Ezetimibe (Zetia) is a novel class of lipid-lowering drugs that inhibits the absorption of cholesterol from the intestine. It acts on the brush border of the intestine limiting the stores of cholesterol in the liver. Unlike statins, it does not affect the synthesis of cholesterol in the liver. Furthermore, it does not affect the absorption of fat-soluble vitamins such as Vitamin A, E, and D.

Ezetimibe (Zetia) Uses:

• Homozygous familial hypercholesterolemia:

  • In combination with simvastatin or atorvastatin 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 not available.

• Homozygous sitosterolemia:

  • It is used 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-3methylglutaryl-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: 
    • It is used 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:
    • It is used 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.

• Off Label Use of Ezetimibe in Adults:

  • Secondary prevention of cardiovascular events after acute coronary syndrome.

Ezetimibe (Zetia) Dose in Adults

Note: Its Use may be considered in patients who do not meet cholesterol treatment goals with dietary modification and maximally-tolerated statin therapy.

Ezetimibe (Zetia) Dose in the treatment of Homozygous familial hypercholesterolemia:

• Oral: 10 mg once a day

Ezetimibe (Zetia) Dose in the treatment of Homozygous sitosterolemia:

• Oral: 10 mg once a day

Ezetimibe (Zetia) Dose in the treatment of Primary hyperlipidemia:

• Oral: 10 mg once a day

Ezetimibe (Zetia) Dose in the treatment of Secondary prevention of cardiovascular events after acute coronary syndrome (off-label):

• Oral: 10 mg once daily.

Ezetimibe (Zetia) Dose in Childrens

Ezetimibe (Zetia) Dose in the treatment of Hyperlipidemia:

• Children 5 to 9 years: Limited data available:

  • Oral: 10 mg once a day.

• Children ≥10 years and Adolescents:

  • Oral: 10 mg once daily in combination with simvastatin.
  • Has also been shown in small pediatric trials to decrease total cholesterol and LDL-Cholesterol when used as monotherapy as an adjunct to dietary changes.

Pregnancy Risk Factor C

• Adverse events were observed in some animal reproduction studies.
• Its use is contraindicated in pregnant women who require combination therapy with an HMG-CoA reductase inhibitor.
• If treatment for familial hypercholesterolemia is needed during pregnancy then other agents are preferred.

Ezetimibe use during breastfeeding:

• It is not known if ezetimibe is present in breast milk or not.
• According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
• Use is contraindicated in breastfeeding women who require combination therapy with an HMG-CoA reductase inhibitor.

Ezetimibe (Zetia) Dose in Kidney Disease:

• No dosage adjustment needed.

Ezetimibe (Zetia) Dose in Liver disease:

• Mild impairment (Child-Pugh class A):

  • No dosage adjustment needed.

• Moderate to severe impairment (Child-Pugh class B or C):

  • The use of ezetimibe is not recommended.

Side Effects of Ezetimibe (Zetia):

• Central nervous system:

  • Fatigue

• Gastrointestinal:

  • Diarrhea

• Hepatic:

  • Increased serum transaminases

• Infection:

  • Influenza

• Neuromuscular & skeletal:

  • Arthralgia
  • Limb pain

• Respiratory:

  • Upper respiratory tract infection
  • Sinusitis

Contraindications to Ezetimibe (Zetia):

• Hypersensitivity to ezetimibe or any component of the formulation.
• Concomitant use with an HMGCoA reductase inhibitor (statin) in patients with active hepatic disease or unexplained persistent elevations in serum transaminases.
• Pregnancy and breastfeeding (when used concomitantly with a statin).

Warnings and Precautions

• Elevated hepatic transaminases:

  • A higher incidence of elevated transaminases (≥3 x ULN) has been observed with concomitant use of statin and ezetimibe 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 if persistently elevated transaminases (ALT or AST ≥3 x ULN).

• Myopathy:

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

• Hepatic impairment:

  • Systemic exposure to ezetimibe is increased in hepatic impairment.
  • Use with caution in patients with mild hepatic impairment (Child-Pugh class A).
  • use is not contraindicated 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).

Ezetimibe: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

ACC/AHA blood cholesterol guideline recommendations:

  Lipid panel (total cholesterol, HDL, LDL, triglycerides):

• Lipid profile (fasting or nonfasting) before starting treatment.
• Fasting lipid profile should be rechecked 4 to 12 weeks after starting therapy and every 3 to 12 months thereafter.

  Hepatic transaminase levels:

• 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.
• When used in combination with fenofibrate, monitor LFTs and signs and symptoms of cholelithiasis.

How to administer Ezetimibe (Zetia)?

• Can 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.

Mechanism of action of Ezetimibe (Zetia):

• It Inhibits the 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 increased clearance of cholesterol from the blood; It decreases total cholesterol, LDL-cholesterol (LDL-C), ApoB, and triglycerides (TG) while increasing HDL cholesterol (HDL-C).

Note:

• Pharmacokinetic data of ezetimibe in children and adolescents ≥10 years of age are reported to be similar to that in adult patients.

The onset of action:

• Within 1 week.
• Maximum effect: 2-4 weeks

Protein binding:

• >90% to plasma proteins

Metabolism:

• Undergoes glucuronide conjugation in the small intestine and liver.
• It forms an active metabolite;
• may undergo enterohepatic recycling

Bioavailability: Variable

• Hepatic impairment:
  • Moderate hepatic impairment (Child-Pugh score 7-9):
    • AUC increased 34 times;
  • Severe hepatic impairment (Child-Pugh 10-15):
    • AUC increased 5-6 times
• Renal impairment:
  • Severe renal dysfunction (CrCl <30 mL/minute/1.73 m²):
    • AUC increased 1.5 times

Half-life elimination:

• 22 hours (ezetimibe and metabolite)

Time to peak, plasma:

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

Excretion:

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

International Brands of Ezetimibe:

• Zetia
• ACH-Ezetimibe
• ACT Ezetimib
• AG-Ezetimib
• APO-Ezetimib
• AURO-Ezetimib
• BIO-Ezetimib
• Ezetrol
• JAMP-Ezetimib
• M-Ezetimib
• Mar-Ezetimib
• MINT-Ezetimib
• MYLAN-Ezetimib
• NRA-Ezetimib
• PMS-Ezetimib
• Priva-Ezetimib
• RAN-Ezetimib
• RIVA-Ezetimib
• SANDOZ Ezetimib
• TEVA-Ezetimib
• Absorcol
• Centex
• Cholinor
• Ezemibe
• Ezentia
• Ezeta
• Ezetib
• Ezetrol
• Ezgal
• Ezitab
• Ezitoget
• Ibet
• Ledipsa
• Maxetibe
• Mibe
• Zemil
• Zemitra
• Zetavim
• Zetex
• Zetia
• Zient
• Zytovyrin

Ezetimibe Brand Names in Pakistan: