DRUG AND PROFILE REPORTS

Olmesartan medoxomil: a guide to its use in hypertension Adapted from Drugs 2008: 68 (9): 1239-72[1]

What is the rationale for developingthe drug?The ultimate goals of antihypertensive therapy are to

lower blood pressure (BP) and to reduce cardiovascularand renal morbidity and mortality.[1] The renin-angiotensin-aldosterone system (RAAS) is an importantmediator in the pathophysiology of hypertension, withexcessive activity in the RAAS playing a key role in targetend-organ damage, such as myocardial infarction,congestive heart failure, coronary artery disease and end-stage renal disease.[1] This system, therefore, is a primetarget for drugs used in the treatment of hypertension, withtwo main classes: ACE inhibitors (e.g. enalapril, captopril)and angiotensin II receptor antagonists (angiotensinreceptor blockers [ARBs]).[1]

Olmesartan medoxomil is a nonpeptide member of theARB drug class, and is approved in many countriesworldwide for the treatment of hypertension.[1] Olmesartanmedoxomil is available as as monotherapy (Olmetec®,Benicar®) or as a fixed-dose tablet in combination withthe diuretic hydrochlorothiazide (HCTZ) [Olmetec Plus®,Benicar HCT®].[1]

How does the drug work?Orally administered olmesartan medoxomil is rapidly

converted to its active metabolite olmesartan duringabsorption from the gastrointestinal tract.[2,3] Olmesartanbinds with high selectivity to the angiotensin type 1 (AT1)receptor and blocks the binding of angiotensin II, but doesnot bind to the type 2 (AT2) receptor.[7] Angiotensin II isthe primary effector peptide of the RAAS, which plays animportant role in the regulation of BP and fluid-electrolytebalance.[1] Activation of the AT1 receptor by angiotensinII is responsible for all of the known cardiovasculareffects of angiotensin II, and results in acute

Table I. Prescribing summary of oral olmesartanmedoxomil alone or in combination withhydrochlorothiazide (HCTZ)[1-6] a

Indication

Olmesartan medoxomil Treatment of hypertension

Olmesartan medoxomil/ Treatment of hypertension inHCTZ patients whose blood pressure

is inadequately controlled witholmesartan medoxomil or HCTZalone

Dosage

Olmesartan medoxomil EU: 10–40 mg once daily[2]

US: 20–40 mg once daily[3]

Olmesartan medoxomil/ EU: 20 mg/12.5 mg to 20 mg/25HCTZ mg once daily[5]

US: 20 mg/12.5 mg to 40 mg/25mg once daily[4]

Availability (film-coated tablets)

Olmesartan medoxomil EU: 10, 20 and 40 mg[2]

US: 5, 20 and 40 mg[3]

Olmesartan medoxomil/ EU: 20 mg/12.5 mg, 20 mg/25HCTZ mg[5]

US: 20 mg/12.5 mg, 40 mg/12.5mg and 40 mg/25 mg[4]

Pharmacokinetic profile of olmesartan (active metaboliteof olmesartan medoxomil)

Bioavailability 26%b

Mean maximum plasma 0.42–0.48 mg/mLb

concentration (Cmax)

Time to Cmax 1.7–2.5 hb

Time to steady state ≈5 d

Plasma protein binding 99.7%

Volume of distribution ≈17 L

Metabolism Virtually none followingabsorption

Total plasma clearance 1.3 L/h

Primary elimination route Faecal (77%)b

Mean elimination half life ≈13 h

a Consult local prescribing information for availability and furtherdetails.

b After administration of a single 20 mg dose of olmesartanmedoxomil in healthy volunteers.

vasoconstriction and increases in salt retention, fluidvolume, aldosterone secretion and sympathetic activity, indicated for the once-daily treatment of hypertension.while activation of the AT2 receptor is believed to result Table I provides a summary of the dosage andin the opposite effects. Olmesartan binds to the AT1 administration of olmesartan medoxomil alone[2,3] or as areceptor with a high degree of insurmountability and with fixed-dose combination with HCTZ[4,5] in the EU[2,5] andgreater affinity than most other ARBs.[1] US,[3,4] as well as the key pharmacokinetic properties of

the drug.Who should receive the drug? Importantly, olmesartan medoxomil should beOral olmesartan medoxomil, either alone or in discontinued as soon as possible when pregnancy is

combination with other antihypertensive agents, is planned or detected, as drugs that act directly on the

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RAAS can cause injury and even death to the developing reductions being significantly (p < 0.05) greater than thosefetus.[2-5] with placebo. At 12 weeks, responder rates (defined as a

decrease in mean trough seated DBP of ≥10 mmHg or aAre dosage adjustments required in any decrease to ≤90 mmHg) were also significantly greater inspecial patient groups? olmesartan medoxomil 10–80 mg groups than in the

placebo group (66–78% vs 46%; all p < 0.01).[9]Dosage adjustments of olmesartan medoxomil are notrequired in elderly patients or those with mild or moderate In patients with moderate to severe hypertension, 8hepatic impairment.[2,3] No assessment has been performed weeks’ treatment with olmesartan medoxomil 5, 20 or 80in patients with severe hepatic impairment. In the EU,[2] mg once daily significantly reduced mean 24-hour DBPthe maximum recommended dosage of olmesartan relative to placebo (primary endpoint).[10] Correspondingmedoxomil in patients with mild or moderate renal placebo-subtracted reductions in mean 24-hour DBP in theimpairment (creatinine clearance [CLCR] 20–60 mL/min) olmesartan medoxomil groups were 9.6, 12.2 and 10.6is 20 mg/day; the drug is not recommended in patients mmHg, and those for reductions in mean 24-hour systolicwith severe renal impairment (CLCR <20 mL/min). Fixed- BP (SBP) were 14.5, 16.5 and 15.4 mmHg (all p < 0.0001dose olmesartan medoxomil/HCTZ is not recommended in vs placebo).patients with CLCR ≤30 mL/min, as loop diuretics are In one of these trials,[10] the 24-hour duration of actionpreferred to HCTZ in this patient population.[4,5] In the of olmesartan medoxomil on BP was confirmed using theUS,[3,4] consideration should be given to the use of a lower placebo-subtracted trough-to-peak (TTP) ratio for DBPinitial dose in patients with possible depletion of and SBP. With once-daily treatment, a drug is consideredintravascular volume (e.g. those receiving diuretics, an effective antihypertensive agent if ≥50% of the peakparticularly those with impaired renal function). effect remains at the end of the 24-hour BP assessment

period. TTP ratios exceeded this level with all olmesartanAre there any important interactions? medoxomil regimens.[10]

Olmesartan medoxomil has a low potential for… or other antihypertensives?pharmacokinetic drug-drug interactions.[1,8] No significant

pharmacokinetic changes have been observed after Overall, olmesartan medoxomil monotherapy for up tocoadministration of olmesartan medoxomil with digoxin, 12 weeks provided better antihypertensive efficacy, inwarfarin, amlodipine, atenolol, HCTZ or antacids.[1-5,8] As terms of the primary endpoint of mean changes fromolmesartan is not metabolized by any cytochrome P450 baseline in trough seated or daytime ambulatory DBP,(CYP) isoenzymes and does not appear to have any than losartan,[11-13] candesartan cilexetil[14] or irbesartan[12]

significant inhibitory or inducing effects on CYP monotherapy and was at least as effective as valsartan[12,13]

isoenzymes, interactions of olmesartan with other drugs treatment in randomized, double-blind clinical trials.that are metabolized by CYP isoenzymes are not expected Notably, the between-group difference for reductions into occur.[2-5] The absorption of olmesartan medoxomil is trough seated or daytime ambulatory DBP were evidentnot significantly affected by food.[2-5]

from 1 or 2 weeks onwards (primary[14] or secondary[12,13]

Interactions may occur between the HCTZ component endpoint), indicating a faster onset of action withof fixed-dose olmesartan medoxomil/HCTZ and other olmesartan medoxomil treatment (figure 1). At mostagents, including those known to affect potassium timepoints, reductions in SBP also generally favouredlevels.[4,5]

olmesartan medoxomil treatment versus that with otherARBs, as did other secondary endpoints, including

What is the efficacy of monotherapy response rates and BP normalization rates.[11-14]

versus placebo … After 8–12 weeks of treatment, olmesartan medoxomilIn a large (n = 800), placebo-controlled, dose-ranging monotherapy provided equivalent antihypertensive

trial in patients with mild to moderate hypertension,[9] the efficacy to amlodipine,[15] was as effective as felodipineoptimal dosage range for olmesartan medoxomil and atenolol,[16] and provided better antihypertensivemonotherapy was 10–40 mg once daily (i.e. recommended efficacy than captopril,[11] in terms of mean reductionsdosages), with no further increase in efficacy at the higher from baseline in trough seated or 24-hour ambulatorydosage of 80 mg once daily. At recommended dosages of DBP in several clinical trials (primary endpoint). Thereolmesartan medoxomil, the mean reduction in seated were generally no significant between-group differencesdiastolic BP (DBP) after 12 weeks’ treatment ranged from for secondary endpoints of mean reductions in trough12.9 to 15.5 mmHg (primary endpoint), with all of these seated or 24-hour ambulatory SBP and response rates.

Drugs Ther Perspect 2009; Vol. 25, No. 1

What is the efficacy of combinationtherapy versus monotherapy …

In a large (n ≈500) randomized, double-blind,multicentre trial in patients with mild to moderatehypertension,[18] noninferiority between olmesartanmedoxomil monotherapy and olmesartan medoxomil plusHCTZ combination therapy was not demonstrated, asdetermined by the change in mean seated DBP during therandomized treatment period in the per-protocolpopulation (primary efficacy endpoint), since the upperlimit of the 95% CI for the between-group difference wasnot <1 mmHg (prespecified limit for noninferiority). Theinability to show noninferiority between these regimensmay be a reflection of the high DBP responder rate (76%of patients; responder defined as having a seated DBP <90mmHg or a decrease in seated DBP of ≥10 mmHg) at theend of 8 weeks’ open-label treatment with olmesartanmedoxomil 20 mg once daily, which resulted in fewerpatients than predicted entering the randomized double-blind phase of the trial. There were no statisticallysignificant differences in DBP response rates ornormalization rates (defined as seated DBP of <90 mmHg)between the treatment groups.

… or other combination regimens?

In randomized, double-blind 12-week trials,combination therapy with olmesartan medoxomil plusHCTZ was at least as effective as treatment with otherantihypertensive combinations.[11,19,20]

Combination therapy with olmesartan medoxomil plusHCTZ for 12 weeks was as effective as that with losartanplus HCTZ in reducing mean trough seated DBP inpatients with moderate to severe hypertension (primaryendpoint), albeit that at earlier timepoints patientsreceiving an olmesartan medoxomil-based regimenexperienced greater reductions in trough seated DBP.[19] Inthis trial, reductions in trough seated SBP were alsosignificantly greater with olmesartan medoxomil-basedtreatment at all timepoints from 1 week onwards and a

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Fig. 1. Antihypertensive efficacy of olmesartan medoxomil (OLM) inpatients (pts) with mild to moderate hypertension. The primaryendpoint was the mean change from baseline at study end[12,14] or at8 wk[13] in seated[12,13] or daytime ambulatory[14] diastolic bloodpressure (DBP) in randomized, double-blind trials conducted by (a)Oparil et al.,[12] (b) Giles et al.[13] and (c) Brunner et al.[14] Wk 1 and 2results were coprimary timepoints in the latter study.[14] Pts receivedoral OLM, losartan (LOS), valsartan (VAL), candesartan cilexetil(CAN) or irbesartan (IRB) once daily. * p = 0.05, ** p = 0.01, *** p <0.001 vs OLM at the same timepoint; † p < 0.05 vs placebo at thesame timepoint.

significantly higher proportion of patients in this groupWhat is its efficacy in the primary achieved a BP of <140/90 mmHg at study end (secondarycare setting? endpoints).

In another 12-week trial in patients with moderate toThe antihypertensive efficacy of olmesartan medoxomil severe hypertension, combination therapy with olmesartan

in the primary care setting has been evaluated in an medoxomil plus HCTZ was shown to be noninferior to8-week, noncomparative study that enrolled approximately that with atenolol plus HCTZ, based on reductions in12 000 patients with hypertension from >3400 clinical mean seated DBP (primary endpoint) and SBP at studypractices in Germany.[17] The most frequently prescribed end, with no significant between-group differences inolmesartan medoxomil dose was 20 mg. After 12 weeks of responder rates.[11]

treatment, the mean reduction from baseline for DBP was In a 12-week noninferiority trial, olmesartan14.2 mmHg and that for SBP was 28.4 mmHg.[17] medoxomil plus HCTZ treatment provided superior

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antihypertensive efficacy than that with benazepril plus 3278 patients discontinued olmesartan medoxomilamlodipine, based on reductions from baseline in seated treatment versus 2.7% of patients in the control groups (nSBP (primary endpoint), with no between-group difference = 1179)[3] and, in combination with HCTZ, 2% of patientsfor mean reductions from baseline in seated DBP.[20] In in both the olmesartan medoxomil plus HCTZ (n = 1243)general, by 12 weeks, significantly more patients receiving and placebo groups (n = 342) discontinued treatment.[4]

an olmesartan medoxomil-based than a benazepril-based In clinical trials, there were no between-groupregimen had achieved prespecified BP targets. differences in the nature or incidence of treatment-

emergent adverse events for active comparatorWhat is its efficacy in elderly patients? groups,[11-15,19,20] including between monotherapy with

olmesartan medoxomil and that with losartan, valsartan,Olmesartan medoxomil treatment with or withoutirbesartan or candesartan cilexetil.[11-14]HCTZ appeared to be as effective in elderly patients (aged

≥65 years) as it was in younger patients (aged <65 years)… as monotherapy …with moderate to severe hypertension in a subgroupPooled data and meta-analyses of placebo-controlledanalysis of pooled data from two double-blind trials of 8

clinical trials (n >3000 patients) indicated that the natureand 12 weeks’ duration with a factorial-design dosageand incidence of treatment-emergent adverse events withregimen.[21] There was no significant difference betweenolmesartan medoxomil monotherapy was generally similarthe two age groups in terms of reductions from baseline into that seen with placebo.[1] Moreover, there were notrough seated DBP for each of the individualbetween-group differences in the tolerability profiles ofmonotherapies and combination regimens, with reductionsolmesartan medoxomil and placebo based on age, genderin the individual age groups being similar to thoseor race.[3]observed in the combined ITT population.

The only adverse event that occurred in >1% ofThese data are supported by another randomized, open-patients and with a higher incidence in the olmesartanlabel trial in which patients followed an algorithm ofmedoxomil monotherapy than in the placebo group wasincreasing dosages of olmesartan medoxomil (in 3-weekdizziness (2.8% vs 0.9%; p = 0.01),[24] with this adversesteps) and then the addition of HCTZ, with patientsevent being the only one to be considered treatment-exiting the study if their BP was normalized (BP <120/80related.[2,5]mmHg).[22] By study end, three-quarters of patients aged

<65 years and approximately two-thirds of those aged ≥65… or combination therapy?years had achieved the BP target of <140/90 mmHg.In combination with HCTZ, treatment-emergent adverseIn randomized, double-blind trial in elderly patients

events that occurred with an incidence of ≥2% and with awith isolated systolic hypertension, 12 weeks’ treatmentnumerically higher incidence in the olmesartan medoxomilwith olmesartan medoxomil was noninferior to that withcombination than in the placebo group were dizziness (9%nitrendipine in terms of reductions in mean seated SBPvs 2%; 1% with olmesartan medoxomil monotherapy and(primary endpoint), as the 97.5% CI intervals were within2% with HCTZ monotherapy), upper respiratory tractthe lower boundary of the predefined equivalence rangeinfection (9% vs 0%; monotherapies 6% and 7%),(i.e. 4.4 mmHg).[23] Noninferiority between the twohyperuricaemia (4% vs 2%; monotherapies 0% and 2%)treatments was also shown in terms of reductions in seatedand nausea (3% vs 0%; monotherapies 2% and 1%).[4]DBP at this timepoint and in seated SBP and DBP at all

other timepoints assessed throughout the study.What is its current positioning?

What is its tolerability profile … Extensive clinical evidence from several large wellTreatment with oral olmesartan medoxomil, as designed trials and the clinical practice setting have

monotherapy or in combination with HCTZ, for up to 24 confirmed the antihypertensive efficacy and goodweeks is generally well tolerated in patients with tolerability profile of oral olmesartan medoxomil, ashypertension or with isolated systolic hypertension.[1] monotherapy or in combination with HCTZ, in patientsTreatment-emergent adverse events were generally of mild with hypertension, including elderly patients with isolatedintensity and transient, with no dose-response relationship systolic hypertension. The consistent antihypertensiveobserved, irrespective of whether olmesartan medoxomil efficacy during the entire 24-hour dosage interval andwas given as monotherapy or in combination with good tolerability profile of olmesartan medoxomil, with orHCTZ.[2-5] Very few patients discontinued treatment without HCTZ, make it a valuable option for the treatmentbecause of an adverse event; with monotherapy, 2.4% of of adult patients with hypertension, including the elderly.

Drugs Ther Perspect 2009; Vol. 25, No. 1

10. Neutel JM, Elliott WJ, Izzo Jr JL, et al. Antihypertensive efficacyof olmesartan medoxomil, a new angiotensin II receptor ant-agonist, as assessed by ambulatory blood pressure measurements. JClin Hypertens 2002; 4 (5): 325-31

11. Ball KJ, Williams PA, Stumpe KO. Relative efficacy of an angio-tensin II antagonist compared with other antihypertensive agents:olmesartan medoxomil versus antihypertensives. J Hypertens 2001;19 Suppl. 1: 49-56

12. Oparil S, Williams D, Chrysant SG, et al. Comparative efficacy ofolmesartan, losartan, valsartan and irbesartan in the control ofessential hypertension. J Clin Hypertens 2001; 3 (5): 283-91

13. Giles TD, Oparil S, Silfani TN, et al. Comparison of increasingdoses of olmesartan medoxomil, losartan potassium, and valsartanin patients with essential hypertension. J Clin Hypertens 2007; 9(3): 187-95

14. Brunner HR, Stumpe KO, Januszewicz A. Antihypertensive effi-cacy of olmesartan medoxomil and candesartan cilexetil assessedby 24-hour ambulatory blood pressure monitoring in patients withessential hypertension. Clin Drug Invest 2003; 23 (7): 419-30

15. Chrysant SG, Marbury TC, Robinson TD. Antihypertensive effi-cacy and safety of olmesartan medoxomil compared with

Adis EvaluationKey clinical benefits and limitations of oral olmesartanmedoxomil in hypertension

Clinical benefits

Binds to the angiotensin type 1 receptor with a high degreeof insurmountability and with greater affinity than most otherangiotensin II receptor antagonistsDisplays antihypertensive efficacy as monotherapy or incombination with hydrochlorothiazide in patients withhypertension, including those who are elderlyHas fast onset of antihypertensive effectAt least as effective as, or more effective than, many otherantihypertensive regimensConvenient once-daily administration provides 24-h efficacy(including during early morning hours)Generally well tolerated

Potential limitations

Data from ongoing clinical outcome trials are required tomore fully determine its relative efficacy and tolerabilityPharmacoeconomic comparisons with other antihypertensiveagents would be of benefit

amlodipine for mild-to-moderate hypertension. J Hum Hypertens2003; 17 (6): 425-32

16. Stumpe KO, Ludwig M. Antihypertensive efficacy of olmesartancompared with other antihypertensive drugs. J Hum Hypertens2002; 16 Suppl. 2: 24-8References

17. Brunner HR. Olmesartan medoxomil: current status of its use in1. Scott LJ, McCormack PL. Olmesartan medoxomil: a review of itsmonotherapy. Vasc Health Risk Manag 2006; 2 (4): 327-40use in the management of hypertension. Drugs 2008; 68 (9):

18. Barrios V, Boccanelli A, Ewald S, et al. Efficacy and tolerability1239-72of olmesartan medoxomil in patients with mild to moderate essen-

2. Olmetec film-coated tablets; summary of product characteristics.tial hypertension: the OLMEBEST study. Clin Drug Investig 2007;

Gerrards Cross: Daiichi Sankyo UK Limited, 2007 Aug 27 (8): 545-583. Benicar® tablets (olmesartan medoxomil): US prescribing informa- 19. Rump LC, Ambrosioni E, Burnier M, et al. Initial combination

tion. Parsippany (NJ): Daiichi Sankyo Inc., 2007 Jul therapy with olmesartan/hydrochlorothiazide in moderate-to-severehypertension [letter]. J Hum Hypertens 2006; 20 (4): 299-3014. Benicar HCT® tablets (olmesartan medoxomil-hydrochlorothia-

zide): US prescribing information. Parsippany (NJ): Daiichi 20. Kereiakes DJ, Neutel JM, Punzi HA, et al. Efficacy and safety ofSankyo Inc., 2007 Jul olmesartan medoxomil and hydrochlorothiazide compared with

benazepril and amlodipine besylate. Am J Cardiovasc Drugs 2007;5. Olmetec Plus film-coated tablets; summary of product characteris-7 (5): 361-72tics. Gerrards Cross: Daiichi Sankyo UK Limited, 2006 Aug

21. Heagerty AM, Mallion J-M. Effect of age on olmesartan medox-6. Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a newomil plus hydrochlorothiazide [abstract no. P-72 MP-38]. J Clin

angiotensin II receptor blocker, in healthy subjects. J ClinHypertens 2007; 9 (5 Suppl. A): 34-5

Pharmacol 2001; 41 (5): 515-2722. Izzo Jr JL, Neutel JM, Silfani T, et al. Efficacy and safety of

7. Mizuno M, Sada T, Ikeda M, et al. Pharmacology of CS-866, a treating stage 2 systolic hypertension with olmesartan andnovel nonpeptide angiotensin II receptor antagonist. Eur J olmesartan/HCTZ: results of an open-label titration study. J ClinPharmacol 1995; 285 (2): 181-8 Hypertens 2007; 9 (1): 36-44

8. Laeis P, Puchler K, Kirch W. The pharmacokinetic and metabolic 23. Mallion J-M, Heagerty A, Laeis P. Systolic blood pressure reduc-profile of olmesartan medoxomil limits the risk of clinically rele- tion with olmesartan medoxomil versus nitrendipine in elderlyvant drug interaction. J Hypertens 2001; 19 Suppl. 1: 21-32 patients with isolated systolic hypertension. J Hypertens 2007; 25

(10): 2168-779. Brunner HR, Nussberger J. Relevance of clinical pharmacologicalmodels for the evaluation of therapeutic dose range of an 24. Neutel JM. Clinical studies of CS-866, the newest angiotensin IIAT1-receptor antagonist. J Hypertens 2001; 19 Suppl. 1: 15-20 receptor antagonist. Am J Cardiol 2001; 87 Suppl. 8A: 37-43

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