Zetsim

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

Primary hypercholesterolemia (type IIa and IIb) in patients who have not responded adequately to diet and other appropriate measures. Coronary heart disease and elevated plasma cholesterol level.

Zetsim is also used to associated treatment for these conditions: Elevated Blood Lipids, Elevated sitosterol and campesterolCardiovascular Events, Diabetes Mellitus, Heterozygous Familial Hypercholesterolemia, High Cholesterol, Homozygous Familial Hypercholesterolemia, Mixed Hyperlipidemia, History of coronary heart disease cardiovascular event, History of stroke or other cerebrovascular disease cardiovascular event

How Zetsim 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.

Simvastatin is a prodrug in which the 6-membered lactone ring of simvastatin is hydrolyzed in vivo to generate the beta,delta-dihydroxy acid, an active metabolite structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Simvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Simvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL). The overall effect is a decrease in plasma LDL and VLDL.

At therapeutic doses, the HMG-CoA enzyme is not completely blocked by simvastatin activity, thereby allowing biologically necessary amounts of mevalonate to remain available. As mevalonate is an early step in the biosynthetic pathway for cholesterol, therapy with simvastatin would also not be expected to cause any accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolized readily back to acetyl-CoA, which participates in many biosynthetic processes in the body.

In vitro and in vivo animal studies also demonstrate that simvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. This includes improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response.

Statins have also been found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an important role in leukocyte trafficking and in T cell activation.

Dosage

Zetsim dosage

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

The patient should be placed on a standard cholesterol lowering diet before receiving Simvastatin and should continue on this during treatment with Simvastatin. The usual starting dose is 10 mg/day given as a single dose in the evening. Adjustment of dosage, if required, should be made at intervals of not less than four weeks, to a maximum of 40 mg daily given as a single dose in the evening. If LDL-cholesterol levels fall below 2 mmol/L or total plasma cholesterol levels fall below 3.5 mmol/L consideration should be given to reducing the dose of Simvastatin. In hypercholesterolemia, the recommended starting dose is 5-10 mg once a day in the evening and the recommended dosing range is 5-40 mg per day as a single dose in the evening. In patients with coronary heart disease and hypercholesterolemia, the starting dose should be 20 mg once a day in the evening. Because Simvastatin does not undergo significant renal excretion, modification of dosage should not be necessary in patients with renal insufficiency. Safety and effectiveness in children and adolescents have not been established.

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.

Simvastatin is generally well tolerated. Headache, fatigue, insomnia, gastrointestinal effects like nausea, constipation or diarrhoea, flatulence, dyspepsia, abdominal cramps and muscular effects like myalgia, myositis and myopathy have been reported. Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been associated with Simvastatin therapy. Hepatitis, pancreatitis, rash, Angio-oedema have also been reported. No potentially life threatening effects have been reported.

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.

• If there is a history of liver disease
• Who take high alcohol
• Liver function test should be done before and during treatment
• If serum transaminase rises three times the upper limit of normal, treatment should be discontinued
• Avoid pregnancy during and for one month after treatment

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.

Digoxin: Concomitant administration of Simvastatin and Digoxin in normal volunteers resulted in a slight elevation (less than 0.3 µgm/ml) in drug concentrations in plasma compared to concomitant administration of placebo and Digoxin.

Coumarin derivatives: Slightly enhance the anticoagulant effect of Warfarin (mean changes in p rothrombin time less than two seconds) in normal volunteers maintained in a state of low therapeutic anticoagulation.

Others: In clinical studies, Simvastatin was used concomitantly with ACE inhibitors, beta-blockers, calcium channel blockers, diuretics and NSAIDs without evidence of clinically significant adverse interactions.

Volume of Distribution

The relative volume of distribution of ezetimibe is 107.5L.

Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin-derived radioactivity crossed the blood-brain barrier.

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.

Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours post-dose. While the recommended therapeutic dose range is 10 to 40 mg/day, there was no substantial deviation from linearity of AUC with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before a test meal.

In a pharmacokinetic study of 17 healthy Chinese volunteers, the major PK parameters were as follows: Tmax 1.44 hours, Cmax 9.83 ug/L, t1/2 4.85 hours, and AUC 40.32ug·h/L.

Simvastatin undergoes extensive first-pass extraction in the liver, the target organ for the inhibition of HMG-CoA reductase and the primary site of action. This tissue selectivity (and consequent low systemic exposure) of orally administered simvastatin has been shown to be far greater than that observed when the drug is administered as the enzymatically active form, i.e. as the open hydroxyacid.

In animal studies, after oral dosing, simvastatin achieved substantially higher concentrations in the liver than in non-target tissues. However, because simvastatin undergoes extensive first-pass metabolism, the bioavailability of the drug in the systemic system is low. In a single-dose study in nine healthy subjects, it was estimated that less than 5% of an oral dose of simvastatin reached the general circulation in the form of active inhibitors.

Genetic differences in the OATP1B1 (Organic-Anion-Transporting Polypeptide 1B1) hepatic transporter encoded by the SCLCO1B1 gene (Solute Carrier Organic Anion Transporter family member 1B1) have been shown to impact simvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) showed that simvastatin plasma concentrations were increased on average 3.2-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals. The 521CC genotype is also associated with a marked increase in the risk of developing myopathy, likely secondary to increased systemic exposure. Other statin drugs impacted by this polymorphism include rosuvastatin, pitavastatin, atorvastatin, lovastatin, and pravastatin.

For patients known to have the above-mentioned c.521CC OATP1B1 genotype, a maximum daily dose of 20mg of simvastatin is recommended to avoid adverse effects from the increased exposure to the drug, such as muscle pain and risk of rhabdomyolysis.

Evidence has also been obtained with other statins such as rosuvastatin that concurrent use of statins and inhibitors of Breast Cancer Resistance Protein (BCRP) such as elbasvir and grazoprevir increased the plasma concentration of these statins. Further evidence is needed, however a dose adjustment of simvastatin may be necessary. Other statin drugs impacted by this polymorphism include fluvastatin and atorvastatin.

Half Life

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

4.85 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.

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.

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

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

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.

Simvastatin should not be used in-

• Active liver disease
• Pregnant and breast feeding mother
• Women of child bearing age unless they have been adequately protected by contraception
• Hypersensitivity to any component of the preparation
• Patients with the homozygous familial hypercholesterolemia who have a complete absence of LDL receptors

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.

There are no data available on overdose. No antidote is available. General measures should be adopted and liver function should be monitored.

Storage Condition

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

Store in a cool, dry place, Away from light keep out of reach of children.

Innovators Monograph

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