Ezetimiba Winthrop

Ezetimiba Winthrop Uses, Dosage, Side Effects, Food Interaction and all others data.

Ezetimiba Winthrop localises at the brush border of the small intestine and inhibits absorption of cholesterol via the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1). This results in decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores and increased clearance of cholesterol from the blood.

Ezetimiba Winthrop was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5%.

The effects of increased exposure to ezetimibe secondary to moderate-severe hepatic impairment have not been assessed - patients meeting these criteria should avoid the use of ezetimibe. Post-marketing reports indicate the potential for myopathy and rhabdomyolysis in patients taking ezetimibe, and this risk appears to be exacerbated in patients concurrently receiving, or having recently received, statin therapy.

Ezetimiba Winthrop
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Ezetimiba Winthrop
Availability	Prescription only
Generic	Ezetimibe
Ezetimibe Other Names	Ezetimiba, ézétimibe, Ezetimibe, Ezetimibum
Related Drugs	Zetia, Nexletol, Nexlizet, Praluent, Repatha, atorvastatin, simvastatin, rosuvastatin, Lipitor, Crestor
Type
Formula	C₂₄H₂₁F₂NO₃
Weight	Average: 409.4252 Monoisotopic: 409.148949953
Protein binding	Ezetimibe and ezetimibe-glucuronide are >90% bound to human plasma proteins. The mean in vitro protein binding ranged from 99.5% to 99.8% for ezetimibe and 87.8% to 92.0% for ezetimibe-glucuronide.
Groups	Approved
Therapeutic Class	Ezetimibe
Manufacturer
Available Country	Colombia
Last Updated:	September 19, 2023 at 7:00 am

Uses

Primary Hypercholesterolemia: Ezetimiba Winthrop 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.Ezetimiba Winthrop 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: Ezetimiba Winthrop 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): Ezetimiba Winthrop 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): Ezetimiba Winthrop is used for adjunctive therapy to diet for use in patients with homozygous familial sitosterolemia

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

How Ezetimiba Winthrop works

Ezetimiba Winthrop 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.

Ezetimiba Winthrop 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. Ezetimiba Winthrop 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

Ezetimiba Winthrop dosage

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

Side Effects

Clinical studies of Ezetimiba Winthrop (administered alone or with an HMG-CoA reductaseinhibitor) demonstrated that Ezetimiba Winthrop was generally well tolerated. The overallincidence of adverse events reported with Ezetimiba Winthrop was similar to that reported withplacebo, and the discontinuation rate due to adverse events was also similar for Ezetimiba Winthropand 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, Ezetimiba Winthrop increased cholesterol in the gallbladder bile. Coadministration of Ezetimiba Winthrop 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.

Ezetimiba Winthrop 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

Ezetimiba Winthrop 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 Ezetimiba Winthrop in pregnant women. Ezetimiba Winthrop 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 Ezetimiba Winthropwith 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 Ezetimiba Winthrop is administered with statin, the dosage instructions for statin, in adolescents should be consulted.

Children < 10 years: Ezetimiba Winthrop 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 Ezetimiba Winthrop have been reported. Administration of Ezetimiba Winthrop,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.