| Active Ingredient | OLMESARTAN MEDOXOMIL |
|---|
| 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BENICAR | (NDA) 021286 | DAIICHI SANKYO | TABLET;ORAL | 5MG, 20 MG, 40 MG | 40 MG | April 25, 2002 | _ | _ | 1 New molecular entity (NME) | S Standard review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | 2,3-dihydroxy-2-butenyl 4(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole5-carboxylate, cyclic 2,3-carbonate |
| CAS No | 144689-24-7 |
| Molecular Formula | C29H30N6O6 |
| Molecular Weight | 558.59 |
| Appearance | White to light yellowish-white powder or crystalline powder |
| Solubility | Sparingly soluble in methanol, |
| Water Solubility | Practically insoluble in water |
| Polymorphism | - |
| pKa (Strongest Acidic) | 0.91 (Predicted) |
| pKa (Strongest Basic) | 5.57 (Predicted) |
| Log P | 5.9 |
| Identification | - |
| Degradation | - |
| Hygroscopic | Non hygroscopic |
| Photostability study | - |
| Melting Point | 175-180 °C |
| BCS Class | II |
| Manufacture of API | - |
| Parameters | Details |
|---|---|
| Indications and Usage | Benicar is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions |
| Dosage and Administration |
Adult Hypertension:- Starting dose: 20 mg once daily , Dose Range: 20 -40 mg once daily Pediatric Hypertension (6 -16 years):- Starting dose:20 to <35 kg 10 mg once daily, ≥35 kg 20 mg once daily , Dose Range: 20 to <35 kg 10 -20 mg once daily ≥35 kg 20 -40 mg once daily • Benicar may be administered with or without food. • If blood pressure is not controlled by Benicar alone, a diuretic may be added. Benicar may be administered with other antihypertensive agents. |
| Mechanism of action |
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. An AT2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure. |
| Absorption |
Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. Benicar tablets and the suspension formulation prepared from Benicar tablets are bioequivalent. The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. |
| Food Effect | Food does not affect the bioavailability of olmesartan. |
| Distribution |
The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses. In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats. |
| Metabolism |
Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. |
| Elimination | Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing. |
| Peak plasma time (Tmax) | 1 to 2 hours |
| Half life | 13 hours |
| Bioavailability | 26% |
| Age, gender | Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men. AUC and Cmax were 10-15% higher in women than in men. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 14953 | A | II | July 14, 2000 | DAIICHI SANKYO PROPHARMA CO LTD |
| 19141 | A | II | January 31, 2006 | GLENMARK PHARMACEUTICALS LTD |
| 19384 | A | II | April 20, 2006 | DR REDDYS LABORATORIES LTD |
| 19629 | A | II | July 25, 2006 | DAIICHI SANKYO CO LTD BENICAR HCTR |
| 20417 | A | II | March 23, 2007 | MYLAN LABORATORIES LTD |
| 21931 | A | II | September 4, 2008 | TEVA PHARMACEUTICAL INDUSTRIES LTD |
| 22721 | A | II | April 14, 2009 | AMINO CHEMICALS LTD |
| 22861 | A | II | August 26, 2009 | CADILA PHARMACEUTICALS LTD |
| 23153 | I | II | September 30, 2009 | NUTRA SPECIALITIES PRIVATE LTD |
| 23617 | I | II | March 20, 2010 | UNIMARK REMEDIES LTD |
| 23658 | A | II | March 27, 2010 | DR REDDYS LABORATORIES LTD |
| 23690 | A | II | April 7, 2010 | MSN LABORATORIES PRIVATE LTD |
| 24180 | A | II | September 29, 2010 | TORRENT PHARMACEUTICALS LTD |
| 24432 | I | II | December 9, 2010 | RANBAXY LABORATORIES LTD |
| 24644 | A | II | February 16, 2011 | CADILA HEALTHCARE LTD |
| 24671 | A | II | February 25, 2011 | ALEMBIC PHARMACEUTICALS LTD |
| 25494 | A | II | November 8, 2011 | APOTEX PHARMACHEM INDIA PVT LTD |
| 25860 | A | II | March 7, 2012 | ULKAR KIMYA SANAYII VE TICARET AS |
| 26035 | A | II | June 1, 2012 | AUROBINDO PHARMA LTD |
| 26143 | A | II | April 28, 2012 | ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD |
| 26198 | A | II | July 10, 2012 | CTX LIFE SCIENCES PVT LTD |
| 26318 | A | II | September 22, 2012 | MACLEODS PHARMACEUTICALS LTD |
| 26420 | I | II | September 6, 2012 | QILU TIANHE PHARMACEUTICAL CO LTD |
| 26782 | A | II | April 18, 2013 | LUPIN LTD |
| 26929 | A | II | March 29, 2013 | JUBILANT GENERICS LTD |
| 26992 | A | II | March 20, 2013 | HETERO LABS LTD |
| 27164 | A | II | May 21, 2013 | AMOLI ORGANICS PVT LTD |
| 27539 | A | II | September 26, 2013 | MICRO LABS LTD |
| 27950 | A | II | January 28, 2014 | DIVIS LABORATORIES LTD |
| 28444 | A | II | July 2, 2014 | CHINOIN PHARMACEUTICAL AND CHEMICAL WORKS PRIVATE CO LTD |
| 29026 | A | II | February 4, 2015 | UNICHEM LABORATORIES LTD |
| 29113 | A | II | March 2, 2015 | VASUDHA PHARMA CHEM LTD |
| 29640 | A | II | August 21, 2015 | QILU TIANHE PHARMACEUTICAL CO LTD |
| 30171 | A | II | January 28, 2016 | HEC PHARM CO LTD |
| 30433 | A | II | March 22, 2016 | HIKAL LTD |
| Parameters | Details | |||
|---|---|---|---|---|
| Strength | 5 MG | 20 MG | 40 MG | |
| Excipients used | Hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose |
Hydroxypropyl cellulose (5 mg), lactose monohydrate (123.2 mg), low-substituted hydroxypropyl cellulose (40 mg), magnesium stearate (1.8 mg), microcrystalline cellulose (20 mg) | Hydroxypropyl cellulose (10 mg), lactose monohydrate ( 246.4 mg ), low-substituted hydroxypropyl cellulose (80 mg), magnesium stearate (3.60 mg), microcrystalline cellulose (40 mg) | |
| Composition of coating material | Hypromellose, talc, titanium dioxide, and yellow iron oxide | Hypromellose (5.76 mg), talc (1.12 mg), titanium dioxide (1.12 mg) | Hypromellose (8.64 mg), talc (1.68 mg), titanium dioxide (1.68 mg) | |
| Composition of caspule shell | - | |||
| Pharmaceutical Development | - | |||
| Manufacture of the product | - | |||
| Tablet / Capsule Image |
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|
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| Appearance | Yellow, round, film-coated, non-scored tablets | White, round, film-coated, non-scored tablets | White, oval-shaped, film-coated, non-scored tablets | |
| Imprint code / Engraving / Debossment | Sankyo;C12 | Sankyo;C14 | Sankyo;C15 | |
| Score | Non-scored | Non-scored | Non-scored | |
| Color | Yelllow | White | White | |
| Shape | Round | Round | Oval | |
| Dimension | 7mm | 9mm | 15mm | |
| Mfg by | - | |||
| Mfg for | Daiichi Sankyo (US) | |||
| Marketed by | Daiichi Sankyo UK Limited (EU) | |||
| Distributed by | - | |||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N021286 | 1 | 5616599 | 25-Apr-16 | Y | Y | U - 500 | - | Download |
| N021286 | 1 | 5616599*PED | 25-Oct-16 | - | - | - | - | Download |
| N021286 | 1 | 6878703 | 19-Nov-21 | - | - | U - 3 | Y | Download |
| N021286 | 1 | 6878703*PED | 19-May-22 | - | - | - | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 50 | 0.05 M Phosphate Buffer, pH 6.8 | 500 mL (5 mg strength); 1000 mL (20 and 40 mg strength) | 10, 15, 20, 30 and 45 | April 2, 2015 |
| 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 | OLMETEC | Download |
| UK | - | |
| US | ALEMBIC PHARMS LTD*(Tentative Approval) | |
| US | AMNEAL PHARMS CO* | |
| US | AUROBINDO PHARMA LTD*(Tentative Approval) | |
| US | BENICAR | Download |
| US | JUBILANT GENERICS*(Tentative Approval) | |
| US | MACLEODS PHARMS LTD*(Tentative Approval) | |
| US | MYLAN PHARMA*(Tentative Approval) | |
| US | SANDOZ*(Tentative Approval) | |
| US | SCIEGEN PHARMS INC*(Tentative Approval) | |
| US | TEVA PHARMS USA* | |
| US | TORRENT PHARMS LTD*(Tentative Approval) |
| Date of first authorisation/renewal of the authorisation in Eu:22 May 2003/12 August 2007 |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
