatin (10 and 20 mg daily, respectively), placebo, or simvastatin alone (20 mg daily) for 1 year to assess the safety of adding ezetimibe to simvastatin; patients in the simvastatin monotherapy group were then re-randomized to the fixed-combination preparation or placebo. After a median duration of follow up of 4.9 years, the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or revascularization excluding dialysis access procedures) was reduced by 16% (based on the primary intent-to-treat analysis in patients initially randomized to the fixed-combination preparation or placebo groups) and the risk of a major atherosclerotic event (nonfatal MI or cardiac death, nonhemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) was reduced by 17% (based on the total number of patients randomized at any time to the fixed-combination preparation or placebo groups) with the fixed-combination preparation compared with placebo. The treatment effect was largely driven by a substantial reduction in ischemic strokes and arterial revascularization procedures. The subgroup of patients receiving dialysis at baseline experienced a smaller risk reduction benefit compared with those not receiving dialysis. In addition, therapy with the fixed-combination preparation did not appear to slow the progression to end-stage renal disease.

Homozygous Familial Hypercholesterolemia

Ezetimibe may be used in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available.

Efficacy and safety of ezetimibe combined with atorvastatin or simvastatin for the management of homozygous familial hypercholesterolemia were established in a randomized, double-blind study of 12 weeks' duration in a limited number of patients with a clinical and/or genotypic diagnosis of homozygous familial hypercholesterolemia who were already receiving atorvastatin (40 mg daily) or simvastatin (40 mg daily), with or without concomitant LDL apheresis. In this study, patients were randomized to receive 1 of 3 regimens: atorvastatin (80 mg daily) or simvastatin (80 mg daily) monotherapy; ezetimibe (10 mg daily) with either atorvastatin (40 mg daily) or simvastatin (40 mg daily); or ezetimibe (10 mg daily) with either atorvastatin (80 mg daily) or simvastatin (80 mg daily). The addition of ezetimibe (10 mg daily) to therapy with atorvastatin (40 or 80 mg daily) or simvastatin (40 or 80 mg daily) was more effective in reducing LDL-cholesterol concentrations (21% additional reduction based on pooled data from 40-mg and 80-mg groups) than increasing the dosage of atorvastatin or simvastatin monotherapy from 40 to 80 mg daily (7% additional reduction based on pooled data from 40-mg and 80-mg groups).

In the entire group of patients receiving higher dosages (80 mg daily) of either atorvastatin or simvastatin in combination with ezetimibe (10 mg daily), LDL-cholesterol concentrations were reduced by approximately 27% compared with a 7% reduction with statin monotherapy. Comparable reductions in LDL-cholesterol concentrations were observed in the subgroup of patients with genotype-confirmed homozygous familial hypercholesterolemia.

Beneficial effects of ezetimibe combined with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia who currently are undergoing LDL apheresis compared with effects in patients not undergoing the procedure have not been established. Effects on clinical outcome and modification of other disease parameters (e.g., xanthoma formation, regression of atherosclerosis) also have not been established.

Homozygous Familial Sitosterolemia (Phytosterolemia)

Ezetimibe is used as an adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia.

Efficacy and safety of ezetimibe in the management of homozygous sitosterolemia were established in a randomized, double-blind study of 8 weeks' duration in a limited number of patients with homozygous sitosterolemia who had plasma sitosterol concentrations exceeding 5 mg/dL and were already receiving standard antilipemic therapy (dietary therapy, bile acid sequestrants, statins, ileal bypass surgery, and/or LDL apheresis). In this study, treatment with ezetimibe (10 mg daily) reduced plasma sitosterol and campesterol concentrations by 21 and 24%, respectively, compared with increases of 4 and 3% in placebo-treated patients. Reductions in sitosterol and campesterol concentrations were consistent between patients receiving ezetimibe with or without bile acid sequestrants. The effect of reducing plasma concentrations of sitosterol and campesterol on cardiovascular morbidity and mortality has not been established.

For additional information on the role of antilipemic therapy in the treatment of lipoprotein disorders, prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.

Dosage and Administration

Administration

Ezetimibe is administered orally without regard to meals. Ezetimibe in fixed combination with simvastatin (Vytorin) is administered orally in the evening without regard to meals. Patients should be placed on a standard cholesterol-lowering diet before initiation of ezetimibe therapy and should remain on this diet during treatment with the drug. For recommendations on dietary and other nondrug therapies (i.e., lifestyle modifications), consult the most recent American Heart Association (AHA)/American College of Cardiology (ACC) Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

When used in combination with a hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor (statin) or fenofibrate for additive antilipemic effects, ezetimibe may be administered at the same time as the statin or fenofibrate, in accordance with the recommended dosing schedule for these drugs. When used in combination with a bile acid sequestrant, ezetimibe should be administered at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant. The manufacturer states that pending further accumulation of data, use of ezetimibe in combination with a fibric acid derivative other than fenofibrate is not recommended.(See Drug Interactions: Antilipemic Agents.)

Dosage

For the management of primary hyperlipidemia, mixed dyslipidemia, homozygous familial hypercholesterolemia, or homozygous familial sitosterolemia in adults and children 10 years of age and older, the recommended dosage of ezetimibe (alone or in combination with a statin or fenofibrate) is 10 mg once daily without regard to meals.

Ezetimibe/Simvastatin Combination Therapy

The recommended initial dosage of the commercially available fixed-combination preparation (Vytorin) for the management of primary hyperlipidemia or mixed dyslipidemia in adults is 10 mg of ezetimibe and 10 or 20 mg of simvastatin once daily in the evening. Patients requiring reductions in LDL-cholesterol concentration of more than 55% to achieve their goal may receive an initial dosage of 10 mg of ezetimibe and 40 mg of simvastatin once daily in the absence of moderate to severe renal impairment (estimated glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m). Serum lipoprotein concentrations should be determined 2 or more weeks after initiation or titration of therapy, and dosage adjusted as needed. The usual maintenance dosage of ezetimibe in fixed combination with simvastatin is 10 mg of ezetimibe and 10-40 mg of simvastatin once daily. Because higher simvastatin dosages (e.g., 80 mg daily) have been associated with a greater risk of myopathy, including rhabdomyolysis, particularly during the first year of treatment, the manufacturer states that patients who are unable to achieve their LDL-cholesterol target goal with the fixed-combination preparation containing 10 mg of ezetimibe and 40 mg of simvastatin should not be titrated to the dosage containing 10 mg of ezetimibe and 80 mg of simvastatin but should be switched to alternative antilipemic agents that provide greater LDL-cholesterol reduction. The manufacturer also states that use of the fixed-combination preparation containing 10 mg of ezetimibe and 80 mg of simvastatin should be restricted to patients who have been receiving long-term therapy (e.g., 12 months or longer) at this dosage without evidence of muscle toxicity.(See Cautions.) Patients currently tolerating the fixed-combination preparation containing 10 mg of ezetimibe and 80 mg of simvastatin who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin) should be switched to an alternative statin or statin-based regimen with less drug interaction potential.

The recommended dosage of ezetimibe in fixed combination with simvastatin for the management of homozygous familial hypercholesterolemia in adults is 10 mg of ezetimibe and 40 mg of simvastatin once daily in the evening. Ezetimibe in fixed combination with simvastatin should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or as an alternative if such therapy is unavailable.

The risk of myopathy appears to be increased among Chinese patients versus non-Chinese patients receiving simvastatin 40 mg daily (alone or in combination with ezetimibe 10 mg daily) concomitantly with preparations containing antilipemic dosages (1 g daily or higher) of niacin. The cause of the increased risk of myopathy is not known, and it is not known whether these findings apply to patients of other Asian ancestries. Because of such increased risk, caution is advised when Chinese patients receive fixed-combination dosages exceeding 10 mg of ezetimibe and 20 mg of simvastatin daily concomitantly with preparations containing antilipemic dosages of niacin. Because the risk of myopathy is dose related, patients of Chinese descent should avoid concomitant use of the fixed-combination preparation containing 10 mg of ezetimibe and 80 mg of simvastatin with preparations containing antilipemic dosages of niacin.

Special Populations

No dosage adjustment is necessary in geriatric patients (65 years of age or older), in patients with mild hepatic impairment, or in patients with renal impairment. However, the manufacturer states that ezetimibe should not be used in patients with moderate or severe hepatic impairment.(See Specific Populations under Cautions: Warnings/Precautions.)

In patients receiving ezetimibe in fixed combination with simvastatin, the manufacturer states that no dosage adjustment is necessary in geriatric patients or in patients with mild renal impairment (estimated GFR of 60 mL/minute per 1.73 m or greater). However, in patients with chronic kidney disease and an estimated GFR of less than 60 mL/minute per 1.73 m, the dosage of the fixed-combination preparation is 10 mg of ezetimibe and 20 mg of simvastatin once daily in the evening; in such patients, higher dosages should be used with caution and close monitoring.(See Specific Populations under Cautions: Warnings/Precautions.)

Cautions

Contraindications

Known hypersensitivity to ezetimibe or any ingredient in the formulation.

Ezetimibe, in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations.

All statins are contraindicated in pregnant or nursing women. If ezetimibe is used in combination with a statin in a woman of childbearing age, the prescribing information for the statin should be consulted for detailed information on contraindications of the drug.

Concomitant use of the fixed combination of ezetimibe and simvastatin with potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4, cyclosporine, danazol, or gemfibrozil is contraindicated.

Warnings/Precautions

Sensitivity Reactions

Anaphylaxis, angioedema, rash, and urticaria have been reported.

Major Toxicities

Hepatic Effects

Consecutive elevations in serum aminotransferase (transaminase) concentrations (i.e., AST, ALT) exceeding 3 times the upper limit of normal were reported in approximately 0.5% of patients receiving ezetimibe and in 0.3% of those receiving placebo in clinical studies. In studies in which ezetimibe was initiated concurrently with a statin, these elevations were reported in 1.3% of patients receiving combination therapy and in 0.4% of those receiving statin monotherapy. Consecutive elevations in serum transaminase concentrations exceeding 3 times the upper limit of normal were reported in approximately 1.7-1.8% of patients receiving the fixed-combination preparation containing ezetimibe and simvastatin; these elevations appeared to be dose related and occurred in 2.6-3.6% of patients receiving the fixed combination containing 10 mg of ezetimibe and 80 mg of simvastatin. In a study in which ezetimibe was used in combination with fenofibrate, consecutive elevations in serum transaminase concentrations exceeding 3 times the upper limit of normal were reported in 2.7% of patients receiving combination therapy and in 4.5% of those receiving fenofibrate monotherapy. Increases in transaminase concentrations generally were asymptomatic and not associated with cholestasis; transaminase concentrations usually returned to pretreatment values during continued therapy or following discontinuance of ezetimibe. Hepatitis has been reported during postmarketing surveillance; however, a causal relationship to the drug has not been established.

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline states that it is reasonable to obtain baseline hepatic aminotransferase concentrations before initiating ezetimibe. When ezetimibe is used in combination with a statin, liver function tests should be performed at initiation of therapy and in accordance with the recommended monitoring schedule for the specific statin and as clinically indicated. If ALT or AST concentrations increase to 3 or more times the upper limit of normal (ULN) and are persistent, discontinuance of ezetimibe and/or the statin should be considered.

Musculoskeletal Effects

Marked (exceeding 10 times the upper limit of normal) elevations of serum creatine kinase (CK, creatine phosphokinase, CPK) were reported in 0.2% of patients receiving ezetimibe and in 0.1% of patients receiving placebo in clinical studies. In clinical studies evaluating safety and efficacy of ezetimibe in combination with a statin, these elevations were reported in 0.1% of patients receiving combination therapy and in 0.4% of those receiving statin monotherapy.

In clinical studies, the incidence of myopathy (manifested as unexplained muscle pain, tenderness, or weakness and increases in serum CK concentration exceeding 10 times the upper limit of normal) or rhabdomyolysis appears to be similar among patients receiving ezetimibe, statin monotherapy, or placebo. Myalgia, myopathy, and/or rhabdomyolysis have been reported during postmarketing surveillance in patients receiving ezetimibe alone or in combination with other antilipemic agents. Most reported cases of rhabdomyolysis have occurred in patients who were receiving statin therapy prior to initiating ezetimibe. However, rhabdomyolysis also has been reported following ezetimibe monotherapy or following addition of ezetimibe to therapy with agents known to be associated with increased risk of rhabdomyolysis (e.g., fibric acid derivatives).

Predisposing factors for the development of myopathy and/or rhabdomyolysis include increased dosages of statins, age exceeding 65 years, uncontrolled hypothyroidism, renal impairment, and potential statin-drug interactions. Patients initiating therapy with ezetimibe should be advised of the risk of myopathy and instructed to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if such manifestations persist after discontinuance of therapy. If myopathy is diagnosed or suspected, ezetimibe and other concomitant antilipemic agents (e.g., statin, fibric acid derivative) should be discontinued immediately.

General Precautions

Combination Therapy with Statins or Fenofibrate

When ezetimibe is used in combination with a statin or fenofibrate, the prescribing information for the specific statin or for fenofibrate also should be consulted for detailed information on the usual cautions, precautions, and contraindications for these drugs.

Risk of Cancer

The fixed combination of ezetimibe and simvastatin was reported in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study to be possibly associated with an increased risk of cancer; these findings prompted the FDA to issue an early communication in 2008 about this potential safety risk. Results of this study in 1873 patients with mild to moderate asymptomatic aortic stenosis revealed a higher incidence of cancer and cancer-related deaths (11.1 and 4.1%, respectively) in patients receiving the fixed-combination preparation compared with those receiving placebo (7.5 and 2.5%, respectively). However, results of 2 subsequent large randomized studies (the Study of Heart and Renal Protection [SHARP] and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]) involving a combined study population of 27,414 patients with chronic kidney disease or acute coronary syndrome found no consistent pattern of increased cancer risk among patients receiving the fixed-combination preparation of ezetimibe and simvastatin. In the SHARP study, cancer or cancer-related mortality occurred in 9.4 or 2.8%, respectively, of patients receiving the fixed-combination preparation, and these rates were similar to those reported in placebo recipients. In the IMPROVE-IT study, cancer or cancer-related mortality occurred in 10.2 or 3.8%, respectively, of patients receiving the fixed combination of ezetimibe and simvastatin and these rates were similar to those reported in patients who received simvastatin monotherapy. Based on the currently available evidence, FDA has concluded that neither ezetimibe nor the fixed-combination preparation of ezetimibe and simvastatin is likely to increase the risk of cancer or cancer-related deaths.

Specific Populations

Pregnancy

Category C.

Category X for fixed combination of ezetimibe and simvastatin (due to simvastatin component).

Lactation

Ezetimibe is distributed into milk in rats. It is not known whether ezetimibe is distributed into milk in humans. Because many drugs are distributed into human milk, caution should be used if ezetimibe is used in nursing women; the drug should not be used in nursing women unless the potential benefits justify the possible risks to the infant.

Pediatric Use

There are no differences in the pharmacokinetics of ezetimibe between adolescents and adults. Pharmacokinetic data are not available for pediatric patients younger than 10 years of age.

Use of ezetimibe in combination with simvastatin has been evaluated in a limited number of adolescent boys and girls with heterozygous familial hypercholesterolemia. In a randomized, double-blind, controlled study in boys and postmenarchal girls 10-17 years of age with heterozygous familial hypercholesterolemia, discontinuance of therapy because of adverse effects occurred in more patients receiving ezetimibe in combination with simvastatin (10-40 mg daily) (6%) than in those receiving simvastatin monotherapy (2%); in addition, increases in aminotransferase or CK concentrations also occurred more frequently in patients receiving combination therapy (3 or 2%, respectively) than in those receiving simvastatin monotherapy (2 or 0%, respectively). There were no detectable adverse effects on growth or sexual maturation in adolescent boys or girls or on duration of menstrual cycle in girls. Use of ezetimibe in combination with simvastatin dosages exceeding 40 mg daily has not been evaluated in adolescents; safety and efficacy of ezetimibe, alone or in fixed combination with simvastatin, have not been evaluated in prepubertal girls or in children younger than 10 years of age.

Geriatric Use

In clinical studies in patients receiving ezetimibe, 28% of patients were 65 years of age or older, and 5% of patients were 75 years of age or older. Following administration of ezetimibe (10 mg daily for 10 days), plasma concentrations of the drug were approximately twofold higher in geriatric individuals (65 years of age or older) than in younger adults; however, no overall differences in safety and efficacy of ezetimibe have been observed in geriatric patients relative to younger adults. Nevertheless, the manufacturer states that the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

In clinical studies in patients receiving ezetimibe in fixed combination with simvastatin, 32% of patients were 65 years of age or older, and 8% of patients were 75 years of age or older. No substantial differences in safety or efficacy of the fixed-combination preparation were observed in geriatric patients relative to younger patients; however, greater sensitivity in some older patients cannot be ruled out. Because advanced age (65 years of age or older) is a risk factor for myopathy, including rhabdomyolysis, ezetimibe in fixed combination with simvastatin should be used with caution in geriatric patients.

Hepatic Impairment

Following a single 10-mg dose of ezetimibe, the mean area under the plasma concentration-time curve (AUC) of total ezetimibe was increased by approximately 1.7 fold in individuals with mild hepatic impairment (Child-Pugh score 5-6). In individuals with moderate (Child-Pugh score 7-9) or severe (Child-Pugh score 10-15) hepatic impairment, the mean AUC of total ezetimibe was increased by approximately threefold to fourfold and that of ezetimibe was increased by approximately fivefold to sixfold. In a multiple-dose study, administration of ezetimibe (10 mg daily) for 14 days resulted in fourfold increases in the AUCs of total ezetimibe and ezetimibe on days 1 and 14 in patients with moderate hepatic impairment compared with healthy individuals. Because the effects of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment currently is not known, the manufacturer states that the drug is not recommended in such patients.

Renal Impairment

Following a single 10-mg dose of ezetimibe, the mean AUC of ezetimibe was increased by approximately 1.5-fold in individuals with severe renal impairment (mean creatinine clearance of 30 mL/minute per 1.73 m or less) compared with healthy individuals. When ezetimibe is used as monotherapy, no dosage adjustment is necessary in patients with renal impairment.(See Dosage and Administration: Special Populations.)

In the SHARP study in patients with moderate to severe renal impairment, the incidence of serious adverse effects, adverse effects leading to discontinuance of therapy, or adverse effects of special interest (adverse musculoskeletal effects, liver enzyme abnormalities, incident cancer) was similar in patients receiving the fixed combination of ezetimibe 10 mg and simvastatin 20 mg compared with those receiving placebo following a median of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, dosages of the fixed-combination preparation exceeding ezetimibe 10 mg and simvastatin 20 mg daily should be used with caution and close monitoring in patients with moderate to severe renal impairment.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving ezetimibe and more frequently with the drug than with placebo include upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity, fatigue, and influenza.

Adverse effects occurring in 2% or more of patients receiving ezetimibe in combination with statins and more frequently with the drug than with placebo include nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea, back pain, influenza, headache, and pain in extremity. Adverse effects occurring in patients receiving ezetimibe in combination with statins generally were similar to those reported in patients receiving statin therapy alone. However, the incidence of increased transaminase concentrations was higher in patients receiving combination therapy (1.3%) than in those who received statin monotherapy (0.4%).(See Hepatic Effects under Warnings/Precautions: Major Toxicities, in Cautions.)

Drug Interactions

When using the fixed-combination preparation containing ezetimibe and simvastatin, the drug interactions associated with simvastatin should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation other than that with extended-release niacin.(See Niacin under Drug Interactions: Antilipemic Agents.)

Drugs Affecting Hepatic Microsomal Enzymes

Based on results of a study evaluating possible interactions with caffeine, dextromethorphan, tolbutamide, and IV midazolam in a limited number of healthy men, the potential for drug interactions mediated by hepatic cytochrome P-450 (CYP) with ezetimibe is low.

Antacids

Concomitant use of ezetimibe (10 mg) and an aluminum and magnesium hydroxides-containing antacid decreased AUC and peak plasma concentration of total ezetimibe by 4 and 30%, respectively.

Antilipemic Agents

Bile Acid Sequestrants

Concomitant administration of cholestyramine (4 g twice daily for 14 days) and ezetimibe (10 mg) decreased the AUC and peak plasma concentration of total ezetimibe by 55 and 4%, respectively. Reduced LDL-cholesterol lowering effect may occur as a result of this interaction. Ezetimibe should be administered at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant.

Fibric Acid Derivatives

Concomitant use of fenofibrate (200 mg daily for 14 days) and ezetimibe (10 mg) increased AUC and peak plasma concentration of total ezetimibe by 48 and 64%, respectively. Concomitant use of fenofibrate (200 mg daily for 14 days) and ezetimibe (10 mg daily for 14 days) increased AUC and peak plasma concentration of fenofibrate by 11 and 7%, respectively.

Concomitant use of gemfibrozil (600 mg twice daily for 7 days) and ezetimibe (10 mg) increased AUC and peak plasma concentration of total ezetimibe by 64 and 91%, respectively. Concomitant use of gemfibrozil (600 mg twice daily for 7 days) and ezetimibe (10 mg daily for 7 days) decreased AUC and peak plasma concentration of gemfibrozil by 1 and 11%, respectively.

Fibric acid derivatives may increase cholesterol excretion into bile, leading to cholelithiasis, and ezetimibe has been shown to increase cholesterol in the gall bladder bile in animals. In clinical studies, cholecystectomy has been reported in 1.7% of patients receiving ezetimibe concomitantly with fenofibrate and in 0.6% of those receiving fenofibrate monotherapy.

The efficacy and safety of concomitant use of ezetimibe with a fibric acid derivative other than fenofibrate have not been established. Such concomitant use currently is not recommended pending further accumulation of data from adequate study in humans. Concomitant use of the fixed combination of ezetimibe and simvastatin with gemfibrozil is contraindicated.(See Ezetimibe/Simvastatin Combination Therapy under Dosage and Administration: Dosage.) If cholelithiasis is suspected in a patient receiving ezetimibe with fenofibrate, gallbladder studies should be performed, and alternative antilipemic therapy should be considered.

Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) Reductase Inhibitors (Statins)

Concomitant use of atorvastatin (10 mg daily for 14 days) and ezetimibe (10 mg) decreased AUC of total ezetimibe by 2% and increased peak plasma concentration of total ezetimibe by 12%. Concomitant use of atorvastatin (10 mg daily for 14 days) and ezetimibe (10 mg daily for 14 days) decreased AUC of atorvastatin by 4% and increased peak plasma concentration of atorvastatin by 7%.

Concomitant use of fluvastatin (20 mg daily for 14 days) and ezetimibe (10 mg) decreased AUC of total ezetimibe by 19% and increased peak plasma concentration of total ezetimibe by 7%. Concomitant use of fluvastatin (20 mg daily for 14 days) and ezetimibe (10 mg daily for 14 days) decreased AUC and peak plasma concentration of fluvastatin by 39 and 27%, respectively.

Concomitant use of lovastatin (20 mg daily for 7 days) and ezetimibe (10 mg) increased AUC and peak plasma concentration of total ezetimibe by 9 and 3%, respectively. Concomitant use of lovastatin (20 mg daily for 7 days) and ezetimibe (10 mg daily for 7 days) increased AUC and peak plasma concentration of lovastatin by 19 and 3%, respectively.

Concomitant use of pravastatin (20 mg daily for 14 days) and ezetimibe (10 mg) increased AUC and peak plasma concentration of total ezetimibe by 7 and 23%, respectively. Concomitant use of pravastatin (20 mg daily for 14 days) and ezetimibe (10 mg daily for 14 days) decreased AUC and peak plasma concentration of pravastatin by 20 and 24%, respectively.

Concomitant use of rosuvastatin (10 mg daily for 14 days) and ezetimibe (10 mg) increased AUC and peak plasma concentration of total ezetimibe by 13 and 18%, respectively. Concomitant use of rosuvastatin (10 mg daily for 14 days) and ezetimibe (10 mg daily for 14 days) increased AUC and peak plasma concentration of rosuvastatin by 19 and 17%, respectively.

Mipomersen

No clinically relevant pharmacokinetic interactions were observed when ezetimibe was used concomitantly with mipomersen. Therefore, dosage adjustment of ezetimibe and mipomersen is not necessary during such concomitant use.

Niacin

Following concomitant use of the fixed combination of ezetimibe and simvastatin (10 mg of ezetimibe and 20 mg of simvastatin administered daily for 7 days) with extended-release niacin (Niaspan 1 g administered daily for 2 days, then 2 g administered daily for 5 days), mean peak plasma concentrations or AUC of niacin were increased by 9 or 22%, respectively; mean peak plasma concentrations or AUC of nicotinuric acid were increased by 10 or 19%, respectively; mean peak plasma concentrations of simvastatin acid were increased by 18%; and mean AUC of total ezetimibe, simvastatin, or simvastatin acid were increased by 26, 20, or 35%, respectively.(See Ezetimibe/Simvastatin Combination Therapy under Dosage and Administration: Dosage.)

Cimetidine

Concomitant use of cimetidine (400 mg twice daily for 7 days) and ezetimibe (10 mg) increased AUC and peak plasma concentration of total ezetimibe by 6 and 22%, respectively.

Cyclosporine

Concomitant use of cyclosporine (75-150 mg twice daily) and ezetimibe (10 mg) in renal transplant recipients with normal renal function or mild renal impairment increased AUC and peak plasma concentration of total ezetimibe by 3.4- and 3.9-fold, respectively. Exposure to ezetimibe may be greater in patients with severe renal insufficiency. In a renal transplant patient with severe renal impairment (creatinine clearance 13.2 mL/minute per 1.73 m) receiving multiple medications in addition to cyclosporine and ezetimibe, a 12-fold increase in total ezetimibe exposure occurred.

Concomitant use of cyclosporine (single 100-dose on day 7) and ezetimibe (20 mg daily for 8 days) increased AUC and peak plasma concentration of cyclosporine by 15 and 10%, respectively.

Because of increased exposure to ezetimibe and cyclosporine, caution should be exercised with concomitant use and cyclosporine concentrations should be monitored. The potential benefits versus risks of such concomitant therapy should be considered.

Digoxin

Concomitant use of digoxin (single 0.5-mg dose) and ezetimibe (10 mg daily for 8 days) increased AUC of digoxin by 2% and decreased peak plasma concentration of digoxin by 7%.

Fat-soluble Vitamins

Pharmacokinetic interactions with vitamins A, D, and E are unlikely.

Glipizide

Concomitant use of glipizide (single 10-mg dose) and ezetimibe (10 mg) increased AUC of total ezetimibe by 4% and decreased peak plasma concentration of total ezetimibe by 8%. Concomitant use of glipizide (10 mg on days 1 and 9) and ezetimibe (10 mg daily on days 2-9) decreased AUC and peak plasma concentration of glipizide by 3 and 5%, respectively.

Oral Contraceptives

Concomitant use of an oral contraceptive containing ethinyl estradiol and levonorgestrel (daily for 21 days) and ezetimibe (10 mg daily on days 8-14) decreased the peak plasma concentrations of ethinyl estradiol and levonorgestrel by 9 and 5%, respectively; AUCs of both components remained unchanged.

Warfarin

Pharmacokinetic or pharmacodynamic interaction with ezetimibe is unlikely based on one small study. Concomitant use of warfarin (single 25-mg dose on day 7) and ezetimibe (10 mg daily for 11 days) decreased the AUCs of R- and S-warfarin by 2 and 4%, respectively, and increased peak plasma concentrations of R- and S-warfarin by 3 and 1%, respectively.

Increased international normalized ratio (INR) with concomitant use of ezetimibe and warfarin has been reported during postmarketing experience; however, most patients also were receiving other drugs. If ezetimibe is initiated in a patient receiving warfarin, the INR should be monitored.

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