EZETIMIBE Drug Interactions: What You Need to Know

INTERACTIONS Ezetimibe and simvastatin tablets

• See full prescribing information for details regarding concomitant use of ezetimibe and simvastatin tablets with other drugs or grapefruit juice that increase the risk of myopathy and rhabdomyolysis. ( 2.3 , 7.1 )
• Cholestyramine : Combination decreases exposure of ezetimibe. ( 2.3 , 7.2 )
• Coumarin Anticoagulants : Obtain INR before ezetimibe and simvastatin tablets initiation and monitor INR during ezetimibe and simvastatin tablets dosage initiation or adjustment. ( 7.3 )
• Digoxin : During ezetimibe and simvastatin tablets initiation, monitor digoxin levels. ( 7.3 )
• Fenofibrates : Combination increases exposure of ezetimibe. If cholelithiasis is suspected in a patient receiving ezetimibe and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. (7.3, 12.3)

7.1 Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Ezetimibe and Simvastatin Tablets Ezetimibe and simvastatin tablets are a substrate of CYP3A4 and of the transport protein OATP1B1. ezetimibe and simvastatin tablets plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and OATP1B1.

Table

2 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with ezetimibe and simvastatin tablets and instructions for preventing or managing them [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )].

Table

2: Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with Ezetimibe and Simvastatin Tablets Strong CYP3A4 inhibitors Clinical Impact: Simvastatin is a substrate of CYP3A4. Concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets increases simvastatin exposure and increases the risk of myopathy and rhabdomyolysis, particularly with higher ezetimibe and simvastatin tablets dosages. Intervention: Concomitant use of strong CYP3A4 inhibitors with ezetimibe and simvastatin tablets are contraindicated [see Contraindications ( 4 )] . If treatment with a CYP3A4 inhibitor is unavoidable, suspend ezetimibe and simvastatin tablets during the course of strong CYP3A4 inhibitor treatment. Examples: Select azole anti-fungals (e.g., itraconazole, ketoconazole, posaconazole, and voriconazole), select macrolide antibiotics (e.g., erythromycin and clarithromycin, telithromycin), select HIV protease inhibitors (e.g., nelfinavir, ritonavir, and darunavir/ritonavir), select HCV protease inhibitors (e.g., boceprevir and telaprevir), cobicistat-containing products, and nefazodone. Cyclosporine, Danazol, or Gemfibrozil Clinical Impact: The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine, danazol, or gemfibrozil with ezetimibe and simvastatin tablets. Gemfibrozil may cause myopathy when given alone. Intervention: Concomitant use of cyclosporine, danazol, or gemfibrozil with ezetimibe and simvastatin tablets are contraindicated [see Contraindications ( 4 )] . Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers Clinical Impact: The risk of myopathy and rhabdomyolysis is increased by concomitant use of amiodarone, dronedarone, ranolazine, or calcium channel blockers with ezetimibe and simvastatin tablets. Intervention: For patients taking verapamil, diltiazem, or dronedarone, do not exceed ezetimibe and simvastatin tablets 10/10 mg daily . For patients taking amiodarone, amlodipine, or ranolazine, do not exceed ezetimibe and simvastatin tablets 10/20 mg daily [see Dosage and Administration ( 2.3 )] .

Lomitapide Clinical

Impact: Simvastatin exposure is approximately doubled with concomitant use of lomitapide and the risk of myopathy and rhabdomyolysis is increased . Intervention: Reduce the dose of ezetimibe and simvastatin tablets by 50% if initiating lomitapide. Do not exceed ezetimibe and simvastatin tablets 10/20 mg daily (or ezetimibe and simvastatin tablets 10/40 mg daily for patients who have previously taken ezetimibe and simvastatin tablets 10/80 mg daily chronically) while taking lomitapide [see Dosage and Administration ( 2.1 , 2.3 )] .

Daptomycin Clinical

Impact: Cases of rhabdomyolysis have been reported with simvastatin administered with daptomycin. Both ezetimibe and simvastatin tablets and daptomycin can cause myopathy and rhabdomyolysis when given alone and the risk of myopathy and rhabdomyolysis may be increased by coadministration. Intervention: If treatment with daptomycin is required, consider temporarily suspending ezetimibe and simvastatin tablets during the course of daptomycin treatment.

Niacin Clinical

Impact: Cases of myopathy and rhabdomyolysis have been observed with concomitant use of lipid modifying dosages of niacin-containing products (≥1 gram/day niacin) with ezetimibe and simvastatin tablets. The risk of myopathy is greater in Chinese patients. In a clinical trial (median follow-up 3.9 years) of patients at high risk of CVD and with well-controlled LDL-C levels on simvastatin 40 mg/day with or without ezetimibe 10 mg/day, there was no incremental benefit on cardiovascular outcomes with the addition of lipid-modifying doses of niacin Intervention: Concomitant use of ezetimibe and simvastatin tablets with lipid-modifying dosages of niacin is not recommended in Chinese patients [see Use in Specific Populations ( 8.8 )]. For non-Chinese patients, consider if the benefit of using lipid-modifying doses of niacin concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug. Fibrates (other than Gemfibrozil)

Clinical

Impact: Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with ezetimibe and simvastatin tablets. Intervention: Consider if the benefit of using fibrates concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Colchicine Clinical

Impact: Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with ezetimibe and simvastatin tablets. Intervention: Consider if the benefit of using colchicine concomitantly with ezetimibe and simvastatin tablets outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration of either drug.

Grapefruit Juice Clinical

Impact: Grapefruit juice can raise the plasma levels of simvastatin and may increase the risk of myopathy and rhabdomyolysis. Intervention: Avoid grapefruit juice when taking ezetimibe and simvastatin tablets.

7.2 Drug Interactions that Decrease the Efficacy of Ezetimibe and Simvastatin Tablets Table 3 presents drug interactions that may decrease the efficacy of ezetimibe and simvastatin tablets and instructions for preventing or managing them.

Table

3: Drug Interactions that Decrease the Efficacy of Ezetimibe and Simvastatin Tablets Bile Acid Sequestrants Clinical Impact: Concomitant cholestyramine administration decreased the mean exposure of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe and simvastatin tablets to cholestyramine may be reduced by this interaction [see Clinical Pharmacology ( 12.3 )] . Intervention: In patients taking a bile acid sequestrant, administer ezetimibe and simvastatin tablets at least 2 hours before or at least 4 hours after cholestyramine [see Dosage and Administration ( 2.3 )] .

7.3 Ezetimibe and Simvastatin Tablets Effect on Other Drugs Table 4 presents ezetimibe and simvastatin tablets effect on other drugs and instructions for preventing or managing them.

Table

4: Ezetimibe and Simvastatin Tablets Effects on Other Drugs Coumarin Anticoagulants Clinical Impact: Ezetimibe and simvastatin tablets may potentiate the effect of coumarin anticoagulants and increase the INR. The concomitant use of simvastatin (20 to 40 mg) and coumarin anticoagulants increased the INR from a baseline of 1.7 to 1.8 in healthy subjects and from 2.6 to 3.4 in patients with hyperlipidemia. There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins (with or without ezetimibe) and coumarin anticoagulants. Intervention: In patients taking coumarin anticoagulants, obtain an INR before starting ezetimibe and simvastatin tablets and frequently enough after initiation, dose titration, or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals.

Digoxin Clinical

Impact: Concomitant use of digoxin with ezetimibe and simvastatin tablets may result in elevated plasma digoxin concentrations [see Clinical Pharmacology ( 12.3 )] . Intervention: Monitor digoxin levels in patients taking digoxin when ezetimibe and simvastatin tablets are initiated.

Fenofibrates Clinical

Impact: Both ezetimibe and fenofibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Intervention: If cholelithiasis is suspected in a patient receiving ezetimibe and simvastatin tablets and a fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see the product labeling for fenofibrate and fenofibric acid] .

Ezetimibe and simvastatin tablets are contraindicated in the following conditions:

• Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions ( 5.1 )].
• Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions ( 5.1 )].
• Hypersensitivity to any component of this medication [see Adverse Reactions ( Error! Hyperlink reference not valid. )].
• Active liver disease or unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions ( 5.3 )].
• Women who are pregnant or may become pregnant . Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because HMG-CoA reductase inhibitors (statins), such as simvastatin, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe and simvastatin may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-controlled studies of ezetimibe and simvastatin use during pregnancy; however, in rare reports congenital anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, simvastatin revealed no evidence of teratogenicity. Ezetimibe and simvastatin should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, ezetimibe and simvastatin should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )].
• Nursing mothers. It is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require ezetimibe and simvastatin treatment should not breastfeed their infants [see Use in Specific Populations ( Error! Hyperlink reference not valid. )].
• Concomitant administration of strong CYP3A4 inhibitors. ( 4 , 5.1 )
• Concomitant administration of gemfibrozil, cyclosporine, or danazol. ( 4 , 5.1 )
• Hypersensitivity to any component of this medication ( 4 , Error! Hyperlink reference not valid. )
• Active liver disease or unexplained persistent elevations of hepatic transaminase levels ( 4 , 5.3 )
• Women who are pregnant or may become pregnant ( 4 , 8.1 )
• Nursing mothers ( 4 , Error! Hyperlink reference not valid. )

AND PRECAUTIONS Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, with the 10 mg/80 mg dose. ( 5.1 ) Patients should be advised to report promptly any unexplained and/or persistent muscle pain, tenderness, or weakness. Ezetimibe and simvastatin tablets should be discontinued immediately if myopathy is diagnosed or suspected. ( 5.1 ). Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks increase with higher doses and concomitant use of certain medicines. Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported. ( 4 , 5.1 , 8.5 , 8.6 ). Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. ( 5.2 ). Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.3 )

5.1 Myopathy/Rhabdomyolysis Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase above ten times the upper limit of normal (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 is increased elevated plasma levels of simvastatin and simvastatin acid. Predisposing factors for myopathy include advanced age (≥ 65 years), female gender, uncontrolled hypothyroidism, and renal impairment. Chinese patients may be at increased risk for myopathy <span class="opacity-50 text-xs">[see Use in Specific Populations (8.8) ]</span> The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was disproportionately higher than that observed at the lower doses. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] &gt; 10 times upper limit of normal [ULN]) in patients on 80 mg/day was approximately 0.9% compared with 0.02% for patients on 20 mg/day. The incidence of rhabdomyolysis (defined as myopathy with a CK &gt; 40 times ULN) in patients on 80 mg/day was approximately 0.4% compared with 0% for patients on 20 mg/day. The incidence of myopathy, including rhabdomyolysis, was highest during the first year and then notably decreased during the subsequent years of treatment. In this trial, patients were carefully monitored and some interacting medicinal products were excluded. The risk of myopathy, including rhabdomyolysis, is greater in patients on simvastatin 80 mg compared with other statin therapies with similar or greater LDL-C-lowering efficacy and compared with lower doses of simvastatin. Therefore, the 10 mg/80 mg dose of ezetimibe and simvastatin tablets should be used only in patients who have been taking ezetimibe and simvastatin tablets 10 mg/80 mg chronically (e.g., for 12 months or more) without evidence of muscle toxicity [ see Dosage and Administration, Restricted Dosing for 10 mg/80 mg ( 2.2 ) ]. If, however, a patient who is currently tolerating the 10 mg/80 mg dose of ezetimibe and simvastatin tablets needs to be initiated on an interacting drug that is contraindicated or is associated with a dose cap for simvastatin, that patient should be switched to an alternative statin or statin-based regimen with less potential for the drug-drug interaction. Patients should be advised of the increased risk of myopathy, including rhabdomyolysis, and to report promptly any unexplained muscle pain, tenderness or weakness. If symptoms occur, treatment should be discontinued immediately [ see Warnings and Precautions ( 5.2 ) ]. In the Study of Heart and Renal Protection (SHARP), 9,270 patients with chronic kidney disease were allocated to receive ezetimibe and simvastatin tablets 10 mg/20 mg daily (n = 4,650) or placebo (n = 4,620). During a median follow-up period of 4.9 years, the incidence of myopathy (defined as unexplained muscle weakness or pain with a serum creatine kinase [CK] &gt; 10 times upper limit of normal [ULN]) was 0.2% for ezetimibe and simvastatin and 0.1% for placebo: the incidence of rhabdomyolysis (defined as myopathy with a CK &gt; 40 times ULN) was 0.09% for ezetimibe and simvastatin and 0.02% for placebo. In postmarketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating ezetimibe. However, rhabdomyolysis has been reported with ezetimibe monotherapy and with the addition of ezetimibe to agents known to be associated with increased risk of rhabdomyolysis, such as fibric acid derivatives. Ezetimibe and simvastatin tablets and a fenofibrate, if taking concomitantly, should both be immediately discontinued if myopathy is diagnosed or suspected. All patients starting therapy with ezetimibe and simvastatin tablets or whose dose of ezetimibe and simvastatin tablets is being increased should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing ezetimibe and simvastatin tablets. Ezetimibe and simvastatin tablet therapy should be discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms and CK increases resolved when simvastatin treatment was promptly discontinued. Periodic CK determinations may be considered in patients starting therapy with ezetimibe and simvastatin tablets or whose dose is being increased, but there is no assurance that such monitoring will prevent myopathy. Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had complicated medical histories, including renal insufficiency usually as a consequence of long-standing diabetes mellitus. Such patients taking ezetimibe and simvastatin tablets merit closer monitoring. Ezetimibe and simvastatin tablet therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Ezetimibe and simvastatin tablet therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

Drug Interactions

The risk of myopathy and rhabdomyolysis is increased by elevated plasma levels of simvastatin and simvastatin acid. Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs that inhibit this metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, ketoconazole, posaconazole, and voriconazole, the macrolide antibiotics erythromycin and clarithromycin, and the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant nefazodone, cobicistat-containing products, or grapefruit juice [see Clinical Pharmacology ( 12.3 ) ]. Combination of these drugs with ezetimibe and simvastatin tablets is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is unavoidable, therapy with ezetimibe and simvastatin tablets must be suspended during the course of treatment [ see Contraindications ( 4 ) and Drug Interactions ( 7 ) ]. The combined use of ezetimibe and simvastatin tablets with gemfibrozil, cyclosporine, or danazol is contraindicated [ see Contraindications ( 4 ) and Drug Interactions ( 7.1 and 7.2 ) ]. Caution should be used when prescribing fenofibrates with ezetimibe and simvastatin tablets, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered [ see Drug Interactions ( 7.2 , 7.7 ) ]. Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing ezetimibe and simvastatin tablets with colchicine [ see Drug Interactions ( 7.9 ) ]. The benefits of the combined use of ezetimibe and simvastatin tablets with the following drugs should be carefully weighed against the potential risks of combinations: other lipid-lowering drugs (fenofibrates, ≥ 1 g/day of niacin, or, for patients with HoFH, lomitapide), amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine [see Dosage and Administration (2.4) , Drug Interactions (7.3 )]. Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥ 1 g/day niacin) of niacin-containing products. [ see Drug Interactions ( 7.4 ) ]. Cases of rhabdomyolysis have been reported with ezetimibe and simvastatin tablets administered with daptomycin. Temporarily suspend ezetimibe and simvastatin tablets in patients taking daptomycin [see Drug Interactions ( 7.10 )]. Prescribing recommendations for interacting agents are summarized in Table 1 [ see also Dosage and Administration ( 2.3 , 2.4 ), Drug Interactions ( 7 ), and Clinical Pharmacology ( 12.3 ) ].

Table

1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, e.g.: Contraindicated with ezetimibe and simvastatin tablets Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone Cobicistat-containing products Gemfibrozil CyclosporineDanazol Niacin (≥1 g/day)

For

Chinese patients, not recommended with ezetimibe and simvastatin tablets Verapamil Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets, daily Diltiazem Dronedarone Amiodarone Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets, daily Amlodipine Ranolazine Lomitapide For patients with HoFH, do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily1 Daptomycin Temporarlly Suspend ezetimibe and simvastatin tablets Grapefruit juice Avoid grapefruit juice 1 For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed ezetimibe and simvastatin tablets, 10 mg/40 mg daily when taking lomitapide. 5.2 immune-mediated necrotizing myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

5.3 Liver Enzymes In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.7% overall for patients treated with ezetimibe and simvastatin tablet and appeared to be dose-related with an incidence of 2.6% for patients treated with ezetimibe and simvastatin tablet 10/80. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8% overall and 3.6% for patients treated with ezetimibe and simvastatin tablet 10/80. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. In SHARP, 9270 patients with chronic kidney disease were allocated to receive ezetimibe and simvastatin tablet 10/20 mg daily (n=4650), or placebo (n=4620). During a median follow-up period of 4.9 years, the incidence of consecutive elevations of transaminases (&gt;3 X ULN) was 0.7% for ezetimibe and simvastatin tablet and 0.6% for placebo. It is recommended that liver function tests be performed before the initiation of treatment with ezetimibe and simvastatin tablet, and thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ezetimibe and simvastatin tablet, promptly interrupt therapy. If an alternate etiology is not found do not restart ezetimibe and simvastatin tablet. Note that ALT may emanate from muscle, therefore ALT rising with CK may indicate myopathy <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span>. ezetimibe and simvastatin tablet should be used with caution in patients who consume substantial quantities of alcohol and/or have a past history of liver disease. Active liver diseases or unexplained persistent transaminase elevations are contraindications to the use of ezetimibe and simvastatin tablet.

5.4 Endocrine Function Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.