VYTORIN 10/10 TABLET

Product Information

Registration Status: Active

VYTORIN 10/10 TABLET is approved to be sold in Singapore with effective from 2004-06-18. It is marketed by MSD PHARMA (SINGAPORE) PTE LTD, with the registration number of SIN13011P.

This product contains Ezetimibe 10mg, and Simvastatin 10mg in the form of TABLET. It is approved for ORAL use.

This product is manufactured by MSD INTERNATIONAL GMBH (SINGAPORE BRANCH) in SINGAPORE, andPT. Merck Sharp Dohme Pharma Tbk. (Primary and Secondary Packager) in INDONESIA REP OF.

It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Ezetimibe
Simvastatin

Description

Ezetimibe is a lipid-lowering compound that inhibits intestinal cholesterol and related phytosterol absorption. The discovery and research of this drug began in the early 1990's, where intravenous administration of radio-labelled compound in rats resulting in subsequent localization of the drug within enterocytes at the intestinal villus, leading to studies of investigating the effect of ezetimibe on intestinal cholesterol absorption [A15202]. Ezetimibe is used as an adjunctive therapy to diet to lower cholesterol levels in primary hyperlipidemia, mixed hyperlipidemia, homozygous familial hypercholesterolemia (HoFH), and homozygous sitosterolemia (phytosterolemia) [FDA Label]. Unlike other classes of cholesterol-reducing compounds including statins and bile acid sequestrants, ezetimibe has a distinct mechanism of action involving the sterol transporter Niemann-Pick C1-Like 1 (NPC1L1), and is the first drug that does not affect absorption of fat-soluble nutrients such as fat-soluble vitamins, triglycerides, or bile acids [A33313]. In genetically NPC1L1-deficient mice, a 70% reduction in intestinal cholesterol absorption was seen and the mice were insensitive to ezetimibe treatment [A15202]. Based on these findings, it is indicated that NPC1L1 plays an essential role in promoting intestinal cholesterol uptake via an ezetimibe-sensitive pathway [A15202]. By interfering with the intestinal uptake of cholesterol and phytosterols, ezetimibe reduces the delivery of intestinal cholesterol to the liver [FDA Label].

Indication

Ezetimibe is indicated to reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin), reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate, reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin, and to reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) [FDA Label].

Mechanism of Action

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 [A15202]. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed at the enterocyte/ 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 [A33309]. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it can bind to the sterol-sensing domain of NPC1L1 and form a NPC1L1/cholesterol complex. The complex can then be internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment [A33309]. 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 [A33309]. 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, a 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 [A33309]. Another study suggested that ezetimibe disrupts the function of other proteins complexes involved in regulating cholesterol uptake, including the CAV1– annexin 2 heterocomplex [A33309].

Pharmacokinetics

Absorption
Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in a peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were achieved within 4 to 12 hours (Tmax) [FDA Label]. The Cmax of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45 to 71 ng/mL and the Tmax was between 1 and 2 hours [FDA Label]. Food consumption had minimal effect on ezetimibe absorption, but the Cmax was increased by 38% with consumption of high-fat meals [FDA Label]. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection [FDA Label].
Distribution
The relative volume of distribution of ezetimibe is 107.5L [F133].
Metabolism
In humans, ezetimibe is rapidly and extensively metabolized via a phase II glucuronide conjugation reaction in the small intestine and liver to form its main phenolic metabolite, ezetimibe glucuronide. The main human liver and/or intestinal uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes responsible for glucuronidating ezetimibe were shown to be UGT1A1, 1A3 and 2B15 _in vitro_ [A15202]. Minimal phase I reaction involving oxidation of ezetimibe also occurs to form SCH 57871, and human jejunum microsomes also produced trace levels of a benzylic glucuronide (SCH 488128) [A15202]. Ezetimibe glucuronide accounts for 80-90% of the total circulating compound in plasma, and retains some pharmacological activity in inhibiting intestinal cholesterol uptake [FDA Label]. In humans, ezetimibe and ezetimibe-glucuronide constitutes approximately 93% of the total drug in plasma [FDA Label]. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling [FDA Label], and about 20% of the drug distributed is reabsorbed due to enterohepatic re-circulation [F133].
Elimination

Clearance

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

Toxicity

Oral LD50 and intraperitoneal LD50 in rat were >2000 mg/kg [MSDS]. Estimated oral LD50 values in mouse and dog are >5000 mg/kg and >3000 mg/kg, respectively [MSDS]. 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 [FDA Label]. In case of overdose, symptomatic treatment is recommended [FDA Label].

Active Ingredient/Synonyms

Ezedoc | Ezetimiba | Ezetimibum | Ezetrol | Ezetimibe |


Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.


Description

Simvastatin is a lipid-lowering agent that is derived synthetically from the fermentation of Aspergillus terreus. It is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (hydroxymethylglutaryl COA reductases), which is the rate-limiting enzyme in cholesterol biosynthesis. It may also interfere with steroid hormone production. Due to the induction of hepatic LDL receptors, it increases breakdown of LDL cholesterol. [PubChem]

Indication

For the treatment of hypercholesterolemia and for the reduction in the risk of cardiac heart disease mortality and cardiovascular events. It can also be used in adolescent patients for the treatment of heterozygous familial hypercholesterolemia.

Mechanism of Action

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. Interference with the activity of this enzyme reduces the quantity of mevalonic acid, a precursor of cholesterol.

Pharmacokinetics

Absorption
Absorption of simvastatin, estimated relative to an intravenous reference dose, in each of two animal species tested, averaged about 85% of an oral dose. 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 availability of the drug in the systemic is low. Peak plasma concentration occurs 1.3 - 2.4 hours after administration.
Distribution
Simvastatin can cross the blood-brain-barrier.
Metabolism
Hepatic, simvastatin is a substrate for CYP3A4. The major active metabolites of simvastatin are β-hydroxyacid metabolite and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives
Elimination

Toxicity

The most common adverse reactions that lead to discontinuation of therapy include gastrointestinal disorders (0.5%), myalgia (0.1%), and arthralgia (0.1%).

Active Ingredient/Synonyms

2,2-Dimethylbutyric acid, 8-ester with (4R,6R)-6-(2-((1S,2S,6R,8S,8ar)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl)ethyl)tetrahydro-4-hydroxy-2H-pyran-2-one | Simvastatin | Simvastatina | Simvastatine | Simvastatinum | Synvinolin | Simvastatin |


Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.

References

  1. Health Science Authority of Singapore - Reclassified POM
  2. Drugbank