Ezetimibe

Pronunciation

Pronunciation: e-ZET-i-mibe
Class: Antihyperlipidemic agent

Trade Names

Zetia
- Tablets, oral 10 mg

Ezetrol (Canada)

Pharmacology

Inhibits absorption of cholesterol by the small intestine.

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Pharmacokinetics

Absorption

C max is 3.4 to 5.5 ng/mL (ezetimibe) and 45 to 71 ng/mL (metabolite). T max is 4 to 12 h (ezetimibe) and 1 to 2 h (metabolite).

Distribution

More than 90% protein bound.

Metabolism

Metabolized (active) in small intestine and liver to ezetimibe-glucuronide.

Elimination

The half-life is approximately 22 h. Approximately 78% is excreted in feces and 11% in urine.

Special Populations

Renal Function Impairment

AUC increased approximately 1.5-fold in those with severe renal disease (CrCl 30 mL/min or less).

Hepatic Function Impairment

AUC increased approximately 1.7-fold in those with mild impairment (Child-Pugh score 5 to 6), 3- to 4-fold in moderate impairment (Child-Pugh score 7 to 9), and 5- to 6-fold in severe impairment (Child-Pugh score 10 to 15).

Elderly

Plasma concentrations are approximately 2-fold higher.

Children

There are no pharmacokinetic differences between adolescents and adults.

Gender

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

Race

There were no pharmacokinetic differences between black and white subjects. Asian subjects had similar pharmacokinetics compared with those seen in white subjects.

Indications and Usage

For administration alone or with HMG-CoA reductase inhibitors as adjunctive therapy to diet for reduction of elevated total cholesterol, LDL cholesterol, non–HDL cholesterol, and apolipoprotein B (apo B) in patients with primary hyperlipidemia; in combination with atorvastatin or simvastatin for the reduction of elevated total cholesterol and LDL cholesterol levels in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments or if such treatments are unavailable; as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia; in combination with fenofibrate as an adjunct to diet for reduction of elevated total cholesterol, LDL cholesterol, apo B, and non–HDL cholesterol in patients with mixed hyperlipidemia.

Contraindications

Concomitant use with HMG-CoA reductase inhibitors in patients with active liver disease or unexplained persistent elevations in serum transaminases; hypersensitivity to any component of the product; women who are pregnant or may become pregnant; breast-feeding.

Dosage and Administration

Adults and children 10 y and older

PO 10 mg once daily.

General Advice

  • Administer with or without food. Administer alone or in combination with other lipid-lowering therapy.
  • Administer 2 h before or 4 h after a bile acid sequestrant.

Storage/Stability

Store at 59° to 86°F. Protect from moisture.

Drug Interactions

Antacids

Aluminum- and magnesium-containing antacids decrease the C max of ezetimibe but not the AUC.

Bile acid sequestrants (eg, cholestyramine)

The AUC of ezetimibe may be decreased. Administer ezetimibe either at least 2 h before or at least 4 h after administration of a bile acid sequestrant.

Cimetidine

Coadministration increased ezetimibe C max with no significant change in AUC.

Cyclosporine

Concentrations of ezetimibe may be significantly increased; concentrations of cyclosporine may be slightly increased. Monitor cyclosporine concentrations and adjust the cyclosporine dose as needed. Monitor patients for adverse reactions.

Fibric acid derivatives (eg, fenofibrate, gemfibrozil)

Concentrations of ezetimibe may be increased. If cholelithiasis is suspected in a patient receiving ezetimibe and fenofibrate, perform gallbladder studies and consider alternative lipid-lowering therapy.

Warfarin

Although coadministration produced very minor changes in warfarin AUC and C max , the INR should be monitored.

Adverse Reactions

CNS

Fatigue (2%); depression, dizziness, headache, paresthesia (postmarketing).

GI

Diarrhea (4%); abdominal pain, nausea, pancreatitis (postmarketing).

Hepatic

Cholecystitis, cholelithiasis, elevations in liver transaminases, hepatitis (postmarketing).

Hypersensitivity

Hypersensitivity, including anaphylaxis, angioedema, rash, and urticaria (postmarketing).

Lab Tests

Elevated CPK (postmarketing).

Musculoskeletal

Arthralgia, pain in extremity (3%); myalgia, myopathy/rhabdomyolysis (postmarketing).

Respiratory

Upper respiratory tract infection (4%); sinusitis (3%); influenza (2%).

Miscellaneous

Erythema multiforme, thrombocytopenia (postmarketing).

Precautions

Monitor

When given with an HMG-CoA reductase inhibitor, monitor LFTs. Ensure that lipids are measured before therapy is started and periodically during therapy. Monitor patients with moderate to severe renal impairment if patients are taking ezetimibe concomitantly with an HMG-CoA reductase inhibitor.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 10 y or in premenarchal girls.

Renal Function

When used as monotherapy, no dosage adjustment is necessary.

Hepatic Function

Use not recommended in patients with moderate to severe hepatic impairment because of unknown effects on liver.

Skeletal muscle effects

Rhabdomyolysis has been reported rarely with ezetimibe monotherapy.

Overdosage

Symptoms

No symptoms reported.

Patient Information

  • Advise patients to take once daily as prescribed without regard to meals.
  • Advise patients to try to take each dose at about the same time each day.
  • Inform patients that this drug helps control, but not does cure, high cholesterol and to continue taking the drug as prescribed even if cholesterol levels are lowered.
  • Caution patients not to change or stop taking the dose unless advised by their health care provider.
  • Advise patients that, if a dose is missed, to take it as soon as possible but to never take more than 1 dose of medicine per day.
  • Instruct patients to continue taking other cholesterol-lowering medications as prescribed by their health care provider.
  • Emphasize to patients the importance of the following other modalities on cholesterol control: dietary changes (eg, increase soluble fiber intake, reduced saturated fat intake), regular exercise, smoking cessation, and weight control.
  • Instruct patients to promptly notify their health care provider of any unexplained muscle pain, tenderness, weakness, or any other unusual feelings.
  • Advise women of childbearing age to use an effective method of birth control to prevent pregnancy while using ezetimibe in combination with a HMG-CoA reductase inhibitor.
  • Advise women not to breast-feed when using ezetimibe in combination with a HMG-CoA reductase inhibitor.

Copyright © 2009 Wolters Kluwer Health.

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