Generic Name: Ezetimibe
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

Introduction

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

Uses for Zetia

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

Slideshow: HealthQuiz - Basics About Stroke Signs and Symptoms

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

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

Zetia 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

Monitoring during Antilipemic Therapy

  • Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.

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 Zetia

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) concentrations3 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

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.1

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 Zetia

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

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

Zetia 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 National Cholesterol Education Program (NCEP)’s dietary recommendations.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.

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Vytorin 10-10MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$148.48 or 90/$422.56

Vytorin 10-20MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$146.00 or 90/$415.99

Vytorin 10-40MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$146.00 or 90/$419.99

Vytorin 10-80MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$144.99 or 90/$411.99

Zetia 10MG Tablets (MERCK/SCHERING-PLOUGH PHARM): 30/$145.99 or 90/$405.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 31, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Merck/Schering-Plough Pharmaceuticals. Zetia (ezetimibe) tablets prescribing information. North Wales, PA; 2006 May.

2. Dujovne CA, Ettinger MP, McNeer JF et al for the Ezetimibe Study Group. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002; 90:1092-7. [IDIS 490188] [PubMed 12423709]

3. Gagne C, Bays HE, Weiss SR et al for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002; 90:1084-91. [IDIS 490187] [PubMed 12423708]

4. Gagne C, Gaudet D, and Bruckert E for the Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002; 105:2469-75. [IDIS 482036] [PubMed 12034651]

5. Kosoglou T, Meyer I, Veltri EP et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol. 2002; 54:309-19. [IDIS 489553] [PubMed 12236852]

6. Sudhop T, Lutjohann D, Kodal A et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation. 2002; 106:1943-8. [IDIS 490884] [PubMed 12370217]

7. Ezzet F, Krishna G, Wexler DB et al. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther. 2001; 23:871-85. [IDIS 467647] [PubMed 11440287]

8. Merck/Schering-Plough, PA: Personal communication.

9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015-23.

10. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda, MD: National Institutes of Health. (NIH publication No. 01-3670.)

11. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: Adult Treatment Panel III Report. From AHA web site.

12. Merck/Schering-Plough. Vytorin (ezetimibe and simvastatin) tablets prescribing information. North Wales, PA; Nov 05.

13. Ballantyne CM, Houri J, Notarbartolo A et al for the Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003; 107:2409-15. [PubMed 12719279]

14. Food and Drug Administration. Vytorin (ezetimibe and simvastatin) tablets [Undated: Merck/Schering-Plough Pharmaceuticals]. Rockville, MD; FDA Action Date October 24, 2006. From Drugs@FDA website.

15. Rossebø AB, Pedersen TR, Boman K et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008; 359:1343-56. [PubMed 18765433]

16. Peto R, Emberson J, Landray M et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med. 2008; 359:1357-66. [PubMed 18765432]

17. Food and Drug Administration. Early communication about an ongoing safety review of ezetimibe/simvastatin (marketed as Vytorin), simvastatin (marketed as Zocor) and ezetimibe (marketed as Zetia): FDA investigates a report from the SEAS trial. Rockville, MD; 2008 Aug 21. Available from FDA website. Accessed 2008 Oct 9.

18. Food and Drug Administration. Follow-up to the January 25, 2008 early communication about an ongoing data review for ezetimibe/simvastatin (marketed as Vytorin), ezetimibe (marketed as Zetia), and simvastatin (marketed as Zocor). Rockville, MD; 2009 Jan 8. Available from FDA website. Accessed 2009 Sep 10.

19. Merck/Schering-Plough Pharmaceuticals. Vytorin (ezetimibe and simvastatin) tablets prescribing information. North Wales, PA; 2011 Jun.

20. Merck & Co., Inc. Vytorin (ezetimibe and simvastatin) tablets prescribing information. Whitehouse Station, NJ; 2012 Jun.

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