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Ezetimibe

Pronunciation

Pronunciation

(ez ET i mibe)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Zetia: 10 mg

Brand Names: U.S.

  • Zetia

Pharmacologic Category

  • Antilipemic Agent, 2-Azetidinone

Pharmacology

Inhibits absorption of cholesterol at the brush border of the small intestine via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). This leads to a decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and an increased clearance of cholesterol from the blood; decreases total C, LDL-cholesterol (LDL-C), ApoB, and triglycerides (TG) while increasing HDL-cholesterol (HDL-C).

Metabolism

Undergoes glucuronide conjugation in the small intestine and liver; forms metabolite (active); may undergo enterohepatic recycling

Excretion

Feces (78%, 69% as ezetimibe); urine (11%, 9% as metabolite)

Onset of Action

Within 1 week; Maximum effect: 2-4 weeks

Time to Peak

Plasma: 4-12 hours (ezetimibe); 1-2 hours (active metabolite); Effects: ~2 weeks

Half-Life Elimination

22 hours (ezetimibe and metabolite)

Protein Binding

>90% to plasma proteins

Special Populations: Elderly

Plasma concentrations are approximately 2-fold higher.

Special Populations: Gender

Plasma concentrations for total ezetimibe were slightly higher (less than 20%) in women than in men.

Use: Labeled Indications

Homozygous familial hypercholesterolemia: In combination with atorvastatin or simvastatin for the reduction of elevated total cholesterol (total-C) and low-density lipoprotein cholesterol (LDL-C) levels in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.

Homozygous sitosterolemia: As adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

Primary hyperlipidemia:

Combination therapy with HMG-CoA reductase inhibitors: In combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia.

Combination therapy with fenofibrate: In combination with fenofibrate as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.

Monotherapy: As adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, apo B, and non-HDL-C in patients with primary (heterozygous familial and nonfamilial) hyperlipidemia.

Contraindications

Hypersensitivity to ezetimibe or any component of the formulation; concomitant use with an HMG-CoA reductase inhibitor (statin) in patients with active hepatic disease or unexplained persistent elevations in serum transaminases; pregnancy and breast-feeding (when used concomitantly with a statin)

Dosing: Adult

Homozygous familial hypercholesterolemia, primary hyperlipidemia, homozygous sitosterolemia: Oral: 10 mg daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Children ≥10 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate to severe impairment (Child-Pugh class B or C): Use of ezetimibe not recommended.

Administration

May be administered without regard to meals. May be taken at the same time as a statin or fenofibrate. Administer ≥2 hours before or ≥4 hours after bile acid sequestrants.

Dietary Considerations

Before initiation of therapy, patients should be placed on a standard cholesterol-lowering diet for 6 weeks and the diet should be continued during drug therapy.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from moisture.

Drug Interactions

Bezafibrate: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Avoid combination

Bile Acid Sequestrants: May decrease the absorption of Ezetimibe. Management: Administer ezetimibe at least 2 hours before or 4 hours after any bile acid sequestrant. Consider therapy modification

CycloSPORINE (Systemic): Ezetimibe may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Ezetimibe. Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Fenofibrate and Derivatives: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Monitor therapy

Gemfibrozil: May enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Gemfibrozil may increase the serum concentration of Ezetimibe. Avoid combination

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Adverse Reactions

1% to 10%:

Central nervous system: Fatigue (2%)

Gastrointestinal: Diarrhea (4%)

Hepatic: Transaminases increased (with HMG-CoA reductase inhibitors) (≥3 x ULN, 1%)

Neuromuscular & skeletal: Arthralgia (3%), pain in extremity (3%)

Respiratory: Upper respiratory tract infection (4%), sinusitis (3%)

Miscellaneous: Influenza (2%)

Postmarketing and/or case reports: Abdominal pain, anaphylaxis, angioedema, autoimmune hepatitis (Stolk, 2006), cholecystitis, cholelithiasis, cholestatic hepatitis (Stolk, 2006), CPK increased, depression, dizziness, erythema multiforme, headache, hepatitis, hypersensitivity reactions, myalgia, myopathy, nausea, pancreatitis, paresthesia, rash, rhabdomyolysis, thrombocytopenia, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Elevated hepatic transaminases: A higher incidence of elevated transaminases (≥3 x ULN) has been observed with concomitant use of ezetimibe and statins compared to statin monotherapy; transaminase changes were generally not associated with symptoms or cholestasis and returned to baseline with or without discontinuation of therapy. Consider discontinuation of ezetimibe and/or the statin for persistently elevated transaminases (ALT or AST ≥3 x ULN).

• Myopathy: Myopathy, including rhabdomyolysis, has been reported (rarely) with ezetimibe monotherapy; risk may be increased with concomitant use of a statin or fibrate. Discontinue ezetimibe and statin or fibrate immediately if myopathy is suspected or confirmed (symptomatic patient with CPK >10 x ULN).

Disease-related concerns:

• Hepatic impairment: Systemic exposure is increased in hepatic impairment. Use with caution in patients with mild hepatic impairment (Child-Pugh class A); use is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh classes B and C).

• Renal impairment: Use with caution in patients with severe renal impairment (CrCl ≤30 mL/minute/1.73 m2); systemic exposure is increased ~1.5-fold. If using concurrent simvastatin in patients with moderate to severe renal impairment (CrCl <60 mL/minute/1.73m2), the manufacturer of ezetimibe recommends that simvastatin doses exceeding 20 mg be used with caution and close monitoring for adverse events (eg, myopathy).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant drug interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.

Monitoring Parameters

Total cholesterol profile prior to therapy, and when clinically indicated and/or periodically thereafter. When used in combination with fenofibrate, monitor LFTs and signs and symptoms of cholelithiasis.

2013 ACC/AHA Blood Cholesterol Guideline recommendations (Stone, 2013): Baseline LFTs (reasonable); when used in combination with statin therapy, monitor LFTs when clinically indicated; discontinue use of ezetimibe if ALT elevations >3 times upper limit of normal persist.

Pregnancy Risk Factor

C

Pregnancy Considerations

Use is contraindicated in women who are or who may become pregnant.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience joint pain, diarrhea, loss of strength and energy, rhinitis, rhinorrhea, cough, or pharyngitis. Have patient report immediately to prescriber muscle pain or muscle weakness (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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