Ezetimibe

Uses

Primary Hypercholesterolemia: Ezetimibe co-administered with statin is used for adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolemia who are not appropriately controlled with a statin alone.Ezetimibe monotherapy is used for adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolemia in whom a statin is considered inappropriate or is not tolerated.

Prevention of Cardiovascular Events: Ezetimibe is used to reduce the risk of cardiovascular events in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS) when added to ongoing statin therapy or initiated concomitantly with a statin.

Homozygous Familial Hypercholesterolaemia (HoFH): Ezetimibe co-administered with a statin, is used for adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g., LDL apheresis).

Homozygous Sitosterolemia (Phytosterolemia): Ezetimibe is used for adjunctive therapy to diet for use in patients with homozygous familial sitosterolemia

Ezetimibe is also used to associated treatment for these conditions: Elevated Blood Lipids, Elevated sitosterol and campesterol

How Ezetimibe works

Ezetimibe mediates its blood cholesterol-lowering effect via selectively inhibiting the absorption of cholesterol and phytosterol by the small intestine without altering the absorption of fat-soluble vitamins and nutrients. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed on enterocytes/gut lumen (apical) as well as the hepatobiliary (canalicular) interface and plays a role in facilitating internalization of free cholesterol into the enterocyte in conjunction with the adaptor protein 2 (AP2) complex and clathrin. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it binds to the sterol-sensing domain of NPC1L1 and forms a NPC1L1/cholesterol complex. The complex is then internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment.

Ezetimibe does not require exocrine pancreatic function for its pharmacological activity; rather, it localizes and appears to act at the brush border of the small intestine. Ezetimibe selectively blocks the NPC1L1 protein in the jejunal brush border, reducing the uptake of intestinal lumen micelles into the enterocyte. Overall, ezetimibe causes a decrease in the delivery of intestinal cholesterol to the liver and reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. While the full mechanism of action of ezetimibe in reducing the entry of cholesterol into both enterocytes and hepatocytes is not fully understood, one study proposed that ezetimibe prevents the NPC1L1/sterol complex from interacting with AP2 in clathrin coated vesicles and induces a conformational change in NPC1L1, rendering it incapable of binding to sterols. Another study suggested that ezetimibe disrupts the function of other protein complexes involved in regulating cholesterol uptake, including the CAV1–annexin 2 heterocomplex.

Dosage

Ezetimibe dosage

The recommended dose of Ezetimibe is 10 mg once daily. Ezetimibe can be administered with or without food.

Side Effects

Clinical studies of Ezetimibe (administered alone or with an HMG-CoA reductaseinhibitor) demonstrated that Ezetimibe was generally well tolerated. The overallincidence of adverse events reported with Ezetimibe was similar to that reported withplacebo, and the discontinuation rate due to adverse events was also similar for Ezetimibeand placebo.

Toxicity

Oral LD₅₀ and intraperitoneal LD₅₀ in rat were >2000 mg/kg. Estimated oral LD50 values in mouse and dog are >5000 mg/kg and >3000 mg/kg, respectively. One case of accidental overdose occurred in clinical studies in one female patient with homozygous sitosterolemia receiving 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In case of overdose, symptomatic treatment is recommended.

Precaution

Exclude or treat secondary causes of dyslipidaemia prior to initiating therapy. Renal and hepatic impairment. Pregnancy and lactation.

Interaction

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in animals, Ezetimibe increased cholesterol in the gallbladder bile. Coadministration of Ezetimibe with fibrates is not therefore recommended until use in patients is studied.

Food Interaction

• Take with or without food. Co-administration with food does not affect absorption.

Ezetimibe Drug Interaction

Moderate: rosuvastatin, rosuvastatinUnknown: aspirin, aspirin, aspirin, aspirin, ubiquinone, ubiquinone, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, metoprolol, metoprolol, metoprolol, metoprolol, cyanocobalamin, cyanocobalamin, ascorbic acid, ascorbic acid, cholecalciferol, cholecalciferol

Ezetimibe Disease Interaction

Major: liver diseaseModerate: myopathy/rhabdomyolysis, renal impairment

Volume of Distribution

The relative volume of distribution of ezetimibe is 107.5L.

Elimination Route

Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in peak plasma concentrations (C_max) of 3.4-5.5 ng/mL within 4-12 hours (T_max). The C_max of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45-71 ng/mL and its T_max was 1-2 hours. Food consumption has minimal effect on ezetimibe absorption, but the C_max is increased by 38% when administered alongside a high-fat meal. The true bioavailability of ezetimibe cannot be determined, as it is insoluble in aqueous media suitable for intravenous injection.

Half Life

Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours.

Clearance

There are no pharmacokinetic data available on the clearance of ezetimibe.

Elimination Route

Approximately 78% and 11% of orally administered radiolabelled ezetimibe are recovered in the feces and urine, respectively. Unchanged parent drug is the major component in feces and accounts for approximately 69% of an administered dose, while ezetimibe-glucuronide is the major component in urine and accounts for approximately 9% of an administered dose. High recovery of unchanged parent drug in feces suggests low absorption and/or hydrolysis of ezetimibe-glucuronide secreted in the bile.

Pregnancy & Breastfeeding use

There are no adequate and well-controlled studies of Ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus

Contraindication

Hypersensitivity to any component of this medication. The combination of Ezetimibewith an HMG-CoA reductase inhibitor is contraindicated in patients with active liverdisease or unexplained persistent elevations in serum transaminases.

Special Warning

Pediatric Use-

10 to 17 years: No dosage adjustment is required. The clinical experience in pediatric and adolescent patients is however limited. When Ezetimibe is administered with statin, the dosage instructions for statin, in adolescents should be consulted.

Children < 10 years: Ezetimibe is not recommended for use in children below age 10 due to insufficient data on safety and efficacy.

Acute Overdose

No cases of overdosage with Ezetimibe have been reported. Administration of Ezetimibe,50 mg/day, to 15 subjects for up to 14 days was generally well tolerated. In the event ofan overdose, symptomatic and supportive measures should be employed.

Storage Condition

Store in a cool & dry place protected from light and moisture. Keep out of reach of children.

Innovators Monograph

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