OLMETEC Olmesartan Medoxomil 10mg Film-Coated Tablet 1's

Only limited data relevant to overdosage with olmesartan medoxomil (Olmetec) in humans are available. The most likely effect of overdosage is hypotension. In the event of overdosage, treatment should be supportive.
No information is available regarding the dialysability of olmesartan.

Pregnancy: Use of drugs which act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal injury and even death. Patients who become pregnant while using olmesartan medoxomil should discontinue treatment as soon as possible.
If Olmesartan medoxomil (Olmetec) is used during pregnancy, or if the patient becomes pregnant while taking Olmesartan medoxomil (Olmetec), the patient should be apprised of the potential hazard to a fetus. Should exposure to Olmesartan medoxomil (Olmetec) have occurred from the second trimester forward, ultrasound examinations of the renal function and of the skull are recommended. Newborns exposed to angiotensin II antagonists in utero must be closely monitored for the occurrence of hypotension, oliguria, and hyperkalemia.
Lactation: It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug.

Store at temperatures not exceeding 30°C.

Pharmacologic Category: Antihypertensive (Angiotensin II Receptor Blocker).
Pharmacology: Pharmacodynamics: Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of the 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 pathway of angiotensin II synthesis.
Oral doses of olmesartan medoxomil 2.5 to 40 mg inhibited the pressor response to exogenous angiotensin I infusion.
Plasma concentrations of angiotensin I, angiotensin II and plasma renin activity increased after single or repeated administration of olmesartan medoxomil to healthy subjects or hypertensive patients. Olmesartan medoxomil administration had little effect on plasma levels of aldosterone.
In clinical trials in hypertensive patients, olmesartan medoxomil treatment resulted in a dose-dependent reduction in arterial blood pressure. The blood pressure lowering effect of olmesartan medoxomil in a once-daily regimen was maintained throughout the 24-hour dose interval. The efficacy of olmesartan medoxomil, with or without added hydrochlorothiazide as needed, was maintained for up to at least 1 year. There was no evidence of rebound hypertension following interruption of therapy at the 1 year time point.
Olmesartan medoxomil was effective in lowering blood pressure regardless of gender, age or race, although the effect appeared to be somewhat less in black patients (usually a low-renin population).
Pharmacokinetics: Absorption and distribution: Following oral administration, olmesartan medoxomil is rapidly metabolized to its pharmacologically active metabolite, olmesartan. The mean absolute bioavailability of olmesartan from a tablet formulation was found to be about 26%.
The mean peak plasma concentration of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single or repeated oral doses over the therapeutic range.
Food does not affect the bioavailability of olmesartan.
No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.
Olmesartan is highly bound to plasma protein (99%). The mean volume of distribution after intravenous dosing is in the range of 16-29 L.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan crossed the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Metabolism and elimination: Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Approximately 30% to 50% of the systemically absorbed drug is excreted in the urine while the remainder is excreted in feces (via the bile).
Depending on ethnic origin, the terminal elimination half-life of olmesartan varied between 6-15 hours. Steady state was reached after the first few doses and no further accumulation was evident with repeated dosing. Renal clearance was approximately 0.5-0.7 L/h.
Pharmacokinetics in special populations: Elderly: In Caucasian patients, the AUC at steady state was increased by about 33% in elderly patients. These increases in bioavailability corresponded to reductions in renal clearance of about 30% in elderly.
Renal Impairment: In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min).
The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.
Hepatic Impairment: Mean olmesartan AUC after single oral administration to patients with moderate hepatic impairment was increased by about 48% compared with healthy controls (total group), or by about 60% when compared with matched controls only.
Interactions: No significant pharmacokinetic interactions were observed in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly affected by antacid (aluminum magnesium hydroxide). Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce or are metabolized by these enzymes are not expected.
Drug interaction with bile acid sequestering agent colesevelam: Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in C_max and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in C_max and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride (seeInteractions).
Toxicology: Preclinical safety data: Preclinical carcinogenicity studies revealed no clinically relevant risk for humans.
In reproductive studies in rats, olmesartan medoxomil did not affect fertility. In common with other angiotensin II receptor antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats; however, there was no indication of a fetotoxic effect.
Clinical Trials: The Randomized Olmesartan And Diabetes Microalbuminuria Prevention (ROADMAP) clinical study included 4447 patients with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor. Patients were randomized to olmesartan 40 mg daily or placebo. The trial met its primary endpoint, delayed-onset of microalbuminuria. For the secondary endpoints, which the study was not designed to formally assess, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients [0.67%] vs. 3 patients [0.14%] [HR=4.94, 95% CI=1.43-17.06]), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).