Zestat

Uses

Atorvastatin is an HMG-CoA reductase inhibitor used to lower lipid levels and reduce the risk of cardiovascular disease including myocardial infarction and stroke.

Atorvastatin is indicated for the treatment of several types of dyslipidemias, including primary hyperlipidemia and mixed dyslipidemia in adults, hypertriglyceridemia, primary dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and heterozygous familial hypercholesterolemia in adolescent patients with failed dietary modifications.

Dyslipidemia describes an elevation of plasma cholesterol, triglycerides or both as well as to the presence of low levels of high-density lipoprotein. This condition represents an increased risk for the development of atherosclerosis.

Atorvastatin is indicated, in combination with dietary modifications, to prevent cardiovascular events in patients with cardiac risk factors and/or abnormal lipid profiles.

Atorvastatin can be used as a preventive agent for myocardial infarction, stroke, revascularization, and angina, in patients without coronary heart disease but with multiple risk factors and in patients with type 2 diabetes without coronary heart disease but multiple risk factors.

Atorvastatin may be used as a preventive agent for non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure and angina in patients with coronary heart disease.

Prescribing of statin medications is considered standard practice following any cardiovascular events and for people with a moderate to high risk of development of CVD. Statin-indicated conditions include diabetes mellitus, clinical atherosclerosis (including myocardial infarction, acute coronary syndromes, stable angina, documented coronary artery disease, stroke, trans ischemic attack (TIA), documented carotid disease, peripheral artery disease, and claudication), abdominal aortic aneurysm, chronic kidney disease, and severely elevated LDL-C levels.

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

Zestat is also used to associated treatment for these conditions: Anginal Pain, Cardiovascular Disease (CVD), Coronary Artery Disease (CAD), Coronary artery thrombosis, Dysbetalipoproteinemia, Fredrickson Type III lipidemia, Heterozygous Familial Hypercholesterolemia, High Blood Pressure (Hypertension), High Cholesterol, Homozygous Familial Hypercholesterolemia, Hospitalizations, Hypertriglyceridemias, Mixed Dyslipidemias, Mixed Hyperlipidemia, Myocardial Infarction, Non-familial hypercholesterolemia, Postoperative Thromboembolism, Primary Hypercholesterolemia, Stroke, Transient Ischemic Attack, Elevation of serum triglyceride levels, Heterozygous familial hyperlipidemia, Non-familial hyperlipidemia, Non-fatal myocardial infarction, Primary Hyperlipidemia, Revascularization procedures, Revascularization process, Thrombotic events, Cardiovascular Primary Prevention, Secondary prevention cardiovascular eventElevated Blood Lipids, Elevated sitosterol and campesterol

How Zestat works

Atorvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis. Atorvastatin 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. Atorvastatin also reduces Very-Low-Density Lipoprotein-Cholesterol (VLDL-C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High-Density Lipoprotein Cholesterol (HDL-C).

In vitro and in vivo animal studies also demonstrate that atorvastatin exerts vasculoprotective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. These effects include improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins were also found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an essential role in leukocyte trafficking and T cell activation.

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

Zestat 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

The reported LD50 of oral atorvastatin in mice is higher than 5000 mg/kg. In cases of overdose with atorvastatin, there is reported symptoms of complicated breathing, jaundice, liver damage, dark urine, muscle pain, and seizures. In case of overdose, symptomatic treatment is recommended and due to the high plasma protein binding, hemodialysis is not expected to generate significant improvement.

In carcinogenic studies with high doses of atorvastatin, evidence of rhabdomyosarcoma, fibrosarcoma, liver adenoma, and liver carcinoma were observed.

In fertility studies with high doses of atorvastatin, there were events of aplasia, aspermia, low testis and epididymal weight, decreased sperm motility, decreased spermatid head concentration and increased abnormal sperm.

Atorvastatin was shown to not be mutagenic in diverse mutagenic assays.

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.

Volume of Distribution

The reported volume of distribution of atorvastatin is of 380 L.

The relative volume of distribution of ezetimibe is 107.5L.

Elimination Route

Atorvastatin presents a dose-dependent and non-linear pharmacokinetic profile. It is very rapidly absorbed after oral administration. After the administration of a dose of 40 mg, its peak plasma concentration of 28 ng/ml is reached 1-2 hours after initial administration with an AUC of about 200 ng∙h/ml. Atorvastatin undergoes extensive first-pass metabolism in the wall of the gut and the liver, resulting in an absolute oral bioavailability of 14%. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration.

Administration of atorvastatin with food results in prolonged Tmax and a reduction in Cmax and AUC.

Breast Cancer Resistance Protein (BCRP) is a membrane-bound protein that plays an important role in the absorption of atorvastatin. Evidence from pharmacogenetic studies of c.421C>A single nucleotide polymorphisms (SNPs) in the gene for BCRP has demonstrated that individuals with the 421AA genotype have reduced functional activity and 1.72-fold higher AUC for atorvastatin compared to study individuals with the control 421CC genotype. This has important implications for the variation in response to the drug in terms of efficacy and toxicity, particularly as the BCRP c.421C>A polymorphism occurs more frequently in Asian populations than in Caucasians. Other statin drugs impacted by this polymorphism include fluvastatin, simvastatin, and rosuvastatin.

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 atorvastatin pharmacokinetics. Evidence from pharmacogenetic studies of the c.521T>C single nucleotide polymorphism (SNP) in the gene encoding OATP1B1 (SLCO1B1) demonstrated that atorvastatin AUC was increased 2.45-fold for individuals homozygous for 521CC compared to homozygous 521TT individuals.[A181493] Other statin drugs impacted by this polymorphism include simvastatin, pitavastatin, rosuvastatin, and pravastatin.

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

The half-life of atorvastatin is 14 hours while the half-life of its metabolites can reach up to 30 hours.

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

Clearance

The registered total plasma clearance of atorvastatin is of 625 ml/min.

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

Elimination Route

Atorvastatin and its metabolites are mainly eliminated in the bile without enterohepatic recirculation. The renal elimination of atorvastatin is very minimal and represents less than 1% of the eliminated dose.

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.

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