Nirav

EZETIMIBE Ezetimibe is a class of lipid lowering compounds that selectively inhibits the intestinal cholesterol and related phytosterols.The chemical name is 1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl)3(s)hydroxypropyl)-4(s)-4(hydroxyphenyl)-2-azetidinone.

STRUCTURE-

EMPIRICAL FORMULA-C14H21F2NO3 MOLECULAR WEIGHT-409.4

DISCOVERY OF EZETIMIBE – It was discovered by Dr. JOHN CLAYDER a scientist working in the SCHERING – PLOUGH RESEARCH INSTITUTE, KENILWORTH, NEW JERSEY, USA. BRAND NAME-ZETIA APPROVAL-It was approved by USA FDA on 25th Oct, 2002.

PRESCRIPTION AVAILABLE:YES NO

GENERIC:

ATHEROSCLEROSIS-

 Coronary artery disease is one of the most commonly encountered syndromes and is the common cause of death and disability  Atherosclerosis is a coronary artery disease. It is characterized by formation of intimal fibro fatty plaques or atheromas  They deposited in wall of artery result in narrowing of arterial lumen.  Arterial atherosclerosis develops by Cholesterol deposition at the tear in inner lining of artery  Deposition harden the arterial lumen so complete blocking of the blood flow to distant tissue  Diminish its elasticity (stretchiness).  Plaques can also rupture, causing debris to migrate downstream within an artery

SYMPTOMS OF ATHEROSCLEROSIS Asymptomatic and not detected by most diagnostic methods during life. Seriously symptomatic when interfering with the coronary circulation supplying the heart or cerebral circulation supplying the brain, it is the most important underlying cause of strokes, heart attacks, heart failure. Peripheral artery occlusive disease (PAOD). Cardiac stress testing. Nuclear stress methods.

CHOLESTEROL ABSORPTION & METABOLISM EXOGENEOUS PATHWAY

EXOGENEOUS PATHWAY

TG

CE

CM

LIPOPROTEIN LIPASE ADIPOSE TISSUE

CM REMNANT

LIVER

ENDOGENEOUS PATHWAY

LIVER

VLDL

Lipoprotien Lipase

IDL

Extra hepatic Tissue

LDL

LIVER

Ezetimibe Interferes With The absorption of cholesterol, thus playing an important role in hypercholesterolemia which is increase in plasma cholesterol(>250 mg/dl). They are seen in the following diseased conditions

 DIBETES MELLITUS  HYPOTHYROIDISM(MYXODEMA)  OBSTRUCTIVE JAUNDICE  NEPHROTIC SYNDROME

EXI STI NG T HE RA PIE S F OR HYP ERC HO LES TE ROL EM IA DRUGS & DOSAGE

MECHANISM OF ACTION

BILEACID Increase excretion SEQUESTRANT of bile,increase LDL Cholestyramine (4- receptor activity, decrease LDL, 24mg/day) increase HDL level.

ADVERSE EFFECTS Constipation

NICOTINIC ACID Niacin(1.5-6g/day)

Decrease VLDL synthesis, decrease LDL cholesterol increase in HDL.

Cutaneous flushing

HMG-REDUCTASE INHIBITORS SIMVASTATIN

Inhibit HMG-CoA , increase LDL receptor activity, decrease LDL.

Mild GIT symptoms

FIBRIC ACID DERIVATIVES Gemfibrozil (1.2g/day)

removal of LDL, moderate reduction of cholesterol level, decrease HDL level.

Diarrhoea,nausea

HERBAL THERAPY FOR HYPERCHOLESTEROLEMIA  GARLIC - Allium sativum & Allium asclonicum  GUGGUL - Commiphora mukul  CURCUMIN - Curcuma longa  PSYLLIUM - Plantago ovata  FISH OIL - Fat of fish  BETA-SITOSTEROL - Plant sterol

DESCRIPTION OF EZETIMIBE • Ezetimibe is a white, crystalline powder. • It is freely soluble in ethanol, methanol, and acetone and practically insoluble in water. • Ezetimibe has melting point of about 163C. • It is stable at ambient temperature. • Each tablet contains 10mg of Ezetimibe • Each tablet along with ezetimibe contains inactive ingredients: croscarmellose sodium NF, lactose monohydrate, magnesium stearate NF, microcrystalline cellulose NF, povidone USP and sodium lauryl sulphate NF.

MECHANISM OF ACTION OF EZETIMIBE

• Ezetimibe localizes at the brush border of the small intestine where the transporter NPC1L1 seems to be located. • Ezetimibe is the specific inhibitor of NPC1L1 channel in the enterocyte, thereby slowing the rate of cholesterol uptake. It blocks the channel to the same degree as if the NPC1L1 gene were deleted.

• Lower intestinal absorption means less cholesterol input into chylomicrons. • In the circulation, chylomicrons deliver triglycerides to the muscle and fat tissue but return to the liver with full component of the cholesterol that was absorbed by the intestine. • Cholesterol is packaged and resecreted by the liver, into the blood as VLDL particles, these VLDL will lower LDL cholesterol. • Ezetimibe reduces LDL production may be inferred from a study in which patients with homozygous familial hypercholesterolemia were treated with Ezetimibe plus statin therapy. • Ezetimibe reduces the flux of cholesterol from intestine to the liver. • Thus through inhibition of the intestinal cholesterol absorption, Ezetimibe effectively reduces the amount of biliary/dietary cholesterol delivered to the liver (via chylomicrons and chylomicron remnants) and reduces the cholesterol content of atherogenic particles

PHARMACOKINETICS Absorption  After a single 10-mg dose to fasted

adults

 Cmax - 3.4 to 5.5 mg/ml  Tmax – 4 to 12 hrs.  Ezetimibe-glucuronide mean cmax to 2 hrs.

values – 45 to 71 mg/ml, Tmax- 1

EFFECT OF FOOD ON ORAL ABSORPTION  The Cmax value of ezetimibewas increased by 38% wiyh consumption of high fat meals. It can be administered with or without food. DISTRIBUTION  Highly bound(>90%) to human plasma proteins. METABOLISM  Metabolised in small intestine and liver via glucuronide conjugate ( a phase 2 reaction) HALF LIFE  22 hrs. EXCREATION  EZETIMIBE in faeces-69%  EZETIMIBE-GLUCURONIDE in urine 9%

CLINICAL TRIALS EZETIMIBE MONOTHERAPY OBJECTIVEEvaluation of the efficacy of EZETIMIBE MONOTHERPY METHODThe clinical trial conducted was randomised and double-blind. Patients were randomized to treatment group 1 or 2. Treatment group 1 received Ezetimibe 10 mg daily for 2 weeks, followed by a 2-week washout period, and then received placebo for 2 weeks. Treatment group 2 received placebo for 2 weeks, followed by a 2week washout period, and then received Ezetimibe 10 mg daily for 2 weeks. RESULTSEzetimibe decreased the intestinal absortion by 54%.Baseline in all the patient for LDL and total cholesterol was- 20.4% and – 15.1% respectively

EZETI MIB E ADD ON TO STA TI N FO R EFFEC TI VEN ESS TR IAL OBJECTIVETo determine whether co-administration of Ezetimibe with Statin (Simvastatin), produced incremental reduction in LDL, while maintaining the same safety profile as Simvastatin monotherapy. METHODEzetimibe (10 mg) was given in combination with Simvastatin (10, 20, 40, 80 mg) to patients (n=668) with primary hypercholesterolemia. RESULTThe co-administration of Ezetimibe and tin Simvasta Mean change in direct LDL of -49.9% Simvastatin monotherapy – 36.1% Ezetimbe+ Simvastatin =13.8% decrease in LDL

EZETIMIBE/SIMVASTATIN COMBINATION VS ATORVASTATIN OBJECTIVE- To determine that the co-administration of

Ezetimibe plus Simvastatin provided additional improvements in lipid profiles across a wide range of doses compared with titration of Atorvastatin monotherapy.

METHOD- 788 patients with high LDL cholesterol levels were assigned to receive either a starting dose of Atorvastatin 10 mg; 10 mg of Simvastatin and 10 mg of Ezetimibe. The patients were titrated over 24 weeks to receive final doses of 80 mg Atorvastatin or 40 mg Simvastatin plus Ezetimibe or 80 mg Simvastatin plus 10 mg of Ezetimibe. RESULT- The combination doses showed decreases of 46% to 50%, while Atorvastatin monotherapy on average reduced LDL cholesterol by 37%.

INDI CA TI ONS FAMILIAL HYPERCHOLESTEROLEMIA Clinical consequences

Tendon xanthomas Xanthelasma palpabrum

Arcus senilis corneae Treatment • Heterozygous FH- It can be treated effectively with statins • Homozygous FH- In this case, high amounts of bile acid sequestrants are often given. • Ezetimibe is very effective in lowering LDL levels in this case since its action is independent of functioning of LDL receptors. • Other treatments used are LDL apheresis,liver transplant

SITOSTEROLEMIA Clinical consequences • • • •

Premature atherosclerosis Coronary heart disease Tendon xanthomas Abnormal liver function tests. Cause

• •

Sitosterolemia is caused by complete mutation in either ABCG5 OR ABCG8 genes. These genes encode ATP-BINDING CASETTE proteins that belong to G family and may work together to pump cholesterol and plant sterols from the brush border of enterocytes into the intestinal lumen and from liver into the bile. Treatment

• •

Available treatments include a diet restricted in cholesterol and plant sterols, bile-salt binding resins, and still if patients continue to have increased levels of plant sterols then Ezetimibe is prescribed. Ezetimibe reduces plasma concentrations of plant sterols blocking their intestinal absorption. 11, 14, 15

ADVERSE EFFECTS ADVERSE EFFECTS2 GASTROINTESTINAL SYSTEM: ABDOMINAL PAIN

COMMON

DIARRHOEA

COMMON

INFECTIONAND INFESTATION: VIRAL INFECTION

LESS COMMON

PHARYNGITIS SINUSITIS

COMMON

MUSCULOSKELETAL: ATHRALGIA

LESS COMMON

BACKPAIN

COMMON

FATIGUE

LESS COMMON

RESPIRATORY SYSTEM COUGHING

LESS COMMON

DRUG INTERACTION Ezetimibe is neither an inhibitor nor an inducer. CO-ADMINITRATION OF ADMINISTRATION OF EZETIMIBE HAD NO SIGNIFICANT EFFECT ON THE BIOAVAILABILITY OF FOLLOWING DRUGS. • WARFARIN • DIGOXIN • ORAL CONTRACEPTIVE • HMG-COA REDUCTASE INHIBITORS • CIMETIDINE • ANTACIDS • GLIPIZIDE

• HOWEVER THERE ARE CERTAIN DRUGS WHICH INCREASE OR DECREASE THE BIOAVAILIBILITY OF EZETIMIBE

• GEMFIBROZIL(600 mg twice daily) Increased the oral bioavailability of Ezetimibe

• FENOFIBRATE (200 mg once daily) It increased the mean Cmax and AUC values of total Ezetimibe approximately 64% and 48%, respectively.

• CHOLESTYRAMINE Decreased the mean AUC values of total Ezetimibe and Ezetimibe approx by 55% and 80% respectively

DOSAGE AND ADMINISTRATION Ezetimibe is commercially available as 10 mg tablets. The recommended dose of Ezetimibe is 10 mg administered by mouth once daily.

OVER DOSE No case of overdose with ezetimibe have been reported.

SPECIAL POPULATIONS Geriatric Patients Plasma concentrations were about 2-fold higher

Pediatric Patients Pharmacokinetic data in the pediatric population are not available.

Gender Plasma concentrations for total Ezetimibe were slightly higher (<20%) in women than in men.9:

Race There were no pharmacokinetic differences between Blacks and Caucasians

Hepatic Insufficiency After a single 10-mg dose of Ezetimibe, the mean area under the curve (AUC) for total Ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency.

Renal Insufficiency After a single 10-mg dose of Ezetimibe in patients with severe renal disease the mean AUC values for total Ezetimibe, Ezetimibe-glucuronide, and Ezetimibe were increased approximately 1.5-fold

Pregnancy and Lactation Ezetimibe is classified as pregnancy-risk category . Ezetimibe has been studied in pregnant rabbits and rats, nursing rats, but it is not known whether Ezetimibe is excreted into human breast milk. Therefore, Ezetimibe should not be used in nursing mothers

MA RK ET ED PR EPA RA TI ONS MFG BY

BRAND

CONTENTS

ZETIA

EZETIMIBE

VY TORIN

EZETIMIBE,SIMV MERCK PHARMA ASTATIN

ZETITOR5,ZETITOR-10

ATORVASTATIN, EZETIMIBE

SIMVO TIN

EZETIMIBE,SIMV RANBAXY ASTATIN

ME RCK PHARM A

GLENMARK PHARM A

MARKET PRICE

Drug

Package

EZETIMIBE

28 tablets

EZETIMIBE

98 tablets

Recommended daily dose

10 mg

10 mg

Price

2.67$

8.14$

SUMMARY • Ezetimibe is a new class of lipid reducing drugs, which selectively hinders the absorption of cholesterol and plant sterols in the jejunum. • The statins and ezetimibe have two different working mechanisms, complementing the reduction of cholesterol levels. • Ezetimibe is indicated as add-on therapy to statin treatment, for patients with primary hypercholesterolemia, homozygous familial hypercholesterolemia and the rare sitosterolemia • Ezetimibe in monotherapy is indicated when statin treatment is not appropriate. Plasma ezetimibeglucuronid 80-90% and ezetimibe 10-20%, both bind > 90% to plasma protein. T½ is app. 22 h.

RO LE O F PH ARMA CI ST • innovative brands of ezetimibe are very costly newer generic brands of ezetimibe which are more economical • Higher Bioequivalence than the innovative brands. • Industrial pharmacist should develop newer combinations of ezetimibe • least side effect and Bioavailability •

Patient awareness regarding the therapy efficacy

CONC LUSIO N: Ezetimibe is indeed proved to be successful in carving a niche as an agent effective in lowering cholesterol. Ezetimibe when added to the ongoing Statin therapy can successfully help to fight agaist raised LDL levels

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