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Drugs

, Volume 68, Issue 9, pp 1239–1272 | Cite as

Olmesartan Medoxomil

A Review of its Use in the Management of Hypertension
  • Lesley J. ScottEmail author
  • Paul L. McCormack
Adis Drug Evaluation

Summary

Abstract

Olmesartan medoxomil (Olmetec®, Benicar®) is an angiotensin II type 1 (AT1) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a key role in the pathogenesis of hypertension. Oral olmesartan medoxomil 10–40 mg once daily is recommended for the treatment of adult patients with hypertension. In those with inadequate BP control using monotherapy, fixed-dose olmesartan medoxomil/hydrochlorothiazide (HCTZ) [Olmetec plus®, Benicar-HCT®] combination therapy may be initiated.

Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, in patients with hypertension, including elderly patients with isolated systolic hypertension (ISH). Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 4 hours of this period. In clinical trials, olmesartan medoxomil monotherapy provided better antihypertensive efficacy than losartan, candesartan cilexetil or irbesartan monotherapy, and was at least as effective as valsartan treatment, with a faster onset of action than other ARBs in terms of reductions from baseline in diastolic BP (DBP) and, in most instances, systolic BP (SBP). Combination therapy with olmesartan medoxomil plus HCTZ was superior to that with benazepril plus amlodipine, as effective as that with losartan plus HCTZ, noninferior to that with atenolol plus HCTZ, but less effective than that with telmisartan plus HCTZ, in individual trials. Data from ongoing clinical outcome trials are required to more fully determine the relative position of olmesartan medoxomil therapy in the management of hypertension. In the meantime, the consistent antihypertensive efficacy during the entire 24-hour dosage interval and good tolerability profile of olmesartan medoxomil, with or without HCTZ, make it a valuable option for the treatment of adult patients with hypertension, including the elderly.

Pharmacological Properties

Olmesartan blocks the action of angiotensin II by binding with high selectivity to the AT1 receptor and not to the type 2 (AT2) receptor. Olmesartan binds to the AT1 receptor with a high degree of insurmountability and with greater affinity than most other ARBs. Olmesartan medoxomil dose-dependently antagonized the vasoconstrictor and pressor responses induced with angiotensin II in animal studies. In healthy volunteers, olmesartan medoxomil increased plasma renin, reduced urinary aldosterone excretion and increased arterial compliance, while in patients with hypertension, it reduced DBP in parallel with increased plasma renin activity and angiotensin II levels. Preliminary evidence suggests that olmesartan medoxomil may exert protective effects against end-organ damage, including renoprotection and anti-atheroslcerotic activity.

Olmesartan medoxomil is rapidly absorbed following oral administration and is completely metabolized to the pharmacologically active metabolite, olmesartan, during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan following a single 20 mg oral dose in healthy volunteers was 26% and peak plasma levels were attained after approximately 2 hours. Olmesartan is highly bound to plasma proteins and has a low volume of distribution. It is not further metabolized and is excreted mainly in the faeces, via the hepato-biliary route, with smaller amounts in the urine. The long elimination half-life permits once-daily administration. Olmesartan seldom requires dosage adjustment and has a low potential for pharmacokinetic drug-drug interactions.

Therapeutic Efficacy

Extensive clinical experience in numerous large (n >150), randomized, double-blind, multicentre trials of up to 24 weeks’ duration have confirmed the antihypertensive efficacy of oral olmesartan medoxomil 20 or 40 mg once daily, as monotherapy or in combination with HCTZ (12.5 or 25 mg once daily), in adult patients with hypertension (most patients had mild to moderate hypertension). These data were supported by the large (n ≈12 000) OLMEPAS study conducted in the primary care setting. In addition, olmesartan medoxomil effectively lowered BP in elderly patients, including those with ISH, and in patients in whom the treatment regimen was based on achieving BP targets as defined in treatment guidelines. In all placebo-controlled trials, olmesartan medoxomil was more effective than placebo in lowering BP, with the benefits on BP sustained for the duration of the 24-hour dosage interval (including the last 4 hours).

Overall, in several of these trials, olmesartan medoxomil monotherapy for up to 12 weeks provided better antihypertensive efficacy, in terms of the primary endpoint of mean changes from baseline in trough seated or daytime ambulatory DBP, than losartan, candesartan cilexetil or irbesartan monotherapy and was at least as effective as valsartan treatment. Notably, the between-group difference for reductions in trough seated or daytime ambulatory DBP were evident from 1 or 2 weeks onwards (primary or secondary endpoint), indicating a faster onset of action with olmesartan medoxomil treatment. At most timepoints, reductions in SBP also generally favoured olmesartan medoxomil treatment versus that with other ARBs, as did other secondary endpoints, including response rates and BP normalization rates.

After 8–12 weeks of treatment, olmesartan medoxomil monotherapy provided equivalent antihypertensive efficacy to amlodipine, was as effective as felodipine and atenolol, and provided better antihypertensive efficacy than captopril, in terms of mean reductions from baseline in trough seated or 24-hour ambulatory DBP in several clinical trials (primary endpoint). There were generally no significant between-group differences for secondary endpoints of mean reductions in trough seated or 24-hour ambulatory SBP and response rates.

Although in the large (n ≈500) OLMEBEST trial noninferiority between monotherapy with olmesartan medoxomil and combination therapy with olmesartan medoxomil plus HCTZ was not established, this was thought to reflect the high response rate during the olmesartan medoxomil monotherapy phase of the study, which, in turn, meant fewer patients than predicted entered the double-blind phase of the trial that was designed to evaluate noninferiority. Nonetheless, in a large, double-blind, factorial-design trial in patients with moderate to severe hypertension, all olmesartan medoxomil plus HCTZ combination regimens significantly reduced seated DBP (primary endpoint) and SBP compared with placebo treatment, with at least one of these combinations being superior to that of its individual components for both seated DBP and seated SBP. These data were confirmed in a pooled analysis of this and another similarly designed trial.

Combination therapy with olmesartan medoxomil plus HCTZ for 12 weeks was as effective as that with losartan plus HCTZ in reducing mean trough seated DBP in patients with moderate to severe hypertension (primary endpoint), albeit that at earlier timepoints patients receiving an olmesartan medoxomil-based regimen experienced greater reductions in trough seated DBP. In this trial, reductions in trough seated SBP were also significantly greater with olmesartan medoxomil-based treatment at all timepoints from 1 week onwards and a significantly higher proportion of patients in this group achieved a BP of <140/90 mmHg at study end (secondary endpoints). In another 12-week trial in patients with moderate to severe hypertension, combination therapy with olmesartan medoxomil plus HCTZ was shown to be noninferior to that with atenolol plus HCTZ, based on reductions in mean seated DBP (primary endpoint) and SBP at study end, with no significant between-group differences in responder rates. In a 12-week noninferiority trial, olmesartan medoxomil plus HCTZ treatment provided superior antihypertensive efficacy than that with benazepril plus amlodipine, based on reductions from baseline in seated SBP (primary endpoint), with no between-group difference for mean reductions from baseline in seated DBP. In general, by 12 weeks, significantly more patients receiving an olmesartan medoxomil-based than a benazepril-based regimen had achieved prespecified BP targets. In an open-label, blinded endpoint trial in patients with moderate hypertension that was not adequately controlled after 8 weeks’ treatment with olmesartan medoxomil or telmisartan monotherapy, the addition of HCTZ for 8 weeks resulted in greater reductions from baseline in 24-hour DBP (primary endpoint), 24-hour ambulatory SBP, and in daytime and night-time BP with the telmisartan regimen than with the olmesartan medoxomil regimen.

Tolerability

In several well designed clinical trials of up to 24 weeks’duration, treatment with oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, was generally well tolerated in patients with hypertension or ISH. Treatment-emergent adverse events were generally of similar nature and frequency to those occurring in placebo recipients and were of mild intensity, transient, showed no dose-response relationship and resulted in ≤2.4% of patients discontinuing treatment. The only adverse event that occurred in >1% of patients and with a higher incidence in the olmesartan medoxomil monotherapy than in the placebo group was dizziness (2.8% vs 0.9%; p = 0.01). In combination with HCTZ, treatment-emergent adverse events that occurred with an incidence of ≥2% and with a numerically higher incidence in the olmesartan medoxomil combination than in the placebo group were dizziness, upper respiratory tract infection, hyperuricaemia and nausea (all ≤9% with olmesartan medoxomil plus HCTZ). There were no between-group differences in the nature or incidence of treatment-emergent adverse events between active comparator groups.

Keywords

Losartan Amlodipine Valsartan Telmisartan HCTZ 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis Data Information BV 2008

Authors and Affiliations

  1. 1.Wolters Kluwer Health ¦ AdisMairangi Bay, North Shore, AucklandNew Zealand
  2. 2.Wolters Kluwer HealthConshohockenUSA

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