Olmesartan Medoxomil in Children and Adolescentswith Hypertensiony

Profile Report

Victoria J. Muir and Gillian M. Keating

Adis, Auckland, New Zealand

Hypertension is being increasingly recognized in children and

adolescents. Estimates of prevalence vary, but approximately

2–5% of children and adolescents in the US have hyperten-

sion.[2-4] Hypertension may be primary (essential) hypertension,

i.e. without an identifiable cause, or secondary hypertension,

where there is an underlying cause or disease. Secondary hy-

pertension is more common in children than it is in adults.[5]

Common causes of secondary hypertension in pediatric pa-

tients include renal parenchymal disease, renovascular disease,

and coarctation of the aorta.[6]

In adults, hypertension is a well recognized risk factor for

cardiovascular disease, including atherosclerosis, myocardial

infarction, congestive heart failure, end-stage renal disease, and

stroke.[7] In children, such cardiovascular sequelae are rarely

observed. However, hypertension in childhood has been es-

tablished as predictive of hypertension in adulthood and is

associated with evidence of end-organ damage including left

ventricular hypertrophy.[2,5,7] In addition, high blood pressure

(BP) is closely linked with obesity, and with the rise in child-

hood obesity, hypertension in children and adolescents is likely

to be of increasing concern.[5,7]

Ideally, hypertension should be managed through diet

and lifestyle changes. In particular, weight reduction is the

primary treatment for obese children and adolescents.[5] How-

ever, pharmacologic intervention is indicated in some cases,

including in symptomatic and secondary hypertension, where

there is evidence of hypertensive end-organ damage, and with

concomitant diabetes mellitus. In addition, drug therapy may

be required where diet and lifestyle modifications have failed.[5]

Several classes of antihypertensive medication are avail-

able, including diuretics, ACE inhibitors, angiotensin II re-

ceptor antagonists (angiotensin II receptor blockers [ARBs]),

b-adrenergic receptor antagonists (b-blockers), and calcium

channel antagonists.[5] In pediatric patients, the choice of the

initial agent is dependent on underlying factors and the pref-

erence of the individual physician.[5,8] For example, in pediatric

patients with diabetes and microalbuminuria or proteinuric

renal diseases, drugs acting on the renin-angiotensin-aldosterone

system, such as ACE inhibitors and ARBs, are preferred be-

cause of the ability of these agents to prevent progression to

renal failure and prevent or delay diabetic nephropathy.[5,8]

Other agents may be more appropriate in the presence of other

co-morbidities.

A step-wise algorithm approach has been suggested for the

use of antihypertensive therapy in children.[5,8] Initially, low-

dose monotherapy in conjunction with nonpharmacologic

intervention should be tried, followed by increasing the mono-

therapy dose. If BP targets are not achieved, a second med-

ication should be added, preferably with a complementary

mechanism of action. Consideration should be given to the

patient’s likelihood of compliance and the potential for adverse

events with different therapies. In particular, therapies with

recognized low adverse event profiles such as ACE inhibitors

and ARBs may be useful in the pediatric population.[8] New

antihypertensive options for pediatric patients are therefore

welcome additions to the physician’s arsenal.

Until recently, clinicians had to treat the pediatric hyper-

tensive population based on data from adults.[8] However, the

US FDAModernization Act (1997) led to several clinical trials

of antihypertensive drugs in children and adolescents, provid-

ing information on dosing and safety in this population.[8] One

such therapeutic agent is olmesartan medoxomil (Benicar�),

which has been approved for use in children and adolescents

aged 6–16 years.[9]

y Adapted and reproduced from the original article published in Drugs 2010; 70 (18): 2439-47.

ADIS PROFILE REPORTPediatr Drugs 2012; 14 (3): 209-2101174-5878/12/0003-0209/$55.55/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

Olmesartan medoxomil is an orally administered ARB, se-

lective for the angiotensin II type 1 receptor, which has estab-

lished antihypertensive efficacy and a good tolerability profile

in adults.[10] The features and properties of olmesartan me-

doxomil in children and adolescents with hypertension are

presented in table I.[9,11]

In children and adolescents with hypertension (n = 302), oralolmesartan medoxomil significantly and dose-dependently re-

duced seated systolic BP and seated dystolic BP from baseline

(the primary endpoint) in a 3-week, dose-response period in a

well designed, phase II/III, clinical trial.[12] Patients received

olmesartan medoxomil high dose (20 or 40mg once daily de-

pending on bodyweight) or low dose (2.5 or 5.0mg once daily

depending on bodyweight). The response was significant for

both cohorts, whichwere stratified by race (cohort Awasmixed

race [62% White] and cohort B was 100% Black).

In addition, BP control was maintained in olmesartan re-

cipients relative to placebo recipients in cohort A and the

combined cohort A +B, but not for patients in cohort B, duringa placebo-controlled withdrawal period of this trial.[12]

Oral olmesartan medoxomil was generally well tolerated in

children and adolescents with hypertension.[12] The majority of

adverse events were of mild to moderate intensity.

Acknowledgments and Disclosures

The full-text article[1] from which this profile report was derived was

reviewed by: F. Kaskel, Division of Pediatric Nephrology, Children’s

Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY,

USA; T. Wensel, McWhorter School of Pharmacy, Samford University,

Birmingham, AL, USA.

Themanufacturer of the agent under reviewwas offered an opportunity

to comment on the original article[1] during the peer review process.

Changes based on any comments received were made by the author on the

basis of scientific and editorial merit. The preparation of the original article

and this profile report was not supported by any external funding.

References1. Muir VJ, Keating GM. Olmesartan medoxomil in children and adolescents

with hypertension. Drugs 2010; 70 (18): 2439-47

2. Hansen ML, Gunn PW, Kaelber DC. Underdiagnosis of hypertension in

children and adolescents. JAMA 2007 Aug 22; 298 (8): 874-9

3. Ostchega Y, Carroll M, Prineas RJ, et al. Trends of elevated blood pressure

among children and adolescents: data from the National Health and Nu-

tritionExamination Survey1988-2006.Am JHypertens 2009 Jan; 22 (1): 59-67

4. Din-Dzietham R, Liu Y, Bielo MV, et al. High blood pressure trends in chil-

dren and adolescents in national surveys, 1963 to 2002. Circulation 2007 Sep

25; 116 (13): 1488-96

5. National High Blood Pressure Education Program Working Group on High

Blood Pressure in Children and Adolescents. The fourth report on the diag-

nosis, evaluation, and treatment of high blood pressure in children and

adolescents. Pediatrics 2004; 114 (2): 555-76

6. Robinson RF, Nahata MC, Batisky DL, et al. Pharmacologic treatment of

chronic pediatric hypertension. Paediatr Drugs 2005; 7 (1): 27-40

7. Flynn JT. Pediatric hypertension: recent trends and accomplishments, future

challenges. Am J Hypertens 2008; 21 (6): 605-12

8. Flynn JT, Daniels SR. Pharmacologic treatment of hypertension in children

and adolescents. J Pediatr 2006; 149 (6): 746-54

9. Daiichi Sankyo Inc. Benicar� (olmesartan medomoxil) tablets: US prescribing

information [online]. Available from URL: http://www.benicar.com/pdf/

prescribing_information.pdf [Accessed 2010 Aug 11]

10. Scott LJ, McCormack PL. Olmesartan medoxomil: a review of its use in the

management of hypertension. Drugs 2008; 68 (9): 1239-72

11. Daiichi Sankyo Inc. Olmesartan pediatric pharmacokinetic (PK) study

[ClinicalTrials.gov identifier NCT00151814]. US National Institutes of Health,

ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.

gov [Accessed 2010 Aug 10]

12. Hazan L, Hernandez Rodriguez OA, Bhorat AE, et al. A double-blind,

dose-response study of the efficacy and safety of olmesartan medoxomil in

children and adolescents with hypertension. Hypertension 2010 Jun; 55 (6):

1323-30

Correspondence: Victoria J. Muir, Adis, 41 Centorian Drive, Private Bag

65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand.

E-mail: demail@adis.co.nz

Table I. Features and properties of olmesartan medoxomil (Benicar�)[1]

Featured indication

Hypertension in children and adolescents aged 6–16 years

Mechanism of action

Angiotensin II receptor antagonist

Dosage and administration

Initial dosage Bodyweight 20 to <35 kg: 10mg/dayBodyweight ‡35 kg: 20mg/day

Maximum dosage Bodyweight 20 to <35 kg: 20mg/dayBodyweight ‡35 kg: 40mg/day

Route of administration Oral

Frequency of administration Once daily

Mean pharmacokinetic properties of olmesartan medoxomil after a

single 20 or 40mg dose (based on bodyweight) in children (aged

6–12 years) and adolescents (aged 13–16 years)

Peak plasma concentration (Cmax) 1227ng/mL (children);

895 ng/mL (adolescents)

Time to Cmax 2.8 hours (children);

2.5 hours (adolescents)

Area under the plasma

concentration-time curve

during the dosage interval

7874ng�h/mL (children);

5851ng�h/mL (adolescents)

Apparent volume of distribution 50.9 L (children); 81.3 L (adolescents)

Apparent clearance 4.3 L/h (children); 6.1 L/h (adolescents)

Elimination half-life 8.4 hours (children);

9.1 hours (adolescents)

Most common treatment-emergent adverse events

Headache, dizziness

210 Muir & Keating

Adis ª 2012 Springer International Publishing AG. All rights reserved. Pediatr Drugs 2012; 14 (3)