Class: Cholesterol Absorption Inhibitors
VA Class: CV350
Chemical Name: [3R - [3α(S*),4β]] - 1 - (4 - fluorophenyl) - 3 - [3 - (4 - fluorophenyl) - 3 - hydroxypropyl] - 4 - (4 - hydroxyphenyl) - 2 - azetidinone
Molecular Formula: C₂₄H₂₁F₂NO₃
CAS Number: 163222-33-1
Brands: Vytorin, Zetia

Introduction

Antilipemic agent;¹ cholesterol absorption inhibitor.^{2 4 5 8}

Uses for Ezetimibe

Primary Hypercholesterolemia and Mixed Dyslipidemia

Use alone or in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, and apolipoprotein B (apo B) concentrations in the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia.^{1 12}

Effects on cardiovascular morbidity and mortality not established.¹

Use in fixed combination with simvastatin (i.e., Vytorin) as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia.¹²

Use in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia.¹ Effects on cardiovascular morbidity and mortality not established.¹ Use with a fibric acid derivative other than fenofibrate not studied and currently not recommended.¹ (See Specific Drugs under Interactions.)

Produces negligible increases in HDL-cholesterol concentrations.^{1 2}

Drug therapy is not a substitute for but an adjunct to nondrug therapies and measures (e.g., dietary management, weight control, physical activity, management of potentially contributory disease), which should be continued when drug therapy is initiated.^{9 10 11}

ACC/AHA cholesterol management guideline states that nonstatin drugs (e.g., ezetimibe) do not provide acceptable atherosclerotic cardiovascular disease (ASCVD) risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD.³⁵⁰ May be useful as adjuncts to statin therapy in high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations ≥190 mg/dL, patients with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy.³⁵⁰ Select nonstatin drug based on favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects and drug interactions) and patient preferences.³⁵⁰ Current recommendations from ACC/AHA regarding prevention of ASCVD and lifestyle modifications to reduce cardiovascular risk are available at or ³⁵²

Homozygous Familial Hypercholesterolemia

Use in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available.^{1 12}

Effects in patients currently undergoing LDL apheresis compared with those in patients not undergoing the procedure not established.⁴ Effects on clinical outcome and modification of other disease parameters (e.g., xanthoma formation, regression of atherosclerosis) not established.⁴

Homozygous Familial Sitosterolemia (Phytosterolemia)

Adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia.^{1 6 8}

Reductions in sitosterol and campesterol concentrations were consistent between patients receiving ezetimibe with or without bile acid sequestrants.¹

Effect of reducing plasma concentrations of sitosterol and campesterol on cardiovascular morbidity and mortality not established.¹

Ezetimibe Dosage and Administration

General

• Patients should be placed on a standard cholesterol-lowering diet before initiation of ezetimibe therapy and should remain on this diet during treatment with the drug.¹

Administration

Oral Administration

Administer orally without regard to meals.¹

Combination therapy with a statin or fenofibrate: May administer ezetimibe at same time as the statin or fenofibrate, in accordance with recommended dosing schedule for these drugs.¹

Combination therapy with a bile acid sequestrant: Administer ≥2 hours before or ≥4 hours after bile acid sequestrant.¹

Ezetimibe/simvastatin fixed-combination preparation: Administer orally in the evening without regard to meals.¹²

Dosage

Pediatric Patients

Dyslipidemias

Primary Hypercholesterolemia and Mixed Dyslipidemia

Oral

Children ≥10 years of age: 10 mg once daily.¹

Homozygous Familial Hypercholesterolemia

Oral

Children ≥10 years of age: 10 mg once daily.¹

Homozygous Familial Sitosterolemia

Oral

Children ≥10 years of age: 10 mg once daily.¹

Adults

Dyslipidemias

Primary Hypercholesterolemia and Mixed Dyslipidemia

Oral

10 mg once daily.¹

Ezetimibe/simvastatin fixed combination (Vytorin): Initially, ezetimibe 10 mg/simvastatin 10 mg or ezetimibe 10 mg/simvastatin 20 mg once daily in the evening.¹⁹ In patients requiring LDL-cholesterol reductions ≥55%, may initiate therapy with ezetimibe 10 mg/simvastatin 40 mg once daily in the absence of moderate to severe renal impairment (GFR <60 mL/minute per 1.73 m²).²⁰ Determine serum cholesterol concentrations ≥2 weeks after initiation of therapy and adjust dosage as needed.¹² Usual maintenance dosage range is ezetimibe 10 mg and simvastatin 10–40 mg once daily.¹⁹ If LDL-cholesterol target goal cannot be achieved with ezetimibe 10 mg/simvastatin 40 mg once daily, do not increase dosage; instead, switch to an alternative antilipemic agent(s) that provides greater LDL-cholesterol reduction.¹⁹ Restrict use of ezetimibe 10 mg/simvastatin 80 mg dosage.¹⁹ (See Prescribing Limits under Dosage and Administration.)

Homozygous Familial Hypercholesterolemia

Oral

10 mg once daily.¹

Ezetimibe/simvastatin fixed combination (Vytorin): Ezetimibe 10 mg/simvastatin 40 mg once daily in the evening.¹⁹ Use as adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.¹²

Homozygous Familial Sitosterolemia

Oral

10 mg once daily.¹

Prescribing Limits

Adults

Oral

Restrict use of ezetimibe 10 mg/simvastatin 80 mg dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects.¹⁹ In patients currently tolerating the ezetimibe 10 mg/simvastatin 80 mg daily dosage who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin), switch to alternative statin or statin-based regimen with less drug interaction potential.¹⁹

Special Populations

Hepatic Impairment

Ezetimibe

Mild hepatic impairment: No dosage adjustment needed.¹

Moderate or severe hepatic impairment: Do not use.¹²

Ezetimibe/Simvastatin Fixed Combination

Mild hepatic impairment: No dosage adjustment needed.¹

Moderate or severe hepatic impairment: Do not use.¹²

Renal Impairment

Ezetimibe

No dosage adjustment needed in patients with renal impairment.¹

Ezetimibe/Simvastatin Fixed Combination

Mild renal impairment (estimated GFR ≥60 mL/minute per 1.73 m²): No dosage adjustment needed.²⁰

Chronic kidney disease and estimated GFR <60 mL/minute per 1.73 m²: Ezetimibe 10 mg/simvastatin 20 mg once daily; use higher dosages with caution and close monitoring.²⁰ (See Renal Impairment under Cautions.)

Geriatric Patients

Ezetimibe

No dosage adjustment needed in geriatric patients (≥65 years of age).¹

Ezetimibe/Simvastatin Fixed Combination

No dosage adjustment needed in geriatric patients (≥65 years of age).¹²

Cautions for Ezetimibe

Contraindications

• Known hypersensitivity to ezetimibe or any ingredient in the formulation.¹

• Fixed combination of ezetimibe and simvastatin: Contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations; in pregnant or nursing women; or in patients receiving concomitant therapy with potent inhibitors of CYP3A4, cyclosporine, danazol, or gemfibrozil.²⁰

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis, angioedema, rash, and urticaria reported.^{1 12}

Major Toxicities

Hepatic Effects

Transient elevations in serum aminotransferase (AST, ALT) concentrations^{3 4} >3 times the ULN reported.^{1 12} Elevations reported more frequently with ezetimibe-statin combination than with statin monotherapy.¹ Hepatitis reported; however, causal relationship not established.^{1 12}

ACC/AHA cholesterol management guideline states it is reasonable to obtain baseline hepatic aminotransferase concentrations before initiating ezetimibe.³⁵⁰ When used with a statin, perform liver function tests at initiation of therapy and in accordance with the recommended monitoring schedule for the specific statin and as clinically indicated.^{1 350} If ALT or AST concentrations increase to ≥3 times the ULN and are persistent, consider discontinuing ezetimibe and/or the statin.³⁵⁵

Musculoskeletal Effects

Marked (>10 times ULN) elevations of CK (CPK) reported.¹ Elevations in CK concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.¹

Myalgia, myopathy (i.e., unexplained muscle pain, tenderness, or weakness and CK concentration >10 times ULN), and/or rhabdomyolysis reported.^{1 12} Most cases of rhabdomyolysis occurred in patients receiving statin therapy prior to initiating ezetimibe; however, rhabdomyolysis also reported very rarely following ezetimibe monotherapy or following addition of ezetimibe to therapy with agents known to be associated with increased risk of rhabdomyolysis (e.g., fibric acid derivatives).^{1 12}

Immediately discontinue ezetimibe and any concomitant statin or fibric acid derivative (e.g., gemfibrozil, fenofibrate) if myopathy is diagnosed or suspected.^{1 12}

General Precautions

Combination Therapy with Statins or Fenofibrate

When used in combination or fixed combination with a statin or fenofibrate, consult prescribing information of specific statin or fenofibrate for detailed information on usual cautions, precautions, and contraindications of these drugs.^{1 12}

Risk of Cancer

Fixed combination of ezetimibe and simvastatin (Vytorin) reported in one trial (Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] study) to be possibly associated with an increased risk of cancer.^{15 17} Preliminary results of this study in approximately 1900 patients revealed a higher incidence of cancer and fatal cancer in patients receiving fixed-combination preparation (11.1 and 4.1%, respectively) compared with those receiving placebo (7.5 and 2.5%, respectively).^{15 17} However, interim data from 2 ongoing randomized trials evaluating >20,000 patients with chronic kidney disease or acute coronary syndrome showed no increased risk of cancer following use of fixed-combination preparation.^{16 17} FDA will review final study report of the SEAS trial to assess additional safety data and provide insight into the risk of cancer.¹⁷

Specific Populations

Pregnancy

Category C.¹

Fixed combination of ezetimibe and simvastatin (Vytorin): Category X (due to simvastatin component).¹²

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use in nursing women not recommended unless potential benefits justify possible risks to infant.¹

Pediatric Use

Safety and efficacy not established in children <10 years of age; use not recommended in these children.¹

Safety and efficacy of ezetimibe in fixed combination with simvastatin not established in prepubertal girls or in children ≤10 years of age.¹⁹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.^{1 12}

Use fixed combination of ezetimibe and simvastatin with caution, since age ≥65 years is a risk factor for myopathy, including rhabdomyolysis.¹⁹

Hepatic Impairment

Safety of increased exposure to ezetimibe in patients with moderate or severe hepatic impairment currently not known; use not recommended in such patients.¹

Use of fixed combination of ezetimibe and simvastatin not recommended in patients with moderate or severe hepatic impairment.¹⁹

Renal Impairment

In patients with moderate to severe renal impairment receiving ezetimibe 10 mg/simvastatin 20 mg in fixed combination, incidence of certain adverse effects (serious effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo.²⁰ Use higher dosages with caution and close monitoring in such patients, since renal impairment increases risk for myopathy.²⁰ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Ezetimibe monotherapy: Back pain,^{1 2} arthralgia,^{1 2} diarrhea,^{1 3} sinusitis,¹ abdominal pain,^{1 3} coughing,¹ pharyngitis,^{1 4} viral infection,¹ fatigue.¹

Ezetimibe in combination with a statin: Upper respiratory tract infection,^{1 2 4 12} headache,^{1 2 4 12} back pain,¹ influenza,¹² myalgia,¹² abdominal pain,¹ sinusitis,¹ arthralgia,¹ diarrhea,¹ pharyngitis,¹ pain in extremity,¹² chest pain,^{1 4} dizziness.¹

Adverse effects associated with combination therapy generally similar to those reported with monotherapy.¹ However, elevations in transaminase concentrations reported more frequently with ezetimibe-statin combination than with statin monotherapy.¹

Interactions for Ezetimibe

Does not inhibit or induce CYP1A2, 2D6, 2C8, 2C9, or 3A4.¹ Pharmacokinetic interactions with drugs metabolized by these isoenzymes (e.g., caffeine, dextromethorphan, tolbutamide, IV midazolam) unlikely.¹

When used in fixed combination with simvastatin, consider drug interactions associated with simvastatin.¹² No formal drug interaction studies to date with fixed-combination preparation other than that with extended-release niacin.²⁰ (See Specific Drugs under Interactions.)

Specific Drugs

Drug	Interaction	Comments
Antacids	Decreased ezetimibe peak plasma concentrations but no effect on AUC1
Bile acid sequestrants	Decreased ezetimibe AUC1	Administer ezetimibe ≥2 hours before or ≥4 hours after bile acid sequestrant1
Caffeine	Pharmacokinetic interaction unlikely1
Cimetidine	Pharmacokinetic interaction unlikely1
Cyclosporine	Increased ezetimibe and cyclosporine concentrations; possible greater ezetimibe exposure in patients with severe renal impairment 1 12	Use concomitantly with caution;1 monitor cyclosporine concentrations with concomitant use1
Dextromethorphan	Pharmacokinetic interaction unlikely1
Digoxin	Pharmacokinetic and pharmacologic interaction unlikely1
Fat-soluble vitamins	Pharmacokinetic interaction with vitamins A, D, and E unlikely1 8
Fibric acid derivatives (fenofibrate, gemfibrozil)	Increased plasma concentrations of ezetimibe1 Ezetimibe associated with increased cholesterol excretion in gall bladder bile;1 fibric acid derivatives may increase cholesterol excretion in bile, leading to cholelithiasis1 Cholecystectomy reported1 Very rare postmarketing reports of myopathy/rhabdomyolysis with concomitant use1	Concomitant use with a fibric acid derivative other than fenofibrate currently not recommended1 (see Musculoskeletal Effects under Cautions) If cholelithiasis is suspected during concomitant use with fenofibrate, perform gallbladder studies and consider alternative antilipemic therapy1
Glipizide	Pharmacokinetic interaction unlikely1
HMG-CoA reductase inhibitors (statins) (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin)	Pharmacokinetic interaction unlikely1 3 5 Rare postmarketing reports of myopathy/rhabdomyolysis with concomitant use1	Monitor liver function according to recommendations for statin with concomitant use1 Discontinue ezetimibe and any concomitant statin if myopathy diagnosed or suspected1 (see Musculoskeletal Effects under Cautions)
Midazolam (IV)	Pharmacokinetic interaction unlikely1
Mipomersen	No clinically relevant pharmacokinetic interactions observed375	No dosage adjustment of ezetimibe or mipomersen required375
Niacin (antilipemic dosages [≥1 g daily])	Extended-release niacin (Niaspan) with fixed combination of ezetimibe and simvastatin: Increased peak plasma concentrations and AUC of niacin and nicotinuric acid; increased peak plasma concentrations of simvastatin acid; increased AUC of total ezetimibe, simvastatin, and simvastatin acid20	Weigh benefits against risks of concomitant therapy with ezetimibe-simvastatin fixed combination; use concomitantly with caution20 Patients of Chinese descent: Caution when used concomitantly with fixed-combination preparation containing dosages exceeding ezetimibe 10 mg/simvastatin 20 mg daily; avoid concomitant use with ezetimibe 10 mg/simvastatin 80 mg daily20
Oral contraceptives	Pharmacokinetic interaction unlikely1
Tolbutamide	Pharmacokinetic interaction unlikely1
Warfarin	Pharmacokinetic and pharmacologic interaction unlikely based on one study1 8 12 Increased INR with combined ezetimibe-warfarin therapy reported during post-marketing experience; most patients also on other drugs1 12	Monitor INR appropriately if ezetimibe is initiated in a patient receiving warfarin1

Ezetimibe Pharmacokinetics

Absorption

Bioavailability

Approximately 93% of dose is absorbed systemically following oral administration.¹

Bioavailability is variable.¹ Absolute bioavailability cannot be determined because ezetimibe is virtually insoluble in aqueous media suitable for injection.¹ Ezetimibe/simvastatin fixed-combination preparation is bioequivalent to corresponding dosages of the individual components.¹²

Peak plasma concentrations attained within 4–12 hours following oral administration.¹

Onset

Maximal or near-maximal reductions in serum lipoprotein and apolipoprotein concentrations achieved within 2 weeks.^{1 2 8}

Duration

Reductions in serum lipoprotein and apolipoprotein concentrations maintained during continued therapy.^{1 2 8}

Food

Food (high-fat or nonfat meals) does not affect extent of absorption.¹ High-fat meals associated with increased peak plasma concentrations.¹

Special Populations

Increased plasma concentrations in geriatric individuals (≥65 years of age), in patients with hepatic impairment, and in patients with severe renal impairment.¹ (See Special Populations under Dosage and Administration.)

No differences in pharmacokinetic parameters between blacks and Caucasians.¹ Studies in Asian individuals indicated similar pharmacokinetics as observed in Caucasian individuals.¹

Distribution

Plasma Protein Binding

>90%.¹

Elimination

Metabolism

Rapidly metabolized principally in small intestine and liver to ezetimibe glucuronide (active).¹ Ezetimibe and ezetimibe glucuronide constitute approximately 10–20% and 80–90%, respectively, of total drug in plasma.¹

Possible enterohepatic recycling.¹

Elimination Route

Excreted in feces (78%) and urine (11%) within 10 days after dosing.¹ Major component in feces is ezetimibe (69% of administered dose); major component in urine is ezetimibe glucuronide (9% of administered dose).¹

Half-life

Approximately 22 hours for both ezetimibe and ezetimibe glucuronide.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹ Protect from moisture.¹

Ezetimibe/simvastatin fixed-combination preparation: Well-closed containers at 20–25°C.¹² When subdividing contents of a large-quantity container, repackage into tightly closed, light-resistant containers; entire contents must be repackaged immediately upon opening.¹²

Actions

• Localizes at brush border of small intestine and inhibits absorption of cholesterol,^{3 4 8} resulting in decreased delivery of intestinal cholesterol to liver.¹ Intestinal absorption of cholesterol reduced by approximately 54% in a limited number of patients with hypercholesterolemia.^{1 6}

• Has been shown to reduce concentrations of noncholesterol sterols,⁸ including sitosterol and campesterol.^{1 6}

• Does not appear to inhibit hepatic cholesterol synthesis or increase bile acid excretion.¹ Does not appear to inhibit absorption of triglycerides, fatty acids, bile acids, progesterone, or ethyl estradiol.¹ No clinically relevant effects on plasma concentrations of fat-soluble vitamins A, D, and E;⁸ does not appear to impair adrenocortical steroid production.¹

• Cholesterol-lowering effects of ezetimibe and statins or of ezetimibe and fenofibrate are additive.¹

Advice to Patients

• Importance of adherence to prescribed directions for use, particularly when used concomitantly with other antilipemic agents.^{1 12}

• Importance of adherence to a standard cholesterol-lowering diet.^{1 8}

• Risk of myopathy; importance of promptly informing clinicians of unexplained muscle pain, weakness, or tenderness.^{1 12}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.^{1 12}

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 12}

• Importance of informing patients of other important precautionary information.^{1 12} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ezetimibe

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	10 mg	Zetia	Merck/Schering-Plough

Ezetimibe Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	10 mg with Simvastatin 10 mg	Vytorin	Merck
		10 mg with Simvastatin 20 mg	Vytorin	Merck
		10 mg with Simvastatin 40 mg	Vytorin	Merck
		10 mg with Simvastatin 80 mg	Vytorin	Merck