| Active Ingredient | EZETIMIBE |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ZETIA | (NDA) 021445 | MSD INTL GMBH | TABLET;ORAL | 10 MG | 10 MG | October 25, 2002 | _ | _ | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | 3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone |
| CAS No | 163222-33-1 |
| Molecular Formula | C24H21F2NO3 |
| Molecular Weight | 409.4 |
| Appearance | white, crystalline powder |
| Solubility | Freely to very soluble in ethanol, methanol, and acetone |
| Water Solubility | Practically insoluble in water |
| Polymorphism | - |
| pKa (Strongest Acidic) | 9.48 (Predicted) |
| pKa (Strongest Basic) | -3 (Predicted) |
| Log P | 4.5 |
| Identification | - |
| Degradation | - |
| Hygroscopic | - |
| Photostability study | - |
| Melting Point | 163°C |
| BCS Class | - |
| Manufacture of API | - |
| Parameters | Details |
|---|---|
| Indications and Usage | ZETIA is an inhibitor of intestinal cholesterol (and related phytosterol) absorption indicated as an adjunct to diet 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 • Reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) Limitations of Use • The effect of ZETIA on cardiovascular morbidity and mortality has not been determined. • ZETIA has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias. |
| Dosage and Administration |
• One 10-mg tablet once daily, with or without food • Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. |
| Mechanism of action |
Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, ZETIA inhibited intestinal cholesterol absorption by 54%, compared with placebo. ZETIA had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D,and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients). The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol. Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate |
| Absorption | After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannotbe determined, as the compound is virtually insoluble in aqueous media suitable for injection. |
| Food Effect | Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered asZETIA 10-mg tablets. The Cmaxvalue of ezetimibe was increased by 38% with consumption of high-fat meals. ZETIA can be administered with or without food. |
| Distribution | Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins. |
| Metabolism | Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibeglucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. |
| Elimination | ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibeglucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93%of the total radioactivity in plasma. After 48 hours, there were no detectable levelsof radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose. |
| Peak plasma time (Tmax) | 4 to 12 hours |
| Half life | Approximately 22 hours |
| Bioavailability | - |
| Age, gender | In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (<20%) in women than in men |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 19717 | A | II | August 30, 2006 | GLENMARK PHARMACEUTICALS LTD |
| 20039 | I | II | December 13, 2006 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 21554 | A | II | April 17, 2008 | MSN LABORATORIES PRIVATE LTD |
| 22573 | I | II | February 25, 2009 | NEULAND LABORATORIES LTD |
| 23541 | A | II | April 7, 2010 | LUPIN LTD |
| 24511 | A | II | December 30, 2010 | CHANGZHOU PHARMACEUTICAL FACTORY |
| 24825 | A | II | April 12, 2011 | GLENMARK PHARMACEUTICALS LTD |
| 25543 | A | II | November 30, 2011 | NEULAND LABORATORIES LTD |
| 25653 | A | II | December 30, 2011 | MYLAN LABORATORIES LTD |
| 26068 | A | II | May 17, 2012 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 26637 | A | II | December 10, 2012 | SIGNA SA DE CV |
| 26972 | A | II | April 1, 2013 | MSN LABORATORIES PRIVATE LTD |
| 27303 | A | II | September 27, 2013 | GLENMARK PHARMACEUTICALS LTD |
| 27896 | A | II | February 6, 2014 | DR REDDYS LABORATORIES LTD |
| 28173 | A | II | April 14, 2014 | LUPIN LTD |
| 28942 | A | II | December 4, 2014 | WATERSTONE PHARMACEUTICALS HUBEI CO LTD |
| 29132 | A | II | March 30, 2015 | MSN LABORATORIES PRIVATE LTD |
| 29158 | A | II | March 16, 2015 | HETERO LABS LTD |
| 29622 | A | II | July 31, 2015 | WUHAN ZY PHARMACEUTICAL CO LTD |
| 29882 | A | II | October 5, 2015 | HETERO LABS LTD |
| Parameters | Details |
|---|---|
| Strength | 10 MG |
| Excipients used | Croscarmellose sodium NF, lactose monohydrate NF (55 mg), magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF |
| Composition of coating material | - |
| Composition of caspule shell | - |
| Pharmaceutical Development | - |
| Manufacture of the product | - |
| Tablet / Capsule Image |
|
| Appearance | White to off-white, capsule-shaped tablets debossed with “414” on one side |
| Imprint code / Engraving / Debossment | “414” on one side |
| Score | No score |
| Color | White to off-white |
| Shape | Capsule-shaped |
| Dimension | 8 mm 2.60 mm thick |
| Mfg by | Schering Corporation |
| Mfg for | MSP Distribution services |
| Marketed by | Merck Sharp & Dohme Limited, (EU) |
| Distributed by | - |
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N021445 | 1 | 7030106 | January 25, 2022 | - | Y | - | - | Download |
| N021445 | 1 | 7030106*PED | July 25, 2022 | - | - | - | - | Download |
| N021445 | 1 | 7612058 | October 30, 2025 | - | - | U - 1173 | - | Download |
| N021445 | 1 | 7612058 | October 30, 2025 | - | - | U - 1173 | - | Download |
| N021445 | 1 | 7612058*PED | April 30, 2026 | - | - | - | - | Download |
| N021445 | 1 | RE37721 | October 25, 2016 | Y | Y | U - 473 | - | Download |
| N021445 | 1 | RE37721*PED | April 25, 2017 | - | - | - | - | Download |
| N021445 | 1 | RE42461 | October 25, 2016 | Y | Y | U - 473 | - | Download |
| N021445 | 1 | RE42461 | October 25, 2016 | Y | Y | U - 473 | - | Download |
| N021445 | 1 | RE42461*PED | April 25, 2017 | - | - | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 50 | 0.45% SLS in 0.05 M Acetate Buffer, pH 4.5 | 500 | 10, 20, 30 and 45 | January 14, 2008 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | Download |
| European Public Assessment Report |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | EZETROL | Download |
| UK | EZETROL | Download |
| US | GLENMARK PHARMS LTD* | Download |
| US | MYLAN PHARMS INC* | |
| US | SANDOZ INC* | |
| US | TEVA PHARMS USA INC* | |
| US | WATSON LABS INC* | |
| US | ZETIA | Download |
| Date of first authorisation/renewal of the authorisation in EU: 3 April 2003/ 17 October 2012. |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
