Olmesartan

446.5

446.50

646-413-5

8W1IQP3U10

759810

DTXSID2040571

C66253

2921590090

130

3.2

Solid

1.3±0.1 g/cm3

186-188ºC

738.3°C at 760 mmHg

400.3±35.7 °C

1.671

1.05e-02 g/L

Store at 20-25 deg C (68-77 deg F)

1.7X10-21 mm Hg at 25 deg C (est)

4.3None

Henry's Law constant = 9.25X10-21 atm-cu m/mol at 25 °C (est)

4.3|pKa1 = 0.91 (carboxyl); pKa2 = 4.96 (amine); pKa3 = 5.57 (amine); pKa4 = 13.93 (tertiary alcohol) (est)

White to light yellowish-powder or crystalline powder. It is practically insoluble in water and sparingly soluble in methanol /Olmesartan medoxomil/|Hydroxyl radical reaction rate constant = 5.21X10-11 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

NI4014100

P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, P501

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including olmesartan medoxomil, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Olmesartan medoxomil/

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The reported LD50 of olmesartan in dogs was reported to be greater of 1500 mg/kg. Overdose is expressed as hypotension, tachycardia, and bradycardia when there is parasympathetic stimulation. In case of overdose, supportive treatment is recommended. Olmesartan was shown to be safe on carcinogenic and fertility studies. However, in _in vitro_ mutagenic studies showed a potential to induce chromosomal aberrations in cells and it tested positive for thymidine kinase mutations in the mouse lymphoma assay.|IDENTIFICATION AND USE: Olmesartan is a white to light yellowish-powder or crystalline powder that is formulated into oral tablets. Olmesartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. HUMAN EXPOSURE AND TOXICITY: Limited data are available related to drug overdose in humans. The most likely manifestations of olmesartan overdose include hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. While olmesartan can be used in hypertensive children, it is not approved for use in children less one 1 year of age. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. The use of olmesartan in pregnancy is also contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated anhydramnios/oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to olmesartan. ANIMAL STUDIES: Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. Also, the fertility of male and female rats was unaffected by administration of olmesartan. No teratogenic effects were observed when drug was administered to pregnant rats at oral doses up to 1000 mg/kg/day or pregnant rabbits at oral doses up to 1 mg/kg/day. However, significant decreases in pup birth weight and weight gain were observed in rats. In addition, delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed in rats. Olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, the drug was shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg.

Olmesartan has been associated with a low rate of serum aminotransferase elevations (

Do not co-administer aliskiren with Benicar in patients with diabetes. Avoid use of aliskiren with Benicar in patients with renal impairment (GFR <60 mL/min).|Dual Blockade of the renin-angiotensin system (RAS)with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Benicar and other agents that affect the RAS.|Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including Benicar. Monitor serum lithium levels during concomitant use.|Potential pharmacologic interaction (attenuated hypotensive effects) when angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors. Possible deterioration of renal function, including possible acute renal failure, in geriatric, volume-depleted (including those receiving concomitant diuretic therapy), or renally impaired patients; renal function should be monitored periodically in patients receiving concomitant therapy with olmesartan and an NSAIA, including selective COX-2 inhibitors.|For more Interactions (Complete) data for Olmesartan (10 total), please visit the HSDB record page.

Children <1 year of age must not receive Benicar for hypertension. The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development. RAAS blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin- angiotensin aldosterone system (RAAS) can alter normal renal development.|Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Olmesartan is highly bound to plasma proteins. 99% of the administered dose is found in a bound state with no penetration in red blood cells.

Olmesartan's production and use as an antihypertensive(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.2X10+4(SRC), determined from a structure estimation method(2), indicates that olmesartan is expected to be immobile in soil(SRC). The estimated pKa values of 4.96 and 5.57(3) indicate that this compound will exist almost entirely in the zwitterion form in the environment. Volatilization from moist soil is not expected because the compound exists as an ion and ions do not volatilize. Olmesartan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-21 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2014).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.2X10+4(SRC), determined from a structure estimation method(2), indicates that olmesartan is expected to adsorb to suspended solids and sediment(SRC). The estimated pKa values of 4.96 and 5.57(3) indicates olmesartan will exist almost entirely in the ion form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from its estimated log Kow(2)and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2014).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), olmesartan, which has an estimated vapor pressure of 1.7X10-21 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase olmesartan may be removed from the air by wet and dry deposition(SRC). Olmesartan contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Olmesartan is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Olmesartan contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated in fish for olmesartan(SRC), using an estimated log Kow of 3.63(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of olmesartan can be estimated to be 1.2X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that olmesartan is expected to be immobile in soil. The estimated pKa values of 4.96 and 5.57(3) indicate that this compound will exist in the zwitterion form in the environment.

The estimated pKa values of 4.96 and 5.57(1) indicate olmesartan will exist almost entirely in the ion form at pH values of 5 to 9 and, therefore, volatilization from water or moist soil surfaces is not expected to be an important fate process(SRC). Olmesartan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-21 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to olmesartan were not located(SRC, 2014), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are, therefore, discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

EXPERIMENTAL: Olmesartan is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.

Occupational exposure to olmesartan may occur through inhalation and dermal contact with this compound at workplaces where olmesartan is produced or used. Exposure to olmesartan among the general population may be limited to those administered the drug. (SRC)

Olmesartan is indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents. Olmesartan is also used off-label for the management Type 2 Diabetes-associated nephropathy, heart failure, and post-myocardial infarction, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as olmesartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Like other ARBs, olmesartan blockade of RAAS slows the progression of diabetic nephropathy due to its renoprotective effects.|FDA Label

Olmesartan is an angiotensin II receptor blocker used in the therapy of hypertension. Olmesartan is associated with a low rate of transient serum aminotransferase elevations, but has yet to be linked to instances of acute liver injury.

Angiotensin II Receptor Antagonists

Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents|Benicar is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Benicar. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. It may be used alone or in combination with other antihypertensive agents. /Included in US product label/|Both angiotensin II receptor antagonists /including olmesartan/ and ACE inhibitors have been shown to slow the rate of progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy, and use of a drug from either class is recommended in such patients. /NOT included in US product label/|Angiotensin II receptor antagonists /inlcuding olmesartan/ have been used with equivocal results in the management of congestive heart failure. While angiotensin II receptor antagonists appear to share the hemodynamic effects of ACE inhibitors, some clinicians state that in the absence of data documenting comparable long-term cardiovascular and/or renal benefits, angiotensin II receptor antagonists should be reserved principally for patients in whom ACE inhibitors are indicated but who are unable to tolerate the drugs (e.g., because of cough). /NOT included in US product label/|The antihypertensive effects of Benicar in the pediatric population were evaluated in a randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The etiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 or 20 mg of Benicar once daily and patients who weighed > or = 35 kg were randomized to 5 or 40 mg of Benicar once daily. At the end of 3 weeks, patients were re-randomized to continuing Benicar or to taking placebo for up to 2 weeks. During the initial dose-response phase, Benicar significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Overall, the two dose levels of Benicar (low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mm Hg from the baseline, respectively. These reductions in systolic blood pressure included both drug and placebo effect. During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2 mm Hg lower and mean diastolic blood pressure at trough was 2.8 mm Hg lower in patients continuing Benicar than in patients withdrawn to placebo. These differences were statistically different. As observed in adult populations, the blood pressure reductions were smaller in black patients. In the same study, 59 patients aged 1 to 5 years who weighed > or = 5 kg received 0.3 mg/kg of Benicar once daily for three weeks in an open label phase and then were randomized to receiving Benicar or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mm Hg lower in the group randomized to Benicar; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).

/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Benicar as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.|Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benicar as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benicar, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.|Neonates with a history of in utero exposure to Benicar: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.|FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./|For more Drug Warnings (Complete) data for Olmesartan (19 total), please visit the HSDB record page.

Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. **Hypotension in Volume- or Salt-Depleted Patients** In patients with an activated renin-angiotensin aldosterone system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with olmesartan. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Valvular Stenosis: there is concern on theoretical grounds that patients with aortic stenosis might be at a particular risk of decreased coronary perfusion, because they do not develop as much afterload reduction. **Impaired Renal Function** As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with olmesartan. In patients whose renal function may depend upon the activity of the renin-angiotensin- aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with olmesartan. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. **Sprue-like Enteropathy** Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. **Electrolyte Imbalances** Olmesartan medoxomil contains olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

Agents that antagonize ANGIOTENSIN II TYPE 1 RECEPTOR. Included are ANGIOTENSIN II analogs such as SARALASIN and biphenylimidazoles such as LOSARTAN. Some are used as ANTIHYPERTENSIVE AGENTS. (See all compounds classified as Angiotensin II Type 1 Receptor Blockers.)|Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)

When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%. Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days.|The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine.|17 L|Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h.|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.|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.|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 does not affect the bioavailability of olmesartan.|Total plasma clearance of olmesartan is 1.3 L/hr, with a renal clearance of 0.6 L/hr. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile. ... 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.|Olmesartan is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. This rapid first-pass metabolism was confirmed by the lack of measurable amounts of olmesartan medoxomil in plasma or excreta. This first-pass metabolism is not driven by cytochrome enzymes and hence it is not expected to interact with other drugs via this mechanism. The pharmacologically active moiety does not appear to undergo further metabolism.|Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan.

The mean plasma olmesartan half-life is reported to be from 10-15 hours after multiple oral administration.|Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours.

Olmesartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which also includes [telmisartan], [candesartan], [losartan], [valsartan], and [irbesartan]. ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects. As the principal pressor agent of the renin-angiotensin system, Angiotensin II causes 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. Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Olmesartan also effects on the renin-angiotensin aldosterone system (RAAS) plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS, which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and preventing ventricular hypertrophy and remodelling.|Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and converts angiotensin (Ang) II to Ang-(1-7), a renoprotective peptide. Urinary ACE2 has been shown to be elevated in patients with chronic kidney disease. However, the effects of antihypertensive agents on urinary ACE2 remain unclear. METHODS: Of participants in the Tanno-Sobetsu cohort study in 2011 (n = 617), subjects on no medication (n = 101) and hypertensive patients treated with antihypertensive agents, including the calcium channel blockers amlodipine and long-acting nifedipine; the ACE inhibitor enalapril; and the Ang II receptor blockers losartan, candesartan, valsartan, telmisartan, and olmesartan, for more than 1 year (n = 100) were enrolled, and urinary ACE2 level was measured. Glucose and hemoglobin A1c were significantly higher in patients treated with enalapril, telmisartan or olmesartan than in the control subjects. Urinary albumin-to-creatinine ratio (UACR) was significantly higher in patients treated with enalapril than in the control subjects. Urinary ACE2 level was higher in the olmesartan-treated group, but not the other treatment groups, than in the control group. Urinary ACE2 level was positively correlated with systolic blood pressure (r = 0.211; P = 0.003), UACR (r = 0.367; P < 0.001), and estimated salt intake (r = 0.260; P < 0.001). Multivariable regression analysis after adjustment of age, sex, and the correlated indices showed that the use of olmesartan was an independent predictor of urinary ACE2 level. In contrast with other antihypertensive drugs, olmesartan may uniquely increase urinary ACE2 level, which could potentially offer additional renoprotective effects.|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 AT receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. An AT 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 AT receptor than for the AT 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.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Treatment and supportive measures. Monitor blood pressure and heart rate for 6 hours after ingestion. If symptomatic or significant hypotension develops, observe for at least 24 hours. 1. If hypotension occurs, treat it with supine positioning and IV fluids. Vasopressors are rarely necessary. 2. Treat angioedema with usual measures (eg, diphenhydramine, corticosteroids) and discontinue the ACE inhibitors. Switching to an AR blocker may not be appropriate as angioedema has also been reported with these agents. 3. Treat hyperkalemia if it occurs. /Angiotensin blockers and ACE inhibitors/|For more Antidote and Emergency Treatment (Complete) data for Olmesartan (6 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs.|/SIGNS AND SYMPTOMS/ Recently, a new enteropathy has been described: olmesartan-associated enteropathy. However, the association has been questioned: a phase 3 trial and a cohort study found no association between gastrointestinal events and olmesartan. We collected French cases of sartan-associated enteropathy to describe further this entity, confirm or refute causality, and determine if the association exists with other sartans. French gastroenterologists were invited to report cases of sartan-associated enteropathy and collect clinical, biological and histological data. Patients with diarrhea and histological duodenal abnormalities were included. Thirty-six patients with olmesartan-associated enteropathy were reported, including 32 with villous atrophy and four without. There was only one patient with irbesartan-associated enteropathy. None of the patients died. Patients with villous atrophy had diarrhea, vomiting, renal failure, hypokalemia, body weight loss and hypoalbuminemia. Thirty-one patients were hospitalized; four required intensive care. Anti-transglutaminase and anti-enterocyte antibodies were negative; anti-nuclear antibodies were positive (9/11). Endoscopic duodenal biopsies showed villous atrophy (32/32) and polyclonal intra-epithelial CD3+CD8+ lymphocytosis (11/11). Exactly, 14/15 patients responded to steroids and/or immunosuppressants, prescribed because of suspected autoimmune enteropathy. Ten olmesartan interruptions were followed by reintroductions before steroids or immunosuppressants. Interruptions were followed by remissions (9/10), but reintroductions were followed by relapses (9/9). Twenty-nine patients were in remission since olmesartan interruption, including 26 without immunosuppressants. Patients with normal villi had similar clinical characteristics, but mild histological abnormalities (intra-epithelial lymphocytosis and lamina propria lymphocytic infiltration). Olmesartan causes a severe and immune-mediated enteropathy, with or without villous atrophy. Enteropathy associated with other sartans seems to be very rare.|/CASE REPORTS/ A woman took olmesartan (dose not specified) for hypertension in the last month of pregnancy. Severe oligohydramnios developed and she delivered a 3.045 kg female infant by cesarean section at 36 weeks gestation. Apgar scores were 7 and 7. The infant received dialysis for renal failure but died on day 45. Autopsy revealed severe tubular dysgenesis and the renal arteries and arteriole walls were thickened.|/CASE REPORTS/ We report on a case of fetal toxicity due to maternal treatment with olmesartan medoxomil. At 29 weeks' gestation, oligohydramnios was found, although the fetus had normal kidneys on ultrasound evaluation. Withdrawal of olmesartan medoxomil, maternal rehydration, and a single dose of furosemide reversed the renal impairment. After term delivery, the neonate was confirmed to have normal renal function. The case suggested that fetal renal impairment due to olmesartan medoxomil may be reversible.|For more Human Toxicity Excerpts (Complete) data for Olmesartan (10 total), please visit the HSDB record page.

4-(hydroxy-1-methylethyl)-2-propyl-1-((2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl)-1H-imidazole-5-carboxylic acid

Table: Olmesartan Medoxomil Preparations [Table#8210]|Table: Olmesartan Medoxomil Combination Preparations [Table#8211]|Oral: 5 mg, 20 mg and 40 mg tablets (Olmetec). /Olmesartan medoxomil/