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Pronunciation
(ez ET i mibe)
Generic Available (U.S.)
No
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Use in combination with dietary therapy for the treatment of primary hypercholesterolemia (as monotherapy or in combination with HMG-CoA reductase inhibitors); homozygous sitosterolemia; homozygous familial hypercholesterolemia (in combination with atorvastatin or simvastatin); mixed hyperlipidemia (in combination with fenofibrate)
Pregnancy Risk Factor
C
Pregnancy Considerations
Safety and efficacy have not been established; use during pregnancy only if the potential benefit to the mother outweighs the possible risk to the fetus.
Lactation
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to ezetimibe or any component of the formulation; concomitant use with an HMG-CoA reductase inhibitor in patients with active hepatic disease, unexplained persistent elevations in serum transaminases; pregnancy; breast-feeding
Warnings/Precautions
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with mild hepatic impairment (Child-Pugh class A); not recommended for use with moderate-or-severe hepatic impairment (Child-Pugh classes B and C).
• Renal impairment: Use with caution in patients with severe renal impairment (Clcr <30 mL/minute).
Concurrent drug therapy issues:
• Fibric acid derivatives (eg, fenofibrate, gemfibrozil): Concurrent use of fibric acid derivatives may increase the risk of cholelithiasis.
Other warnings/precautions:
• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to 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
Metabolism/Transport Effects
Substrate of SLCO1B1
Drug Interactions
Bile Acid Sequestrants: May decrease the absorption of Ezetimibe. Risk C: Monitor therapy
CycloSPORINE: May increase the serum concentration of Ezetimibe. Ezetimibe may increase the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
CycloSPORINE (Systemic): May increase the serum concentration of Ezetimibe. Ezetimibe may increase the serum concentration of CycloSPORINE (Systemic). Risk D: Consider therapy modification
Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Management: According to eltrombopag prescribing information, consideration of a preventative dose reduction may be warranted. Risk D: Consider therapy modification
Fibric Acid Derivatives: May increase the serum concentration of Ezetimibe. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Ezetimibe did not cause meaningful reductions in fat-soluble vitamin concentrations during a 2-week clinical trial. Effects of long-term therapy have not been evaluated.
Storage
Store at controlled room temperature of 25°C (77°F). Protect from moisture.
Mechanism of Action
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).
Pharmacodynamics/Kinetics
Protein binding: >90% to plasma proteins
Metabolism: Undergoes glucuronide conjugation in the small intestine and liver; forms metabolite (active); may undergo enterohepatic recycling
Bioavailability: Variable
Half-life elimination: 22 hours (ezetimibe and metabolite)
Time to peak, plasma: 4-12 hours
Excretion: Feces (78%, 69% as ezetimibe); urine (11%, 9% as metabolite)
Dosage
Oral:
Children ≥10 years and Adults: 10 mg/day
Elderly: Refer to adult dosing
Dosage adjustment in renal impairment: AUC increased with severe impairment (Clcr <30 mL/minute); no dosing adjustment necessary
Dosage adjustment in hepatic impairment: AUC increased with hepatic impairment
Mild impairment (Child-Pugh class A): No dosing adjustment necessary
Moderate-to-severe impairment (Child-Pugh classes B and C): Use of ezetimibe not recommended
Administration: Oral
May be administered without regard to meals. May be taken at the same time as HMG-CoA reductase inhibitors. Administer ≥2 hours before or ≥4 hours after bile acid sequestrants.
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.
Dietary Considerations
May be taken without regard to meals. 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.
Patient Education
Take at the same time of day, without regard for meals. Take 2 hours before or 4 hours after bile acid binding agents (eg, Questran®). This medication does not replace the need for dietary and exercise recommendations of prescriber. May cause headache, dizziness, fatigue, diarrhea, or abdominal pain. Report yellowing of skin or sclera; dark urine or pale stools; excessive tiredness; chest pain or palpitations; muscle, skeletal, or joint pain; twitching or numbness; increased perspiration; or changes in urinary pattern.
Geriatric Considerations
The definition of and, therefore, when to treat hyperlipidemia in the elderly is a controversial issue. The National Cholesterol Education Program recommends that all adults maintain a plasma cholesterol <160 mg/dL. For elderly patients with one additional risk factor, goal LDL would be <130 mg/dL. It is the authors' belief that pharmacologic treatment be reserved for those who are unable to obtain a desirable plasma cholesterol concentration by diet alone and for whom the benefits of treatment are believed to outweigh the potential adverse effects, drug interactions, and cost of treatment.
Additional Information
When studied in combination with fenofibrate for mixed hyperlipidemia, the dose of fenofibrate was 160 mg daily.
Cardiovascular Considerations
Ezetimibe decreases cholesterol concentrations by inhibiting the oral absorption of cholesterol. More specifically, ezetimibe inhibits the cholesterol transport system located within intestinal cell walls. Ezetimibe lowers LDL-C by ~18%. Additionally, it lowers TGs by ~5% and raises HDL-C by ~3%. Peak effects of ezetimibe are reached at 2 weeks. Ezetimibe does not interfere with the absorption of fat soluble vitamins. Ezetimibe can be taken concurrently with an HMG-CoA reductase inhibitor or fenofibrate. Asymptomatic increase in transaminase elevations (>3 times ULN) occurs at a slightly higher incidence (1.3%) when used concurrently with a HMG-CoA reductase inhibitor than with the HMG-CoA reductase inhibitor alone (0.4%). Use of ezetimibe and fenofibrate (160 mg daily) may increase rate of cholecystectomy.
Given the lack of clinical outcome data, the use of ezetimibe as initial monotherapy in treating hyperlipidemia would not be expected unless a patient was intolerant to HMG-CoA reductase inhibitor treatment. Ezetimibe enhances the LDL-C lowering effect of HMG-CoA reductase inhibitors by an additional 15% to 20%; and therefore, may be helpful in combination with an HMG-CoA reductase inhibitor to reach therapeutic goals. Ezetimibe may also be useful as combined therapy in patients who require a lower dose of HMG-CoA reductase inhibitor because they developed side effects when using a higher dose. Ezetimibe is also indicated in the treatment of sitosterolemia.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness and fatigue
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Use caution in presence of renal or hepatic impairment. Assess lipid profile at beginning of and at regular intervals during therapy. Teach patient to report signs of hepatic or muscle reactions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Zetia®: 10 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Zetia)
10 mg (30): $139.99
References
Gustavson LE, Schweitzer SM, Burt DA, et al, “Evaluation of the Potential for Pharmacokinetic Interaction Between Fenofibrate and Ezetimibe: A Phase I, Open-Label, Multiple-Dose, Three-Period Crossover Study in Healthy Subjects,” Clin Ther, 2006, 28 (3):373-87.
Jacobson TA, Marman A, McKenney JM, et al, “Safety Considerations With Gastrointestinally Active Lipid-Lowering Drugs,” Am J Cardiol, 2007, 99(6A):47C-55C.
Mauro VF and Tuckerman CE, “Ezetimibe for Management of Hypercholesterolemia,” Ann Pharmacother, 2003, 37(6):839-48.
McPherson R, Frohlich J, Fodor G, et al, “Canadian Cardiovascular Society Position Statement--Recommendations for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease,” Can J Cardiol, 2006, 22(11):913-27; published erratum appears in Can J Cardiol, 2006, 22(12):1077.
Peto R, Emberson J, Landray M, et al, “Analysis of Cancer Data From Three Ezetimibe Trials,” N Engl J Med, 2008, 359(13):1357-66. Available at http://content.nejm.org/cgi/content/full/NEJMsa0806603
Rossebo AB, Pederson TR, Boman K, et al, “Intensive Lipid Lowering With Simvastatin and Ezetimibe in Aortic Stenosis,” N Engl J Med, 2008, 359(13):1343-56. Available at http://content.nejm.org/cgi/content/full/NEJMoa0804602
Smith SC Jr, Benjamin EJ, Bonow RO, et al, “AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2011 Update: A Guideline From the American Heart Association and American College of Cardiology Foundation,” Circulation, 2011, 124(22):2458-73.
Stolk MF, Becx MC, Kuypers KC, et al, “Severe Hepatic Side Effects of Ezetimibe,” Clin Gastroenterol Hepatol, 2006, 4(7):908-11.
“Three New Drugs for Hyperlipidemia,” Med Lett Drugs Ther, 2003, 45(1151):17-9.
von Bergmann K, Salen G, Lutjohann D, et al, “Ezetimibe Effectively Reduces Serum Plant Sterols in Patients With Sitosterolemia (abstract).” 73rd European Atherosclerosis Society Congress, 2002. Available at http://www.kenes.com/73eas/program/abstracts/405.doc
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
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