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  • CLASSES

    Sterol Transporter Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antilipemic; cholesterol absorption inhibitor indicated to treat hypercholesterolemia; approved for monotherapy or use in combination with HMG-CoA reductase inhibitors ('statins') or fenofibrate; synergistic antilipemic effects with statins.

    COMMON BRAND NAMES

    Zetia

    HOW SUPPLIED

    Ezetimibe/Zetia Oral Tab: 10mg

    DOSAGE & INDICATIONS

    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:.
    NOTE: 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.
    For monotherapy.
    Oral dosage
    Adults

    10 mg PO once daily.

    Children >= 10 years 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—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 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 (see Contraindications).

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO.

    Elderly

    10 mg/day PO.

    Adolescents

    10 mg/day PO.

    Children

    >= 10 years: 10 mg/day PO.
    < 10 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    No dosage adjustment is needed.
     
    Intermittent hemodialysis
    No dosage adjustment is needed.

    ADMINISTRATION

     
    NOTE: Patients receiving ezetimibe therapy should also be placed on a standard cholesterol-lowering diet, and this diet should be continued throughout therapy. Serum lipoprotein concentrations should be determined periodically and dosage adjusted according to individual response and established NCEP treatment guidelines.

    Oral Administration

    Ezetimibe may be administered with or without food.
    If taken with a HMG-CoA reductase inhibitor ('statin'), the daily dose of ezetimibe may be taken at the same time as the statin.
    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.

    STORAGE

    Zetia:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

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

    Hepatic disease

    Due to the unknown clinical effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic disease, ezetimibe is not recommended in these patients. In patients with mild (Child-Pugh score 5—6), moderate (Child Pugh score 7—9), or severe hepatic impairment (Child-Pugh score 10—15), the mean AUC values for total ezetimibe are increased approximately 1.7-fold, 3—4-fold, or 4-fold, respectively, compared to healthy subjects. The combination of ezetimibe with a 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 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 a 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.

    Myopathy

    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 CPK > 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.

    Geriatric

    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 pre-marketing clinical trials, 948 elderly (aged > 65 years) patients have received ezetimibe (this included 206 participants aged >= 75 years). No dosage adjustments are needed in the elderly per the manufacturer. Also, no dosage adjustment of ezetimibe is needed in patients with renal impairment per the manufacturer.

    Pregnancy

    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. All HMG-CoA reductase inhibitors are contraindicated in pregnant women. When ezetimibe is administered with a HMG-CoA reductase inhibitor in a female of childbearing potential, refer to the pregnancy category and package labeling for the specific HMG-CoA reductase inhibitor.

    Breast-feeding

    According to the manufacturer, it is not known whether ezetimibe is excreted into human breast milk. All HMG-CoA reductase inhibitors are contraindicated in breast-feeding women. When ezetimibe is administered with a HMG-CoA reductase inhibitor in a female who is lactating, refer to the package labeling for the specific HMG-CoA reductase inhibitor. Because lipids play a crucial role in growth and development and 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 in 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.

    Children

    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 > 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.

    ADVERSE REACTIONS

    Severe

    myoglobinuria / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    pancreatitis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    cholecystitis / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 0.5-3.0
    myasthenia / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known

    Mild

    infection / Delayed / 2.9-4.3
    diarrhea / Early / 2.5-4.1
    back pain / Delayed / 2.4-4.1
    pharyngitis / Delayed / 2.7-3.7
    myalgia / Early / 3.2-3.2
    arthralgia / Delayed / 2.6-3.0
    abdominal pain / Early / 3.0-3.0
    sinusitis / Delayed / 2.8-2.8
    fatigue / Early / 2.0-2.4
    cough / Delayed / 2.3-2.3
    influenza / Delayed / 2.0-2.2
    muscle cramps / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    rash / Early / Incidence not known
    nausea / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    headache / Early / Incidence not known
    dizziness / Early / Incidence not known

    DRUG INTERACTIONS

    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.
    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; 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; 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.
    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) Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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. All HMG-CoA reductase inhibitors are contraindicated in pregnant women. When ezetimibe is administered with a HMG-CoA reductase inhibitor in a female of childbearing potential, refer to the pregnancy category and package labeling for the specific HMG-CoA reductase inhibitor.

    According to the manufacturer, it is not known whether ezetimibe is excreted into human breast milk. All HMG-CoA reductase inhibitors are contraindicated in breast-feeding women. When ezetimibe is administered with a HMG-CoA reductase inhibitor in a female who is lactating, refer to the package labeling for the specific HMG-CoA reductase inhibitor. Because lipids play a crucial role in growth and development and 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 in 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.

    MECHANISM OF ACTION

    Mechanism of Action: 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.

    PHARMACOKINETICS

    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 (> 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—20% and 80—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.

    Oral Route

    After oral administration of a single 10 mg dose to fasting adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4—5.5 ng/mL are attained within 4—12 hours. Mean peak concentrations (Cmax 45—71 ng/mL) of ezetimibe-glucuronide are attained within 1—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—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, co-administration with a high-fat meal increases the peak concentration (Cmax) of ezetimibe by 38%.