EZETIMIBE (Generic for ZETIA)

Ezetimibe is an oral antilipemic agent, approved for use as monotherapy or in combination with HMG-CoA reductase inhibitors ('statins') or fenofibrate for the treatment of hypercholesterolemia. It is the first available 2-azetidinone compound, a potent cholesterol absorption inhibitor. Ezetimibe selectively blocks the intestinal absorption of cholesterol and related phytosterols. Monotherapy is primarily effective in reducing total cholesterol (total-C, 13%), LDL-cholesterol (LDL-C, 18%), and Apo-B (16%). Its effects to reduce triglycerides (8%) or to lower HDL-cholesterol (HDL-C, 1%) are less prominent; ezetimibe typically increases HDL-C. The reduction in LDL-C seen with ezetimibe monotherapy (18%) is lower than the more potent reductions (25 to 40%) typically achieved with statin monotherapy. Combining ezetimibe with a statin results in synergistic cholesterol-lowering effects ; and coadministration is more effective in improving serum total cholesterol, LDL-C, Apo-B, triglyceride, and HDL-C concentrations than either treatment given as monotherapy. When used in combination with 10 to 80 mg of either simvastatin or atorvastatin, LDL-C reductions of approximately 51% or 56%, respectively, are seen compared to LDL-C reductions of 36% with simvastatin or 44% with atorvastatin monotherapy. When used in combination with 10 to 40 mg of either pravastatin or lovastatin, LDL-C reductions of approximately 39% or 40%, respectively, are seen compared to LDL-C reductions of 25% with either pravastatin or lovastatin monotherapy. The adverse effect profile for combined ezetimibe/statin therapy is similar to statin monotherapy, except for an increase in the incidence of hepatic enzyme elevations. Administration of ezetimibe with fenofibrate is effective in improving serum total cholesterol, LDL-C, Apo-B, and non-HDL cholesterol concentrations in patients with mixed hyperlipidemia compared to monotherapy with either treatment. The percent decrease in triglycerides and percent increase in HDL-C for ezetimibe coadministered with fenofibrate are comparable to values achieved by fenofibrate monotherapy. The effects of ezetimibe given either alone or in addition to an HMG-CoA reductase inhibitor or fenofibrate on cardiovascular morbidity and mortality have not been established. The Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial, which was designed to evaluate the progression of atherosclerotic plaque in carotid arteries based on images obtained through ultrasound in patients with familial hypercholesterolemia treated with ezetimibe plus simvastatin or simvastatin alone, showed no significant difference between ezetimibe plus simvastatin and simvastatin alone in progression of atherosclerotic plaque in the inner walls of the carotid arteries despite greater lowering of LDL-C with ezetimibe plus simvastatin compared to simvastatin alone. Results from ENHANCE indicate that following two years of treatment, carotid artery thickness increased by 0.011 mm in the ezetimibe plus simvastatin group and by 0.006 mm in the simvastatin alone group; this difference was not statistically significant. However, there was a significantly greater reduction in the LDL-C concentration in the ezetimibe plus simvastatin group vs. the simvastatin alone group (56% and 39%, respectively). In January 2009, after reviewing the ENHANCE clinical study report, the FDA released a statement that their position remained that an elevated LDL-C is a risk factor for cardiovascular disease and that lowering LDL-C reduces the risk for cardiovascular disease. Based on currently available data, FDA recommends that patients should not stop taking ezetimibe; simvastatin or other cholesterol-lowering medications. In addition, the ARBITER 6-HALTS trial demonstrated that the addition of extended-release niacin 2000 mg/day to statin therapy results in significant regression in atherosclerosis as measured by carotid intima-media thickness (CIMT), and is superior to the combination of ezetimibe and a statin. Although there was a greater reduction in LDL-C in the ezetimibe group (-17.6 +/- 20.1 mg/dL) compared to the niacin group (-10 +/- 24.5 mg/dL), there was an increase in the CIMT in the ezetimibe group that was inversely related to the change in LDL-C. The incidence of major adverse cardiovascular events (i.e., myocardial infarction, myocardial revascularization, hospital admission for ACS, or death due to coronary heart disease was also significantly increased in the ezetimibe group compared to the niacin group (5% vs 1%, p=0.04). Ezetimibe (Zetia) was approved by the FDA in October 2002; it was approved for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Ezetimibe may be administered with or without food.
-If taken with a HMG-CoA reductase inhibitor ('statin') or fenofibrate, the daily dose of ezetimibe may be taken at the same time as the statin or fenofibrate.
-If prescribed concurrently with a bile acid sequestrant, administer ezetimibe at least 2 hours before or 4 hours after a dose of the bile acid sequestrant.

Preliminary results from the SEAS trial reported a potential association between the use of ezetimibe; simvastatin and increased diagnosis/death-rate for all types of cancer compared to placebo. However, cancer occurrence data from the SHARP and IMPROVE-IT trials combined indicate no overall excess of cancer (313 vs. 326 control; risk ratio, 0.96; 95% CI 0.82-1.12; p = 0.61). Based on a review of the final SEAS report, as well as a review of interim data from SHARP and IMPROVE-IT, FDA believes it is unlikely that ezetimibe; simvastatin or ezetimibe increase the risk of cancer or cancer-related death, although an association cannot be definitively ruled out. FDA does not advise discontinuation of therapy, but does recommend the evaluation of clinical benefit and potential risk compared to other available cholesterol-lowering medications.

Ezetimibe, administered alone or with a HMG-CoA reductase inhibitor ('statin'), was generally well tolerated during pre-marketing clinical trials. The discontinuation rate due to adverse events during ezetimibe therapy was similar to placebo. For ezetimibe monotherapy, adverse events that were reported at a frequency 2% or greater and exceeding placebo (regardless of causality) included: fatigue (2.4% vs. 1.5% placebo), abdominal pain (3% vs. 2.8%), diarrhea (4.1% vs. 3.7%), influenza (2% vs. 1.5%), upper respiratory tract infection (4.3% vs. 2.5%), pharyngitis (2.3% vs. 2.1%), sinusitis (2.8% vs. 2.2%), arthralgia (3% vs. 2.2%), back pain (4.1% vs. 3.9%), pain in extremity (2.7% vs. 2.5%), and cough (2.3% vs. 2.1%). During 11 placebo-controlled trials of patients taking combination ezetimibe/statin therapy, adverse events were similar between patients ezetimibe given concurrently with a statin (ezetimibe/statin) and statin monotherapy. Adverse experiences reported in 2% or greater of patients and at an incidence greater than placebo included: fatigue (2% vs. 1.6%), diarrhea (2.5% vs. 2.2%), naso-pharyngitis (3.7% vs. 3.3%), upper respiratory tract infection (2.9% vs. 2.8%), influenza (2.2% vs. 2.1%), arthralgia (2.6% vs. 2.4%), pain in extremity (2.1% vs. 1.9%), and back pain (2.4% vs. 2.3%).

During clinical trials, myalgia was reported in 3.2% of patients taking ezetimibe in combination with a 'statin' compared to 2.7% of patients taking a 'statin' alone. Combination therapy included 10 mg PO once daily of ezetimibe coadministered with once-daily dosing of either atorvastatin 10 to 80 mg/day, lovastatin 10 to 40 mg/day, pravastatin 10 to 40 mg/day, or simvastatin 10 to 80 mg/day. During clinical trials, the incidence of elevated creatinine phosphokinase concentrations (CPK greater than 10 times the upper limit of normal) was 0.1% for placebo, 0.1% for combination therapy (ezetimibe/statin), 0.4% for statin monotherapy, and 0.2% for ezetimibe monotherapy. In one trial evaluating the effects of ezetimibe coadministered with simvastatin compared to simvastatin alone in 246 children older than 10 years of age and adolescents, elevations of CPK occurred in 2 (2%) patients in the ezetimibe and simvastatin group and in zero individuals in the simvastatin monotherapy group. There was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the comparator groups (placebo or statin monotherapy). During post-marketing surveillance of ezetimibe, myalgia, increased CPK serum concentrations, and very rarely, myopathy/rhabdomyolysis, have been reported with ezetimibe monotherapy. The myopathy risk is higher when ezetimibe is coadministered with statin therapy or other drugs known to increase the risk such as fibrates. Patients receiving ezetimibe should be monitored for signs and symptoms of myopathy and/or rhabdomyolysis/myoglobinuria (myalgia, muscle cramps, musculoskeletal pain, lethargy, fatigue, fever, and/or myasthenia).

In controlled clinical monotherapy studies, the incidence of consecutive elevations (3 or more times the upper limit of normal) in serum transaminases (ALT/AST) was similar between ezetimibe monotherapy (0.5%) and placebo (0.3%). The frequency of elevated hepatic enzymes was higher in patients receiving combination therapy with ezetimibe/statins than in patients treated with statin monotherapy. In controlled trials, the incidence of consecutive elevations in serum transaminases was 1.3% for ezetimibe/statin combination therapy vs. 0.4% for statin monotherapy. Additionally, in a clinical trial comparing fenofibrate monotherapy to ezetimibe/fenofibrate combination therapy, the incidence of elevated hepatic enzymes to greater than 3 times the upper limit of normal were 4.5% for fenofibrate monotherapy and 2.7% for ezetimibe/fenofibrate combination therapy. The elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation or continuation of therapy. In one trial evaluating the effects of ezetimibe coadministered with simvastatin compared to simvastatin alone in 246 children older than 10 years of age and adolescents, hepatic transaminase elevations occurred in 4 (3%) patients in the ezetimibe and simvastatin group and in 2 (2%) patients in the simvastatin alone group. During post-marketing surveillance, elevated hepatic enzymes, hepatitis, and hepatic failure have been reported. When ezetimibe is coadministered with a HMG-CoA reductase inhibitor, liver function tests (LFTs) should be evaluated prior to initiating therapy and repeated according to the recommendations of the specific HMG-CoA reductase inhibitor.

During post-marketing experience with ezetimibe therapy, hypersensitivity or anaphylactoid reactions, including angioedema, anaphylaxis, urticaria, erythema multiforme, and rash (unspecified), have been reported. In addition, depression, dizziness, headache, nausea, pancreatitis, paresthesias, and thrombocytopenia have been reported.

Cholecystitis and cholelithiasis have been reported during post-marketing experience with ezetimibe therapy. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Ezetimibe has been studied in combination with fenofibrate during clinical trials for treatment of mixed hyperlipidemia. Fenofibrate is associated with an independent risk for cholelithiasis and gallbladder disease. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

Concurrent administration of ezetimibe with a HMG-CoA reductase inhibitor ('statin') or a fibrate should be in accordance with the product labeling for that specific HMG-CoA reductase inhibitor or fibrate.

Due to the unknown clinical effects of increased ezetimibe exposure in patients with moderate or severe hepatic disease, ezetimibe is not recommended in these patients. Following administration of a single 10 mg ezetimibe dose in patients with mild hepatic impairment (Child-Pugh A), the mean AUC for total ezetimibe increased by 1.7-fold compared to healthy subjects. In patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, the mean AUC values for ezetimibe (unconjugated and conjugated) and ezetimibe increased 3 to 4-fold and 5 to 6-fold, respectively, compared to healthy patients Compared to patients without hepatic impairment, the mean AUC for total ezetimibe increased by approximately 4-fold following administration of ezetimibe 10 mg PO once daily for 14 days in patients with moderate hepatic impairment. The combination of ezetimibe with an HMG-CoA reductase inhibitor is contraindicated in patients with active hepatic disease or unexplained persistent elevations in serum transaminases. The incidence of consecutive elevations (3 or more times the upper limit of normal) in serum transaminases is similar between ezetimibe monotherapy (0.5%) and placebo (0.3%). However, combined therapy with ezetimibe plus a statin (ezetimibe/statin) results in a greater frequency of consecutive elevations in liver function tests (LFTs) compared to statin monotherapy (1.3% ezetimibe/statin vs. 0.4% statin monotherapy). These elevations in transaminases are generally asymptomatic, not associated with cholestasis, and generally return to baseline after discontinuation or continuation of therapy. When ezetimibe is co-administered with an HMG-CoA reductase inhibitor, liver LFTs should be evaluated prior to initiating therapy and repeated according to the recommendations for the specific HMG-CoA reductase inhibitor. Consider discontinuation of ezetimibe if ALT or AST elevations (3 or more times the upper limit of normal) persist.

Myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors ('statins') and other lipid-lowering drugs. According to the manufacturer, the frequency of myopathy (or complications such as rhabdomyolysis) associated with ezetimibe has not been excessive compared with the comparator control groups (placebo or statin monotherapy). During pre-marketing clinical trials, the incidence of creatine phosphokinase (CPK) greater than 10 times the upper limit of normal has been reported to be 0.1% for placebo, 0.1% for ezetimibe/statin combination therapy, 0.4% for statin monotherapy, and 0.2% for ezetimibe monotherapy. If myopathy is diagnosed or suspected, discontinue ezetimibe and any fibrate or statin the patient may be receiving.

The effectiveness and safety of ezetimibe are similar between geriatric patients and younger subjects. However, greater sensitivity of some elderly patients cannot be ruled out. During monotherapy clinical trials, 669 elderly (65 years and older) patients have received ezetimibe (this included 111 participants 75 years and older). No dosage adjustments are needed in the elderly per the manufacturer.

Ezetimibe is classified by the FDA as a pregnancy risk category C drug. There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. Ezetimibe was not teratogenic when orally administered to pregnant rats and rabbits at doses that were 10 to 150 times the maximum recommended human dose (MRHD). An increase in the incidence of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) was observed in pregnant rats that received 10 times the MRHD of ezetimibe. In pregnant rabbits at doses 150 times MRHD, an increased incidence of extrathoracic ribs was reported. Placental transfer studies found the fetal-maternal plasma exposure for total ezetimibe (conjugated and unconjugated ezetimibe) to be 1.5 for rats and 0.03 for rabbits on gestation day 20 and 22, respectively. When ezetimibe and a statin were coadministered to rats and rabbits during organogenesis, reproductive findings were found to occur at lower doses with combination therapy compared to either agent administered alone.

According to the manufacturer, it is not known whether ezetimibe is excreted into human breast milk. Caution should be utilized when ezetimibe is administered to breast-feeding women. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for infant growth and development, including synthesis of steroids and cell membranes. Since the effect of ezetimibe on infant lipid metabolism is unknown, the drug should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant. If pharmacotherapy is necessary for the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thus will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Ezetimibe has not been studied in children younger than 10 years of age or in premenarchal girls; use in these populations is not recommended. Ezetimibe with simvastatin doses greater than 40 mg/day has not been studied in adolescents. In a 53-week trial comparing ezetimibe coadministered with simvastatin to simvastatin alone in 248 children greater than 10 years of age and adolescents, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.

No dosage adjustment is needed when ezetimibe is administered to patients with renal impairment. However, because a risk factor for statin-associated myopathy is renal impairment, the manufacturer of ezetimibe recommends that caution be utilized with coadministration of simvastatin at doses greater than 20 mg in patients with severe renal impairment (CrCl less than 60 mL/min/1.73 m2). The Study of Heart and Renal Protection (SHARP) trial involving patients with moderate or severe renal impairment found a similar incidence of musculoskeletal adverse events, liver enzyme abnormalities, or incident cancer between ezetimibe/statin therapy and placebo.

Ezetimibe is recommended as second-line therapy in addition to maximally tolerated statin therapy in patients with clinical ASCVD and comorbidities that require less than 25% additional LDL reduction. Factors to consider include patient comorbidities, low cost, and patient preference for oral medications.

For use as adjunctive therapy to diet and exercise for the reduction of elevated total cholesterol, LDL-cholesterol, Apo-B, and non-HDL-cholesterol in patients with primary (heterozygous familial and non-familial) hyperlipidemia; reduction of elevated sitosterol and campesterol in patients with homozygous familial sitosterolemia; in combination with atorvastatin or simvastatin for reduction of elevated total cholesterol and LDL-cholesterol in patients with homozygous familial hypercholesterolemia:
-for monotherapy:
Oral dosage:
Adults: 10 mg PO once daily.
Children 10 years or older and Adolescents: 10 mg PO once daily. The effects of ezetimibe coadministered with simvastatin compared to simvastatin monotherapy were evaluated in 142 boys and 106 postmenarchal girls, aged 10 to 17 years, with heterozygous familial hypercholesterolemia. The patients received ezetimibe 10 mg coadministered with simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin alone for 6 weeks, 10 mg ezetimibe and 40 mg simvastatin or 40 mg simvastatin alone for the next 27 weeks, and open-label ezetimibe with simvastatin for 20 weeks thereafter. The mean percent difference at Week 6 between the pooled ezetimibe coadministered with simvastatin and the pooled simvastatin alone was -12% for total cholesterol (95% CI, -15% to -9%), -15% for LDL-C (95% CI, -18% to -12%), -12% for Apo B (95% CI, -15% to -9%) and -14% for non-HDL-C (95% CI, -17% to -11%). In this 53-week trial, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.
-for use in combination with a HMG-CoA reductase inhibitor ("statin"):
Oral dosage:
NOTE: Administration of ezetimibe with an HMG-CoA reductase inhibitor is more effective in improving serum total cholesterol, LDL cholesterol, Apo-B, triglyceride, and HDL cholesterol concentrations than either treatment given alone.
Adults: 10 mg PO once daily. The daily dosage may be given at the same time as the HMG-CoA reductase inhibitor. Monitor for myopathy, drug interactions, and elevated hepatic enzymes as indicated for the specific HMG-CoA reductase inhibitor.
Children 10 years or older and Adolescents: 10 mg PO once daily.
-for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipoproteinemia:
NOTE: Administration of ezetimibe with fenofibrate is effective in improving serum total cholesterol, LDL cholesterol, Apo-B, and non-HDL cholesterol concentrations in patients with mixed hyperlipidemia compared to monotherapy with either treatment. The percent decrease in triglycerides and percent increase in HDL-cholesterol for ezetimibe coadministered with fenofibrate are comparable to values achieved by fenofibrate monotherapy.
Oral dosage:
Adults: 10 mg PO once daily. The daily dose may be given at the same time as fenofibrate. Monitor for myopathy.

Maximum Dosage Limits:
-Adults
10 mg/day PO.
-Geriatric
10 mg/day PO.
-Adolescents
10 mg/day PO.
-Children
10 years and older: 10 mg/day PO.
Younger than 10 years: Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
No dosage adjustment is needed in patients with mild hepatic impairment. Due to insufficient data, the manufacturer does not recommend ezetimibe for patients with moderate to severe hepatic impairment.

Patients with Renal Impairment Dosing
No dosage adjustment is needed.

Intermittent hemodialysis
No dosage adjustment is needed.

*non-FDA-approved indication

Antacids: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Calcium Carbonate: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Calcium Carbonate; Magnesium Hydroxide: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Calcium Carbonate; Risedronate: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Calcium Carbonate; Simethicone: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Calcium; Vitamin D: (Minor) Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Cholestyramine: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants, such as cholestyramine. The incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively.

Colesevelam: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colesevelam with ezetimibe; however, this potential interaction has not been studied.

Colestipol: (Moderate) The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants; the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colestipol with ezetimibe; however, this potential interaction has not been studied.

Cyclosporine: (Major) Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.

Eltrombopag: (Moderate) Use caution and monitor for adverse reactions if eltrombopag and ezetimibe are coadministered. Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as ezetimibe, may exhibit an increase in systemic exposure if coadministered with eltrombopag.

Fenofibrate: (Moderate) Monitor for cholelithiasis symptoms during concomitant ezetimibe and fenofibrate use. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. If cholelithiasis is suspected, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered.

Fenofibric Acid: (Moderate) Ezetimibe was approved by the FDA for use in combination with fenofibrate as adjunctive therapy to diet for the treatment of hypercholesterolemia in patients with mixed hyperlipidemia in May 2006. However, the safety and effective use of ezetimibe when coadministered with other fibric acid derivatives such as gemfibrozil or clofibrate has not been established. Until further data are available to support efficacy and safety, ezetimibe is not recommended for use with gemfibrozil. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.

Gemfibrozil: (Major) The safety and effectiveness of ezetimibe when coadministered with gemfibrozil have not been established. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. Coadministration of ezetimibe with gemfibrozil is not recommended. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. The incidence rates for cholecystectomy have been reported as 0.6% for fenofibrate monotherapy and 1.7% for combination therapy (ezetimibe plus fenofibrate), respectively. According to the manufacturer, the number of patients exposed to combination therapy versus fenofibrate or ezetimibe monotherapy has been inadequate to assess gallbladder disease risk. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5- or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.

Omeprazole; Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Sodium Bicarbonate: (Minor) Antacids may decrease the peak plasma concentration (Cmax) of total ezetimibe by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.

Warfarin: (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored.

Ezetimibe lowers serum cholesterol concentrations by selectively inhibiting the absorption of cholesterol and related phytosterols by the small intestine. Ezetimibe has a mechanism of action that is unique compared to other available antilipemic agents and is complementary to that of the HMG-CoA reductase inhibitors, resulting in synergistic cholesterol-lowering effects when these drugs are used in combination. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. Ezetimibe localizes at the brush border of the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the blood clearance of cholesterol. When ezetimibe is given as monotherapy, a compensatory increase in cholesterol synthesis occurs. With ongoing therapy, the overall effects of ezetimibe monotherapy are to reduce total cholesterol (13%), LDL-cholesterol (18%), and Apo-B (16%) in patients with hypercholesterolemia. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols (sitosterol and campesterol). In a 2 week study of 18 hypercholesterolemic patients, ezetimibe has been reported to inhibit intestinal cholesterol absorption by 54% relative to placebo.

In humans, the effects of ezetimibe to reduce triglycerides (8%) or to lower HDL-cholesterol (1%) are less prominent than its LDL-lowering effects; ezetimibe therapy usually results in increased HDL-C levels. In animal models (rodents), ezetimibe reduces the cholesterol content in chylomicrons without affecting the triglyceride content. In rodents, ezetimibe has no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins (A, D, and E), and does not impair adrenocortical steroid hormone production.

Ezetimibe is administered orally. Following systemic absorption, ezetimibe is extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human plasma proteins. Ezetimibe is rapidly metabolized by glucuronidation to ezetimibe-glucuronide in the small intestine and liver. Metabolism by oxidative metabolism is minimal. Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10% to 20% and 80% to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from the plasma with a half-life of about 22 hours. Ezetimibe is enterohepatically recirculated, as evidenced by multiple peaks in its plasma concentrations. After oral administration of radiolabeled ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) accounts for approximately 93% of the total plasma radioactivity. After 48 hours, the plasma radioactivity is undetectable. Over a 10 day period, approximately 78% and 11% of the administered dose is recovered in the feces and urine, respectively. Ezetimibe is the major component recovered in the feces and accounts for 69% of the administered dose, while ezetimibe-glucuronide is the major component recovered in the urine and accounts for 9% of the administered dose.

Affected cytochrome P450 (CYP) isoenzymes and drug transporters: None


-Route-Specific Pharmacokinetics
Oral Route
After oral administration of a single 10 mg dose to fasting adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL are attained within 4 to 12 hours. Mean peak concentrations (Cmax 45 to 71 ng/mL) of ezetimibe-glucuronide are attained within 1 to 2 hours. The absolute bioavailability of ezetimibe is not known. The apparent oral bioavailability of ezetimibe is variable; the coefficient of variation, based on intersubject variability, is 35 to 60% for AUC values. The concomitant administration of food (high-fat vs. non-fat meals) has no effect on the extent of absorption of ezetimibe. However, coadministration with a high-fat meal increases the peak concentration (Cmax) of ezetimibe by 38%.


-Special Populations
Hepatic Impairment
Although pharmacokinetic differences have been identified in patients with mild hepatic impairment (Child-Pugh A), no dosage adjustments for ezetimibe are indicated. Significant increases in ezetimibe exposure occur in patients with moderate to severe hepatic impairment (Child-Pugh B or C); ezetimibe is not recommended for use in these patients. Following administration of a single 10 mg ezetimibe dose in patients with mild hepatic impairment (Child-Pugh A), the mean AUC for total ezetimibe increased by 1.7-fold compared to healthy subjects. In patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, the mean AUC values for ezetimibe (unconjugated and conjugated) and ezetimibe increased 3 to 4-fold and 5 to 6-fold, respectively, compared to healthy patients Compared to patients without hepatic impairment, the mean AUC for total ezetimibe increased by approximately 4-fold following administration of ezetimibe 10 mg PO once daily for 14 days in patients with moderate hepatic impairment.

Renal Impairment
Although pharmacokinetic differences have been identified in severe renal impairment, no dosage adjustments for ezetimibe are indicated. In 8 patients with severe renal impairment (mean CrCl less than 30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe are increased by approximately 1.5-fold, compared to healthy subjects.

Pediatrics
The absorption and metabolism of ezetimibe are similar in adolescents (10 to 18 years) and adults.

Geriatric
With repeated dosing for 10 days, plasma concentrations for total ezetimibe are about 2-fold higher in elderly subjects (65 years and older) compared to younger adults; however, no dosage adjustment is recommended for elderly patients.

Gender Differences
Although pharmacokinetic differences have been identified in women, no dosage adjustments for ezetimibe are indicated. In a multiple-dose study of 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) for women relative to men.

Ethnic Differences
No pharmacokinetic differences between Black and Caucasian patients were found in a meta-analysis of multiple pharmacokinetic studies. In clinical studies, ezetimibe pharmacokinetics were found to be similar between Asian and Caucasian patients.