Olmesartan Medoxomil

Pronunciation

Class: Angiotensin II Receptor Antagonists
VA Class: CV805
Chemical Name: Cyclic 2,3 carbonate 2,3 - dihydroxy - 2 - butenyl - 4 - (1 - hydroxy - 1 - methylethyl) - 1 - propyl - 1 - [p - (o - 1H - tetrazol - 5 - ylphenyl)benzyl]imidazole - 5 - carboxylate
Molecular Formula: C29H30N6O6
CAS Number: 144689-63-4
Brands: Azor (combination), Benicar, Benicar HCT, Tribenzor

Warning(s)

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 31 42 43 44 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue the drug as soon as possible.1 31 43 44

Introduction

Olmesartan is an angiotensin II type 1 (AT1) receptor antagonist.1 2 3 16 28 31 44 139

Uses for Olmesartan Medoxomil

Hypertension

Olmesartan is used for management of hypertension (alone or in combination with other classes of antihypertensive agents);1 2 3 8 9 28 31 44 139 may be used in fixed combination with amlodipine and/or hydrochlorothiazide when such combined therapy is indicated.31 44 139

Slideshow: Can Prescription Drugs Lead to Weight Gain?

Angiotensin II receptor antagonists are one of several preferred initial therapies in hypertensive patients with chronic kidney disease, diabetes mellitus, or heart failure.30

Angiotensin II receptor antagonists can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.30

Diabetic Nephropathy

Angiotensin II receptor antagonists or ACE inhibitors are first-line agents in the treatment of diabetic nephropathy in patients with type 2 diabetes mellitus and hypertension.

CHF

Angiotensin II receptor antagonists are second-line agents in the treatment of CHF; should be used only in those intolerant of ACE inhibitors.

Olmesartan Medoxomil Dosage and Administration

General

Hypertension

  • Fixed-combination olmesartan/amlodipine, olmesartan/hydrochlorothiazide, and olmesartan/amlodipine/hydrochlorothiazide tablets should not be used for initial treatment of hypertension.31 44 139

Administration

Oral Administration

Administer olmesartan orally once daily without regard to meals.1 2

May administer as extemporaneously prepared oral suspension in pediatric patients unable to swallow tablets.1

Reconstitution

Preparation of extemporaneous suspension containing olmesartan medoxomil 2 mg/mL: Add 50 mL of purified water to an amber polyethylene terephthalate (PET) bottle containing twenty 20-mg tablets of olmesartan medoxomil; allow contents to stand for ≥5 minutes.1 Shake container for ≥1 minute and allow to stand for ≥1 minute; repeat this alternating shaking and standing step 4 additional times.1 Dilute concentrated suspension with 100 mL of syrup (Ora-Sweet) and 50 mL of suspending vehicle (Ora-Plus) and shake well for ≥1 minute to disperse ingredients.1 Shake suspension well before dispensing each dose.1

Dosage

Olmesartan is available as olmesartan medoxomil; dosage expressed in terms of the salt.1 31 44

Pediatric Patients

Hypertension
Oral

Pediatric patients 6–16 years of age who weigh 20 to <35 kg: Initially, 10 mg once daily; may increase to maximum of 20 mg once daily after 2 weeks.1 137

Pediatric patients 6–16 years of age who weigh ≥35 kg: Initially, 20 mg once daily; may increase to maximum of 40 mg once daily after 2 weeks.1 137

Adults

Hypertension
Olmesartan Therapy for Hypertension
Oral

Initially, olmesartan medoxomil 20 mg once daily in adults without intravascular volume depletion.1 Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients) to achieve BP control.4 30

Usual olmesartan medoxomil dosage: 20–40 mg once daily; no additional therapeutic benefit with higher dosages1 30 or with twice-daily dosing.1 28

Olmesartan/Amlodipine Fixed-combination Therapy for Hypertension
Oral

If BP is not adequately controlled by monotherapy with olmesartan (or another angiotensin II receptor antagonist) or amlodipine (or another dihydropyridine-derivative calcium-channel blocker), can switch to the fixed-combination preparation containing olmesartan medoxomil 20 mg and amlodipine 5 or 10 mg or, alternatively, olmesartan medoxomil 40 mg and amlodipine 5 or 10 mg.44

Can use the fixed combination as a substitute for the individually titrated drugs.44 Can switch to the fixed-combination preparation containing the corresponding individual doses of olmesartan and amlodipine; alternatively, can increase the dosage of one or both components for additional antihypertensive effects.44

Adjust dosage of olmesartan/amlodipine fixed combination, up to a maximum dosage of olmesartan medoxomil 40 mg and amlodipine 10 mg daily, according to patient’s response after ≥2 weeks at the current dosage.44

Olmesartan/Hydrochlorothiazide Fixed-combination Therapy for Hypertension
Oral

If BP is not adequately controlled by monotherapy with olmesartan or hydrochlorothiazide, can switch to fixed-combination olmesartan/hydrochlorothiazide tablets.31 In patients already receiving olmesartan, initiate hydrochlorothiazide at dosage of 12.5 mg once daily; in those receiving hydrochlorothiazide, consider reducing hydrochlorothiazide dosage to 12.5 mg and initiate olmesartan medoxomil at dosage of 20 mg once daily.31 Increase dosages to olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg once daily, if needed, to control BP.31

If BP is controlled with olmesartan and hydrochlorothiazide (administered separately), can switch to the fixed-combination preparation containing the corresponding individual doses for convenience.31

Adjust dosage of olmesartan/hydrochlorothiazide fixed combination according to patient’s response after 2–4 weeks at the current dosage.31

Olmesartan/Amlodipine/Hydrochlorothiazide Fixed-combination Therapy for Hypertension
Oral

Can switch to fixed-combination olmesartan/amlodipine/hydrochlorothiazide tablets if BP is not adequately controlled with maximally tolerated, labeled, or usual dosages of any 2 of the following drug classes: angiotensin II receptor antagonists, calcium-channel blockers, or diuretics.139

In patients who experience dose-limiting adverse effects to olmesartan, amlodipine, or hydrochlorothiazide while receiving any dual combination of these drugs, may switch to the triple fixed-combination preparation containing a lower dose of that component.139

Can use the fixed combination as a substitute for the individually titrated drugs.139

May increase dosage of the fixed combination after 2 weeks if additional BP control is needed (up to maximum of olmesartan medoxomil 40 mg, amlodipine 10 mg, and hydrochlorothiazide 25 mg daily).139

Special Populations

The following information addresses dosage of olmesartan in special populations. Dosages of drugs administered in fixed combination with olmesartan also may require adjustment in certain patient populations; the need for such dosage adjustments must be considered in the context of cautions, precautions, and contraindications specific to that population and drug.31 44

Hepatic Impairment

No adjustment of initial olmesartan dosage necessary in patients with moderate to severe hepatic impairment.1 31

Amount of amlodipine in olmesartan/amlodipine fixed combinations exceeds the recommended initial dosage of amlodipine (2.5 mg daily) in patients with hepatic impairment.44 139

Renal Impairment

Manufacturer states that no adjustment of initial olmesartan dosage is necessary in patients with moderate to severe renal impairment (Clcr <40 mL/minute).1 31 44 However, some clinicians recommend lower initial dosage in patients with Clcr <20 mL/minute, with maximum dosage of 20 mg once daily in such patients.10

Dosage of olmesartan in patients with end-stage renal disease not determined.29

Fixed combinations containing hydrochlorothiazide are not recommended in patients with severe renal impairment (Clcr ≤30 mL/minute).31 139 Loop diuretics are preferred to thiazides in these patients.31 139

Geriatric Patients

No adjustment of initial olmesartan dosage is necessary.1 31

Amount of amlodipine in olmesartan/amlodipine fixed combinations exceeds the recommended initial dosage of amlodipine (2.5 mg daily) in patients ≥75 years of age.44 139

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of olmesartan therapy or initiate therapy under close medical supervision using lower initial dosage.1 31 44

Cautions for Olmesartan Medoxomil

Contraindications

  • Known hypersensitivity to olmesartan or any ingredient in the formulation.31

  • When olmesartan is used in fixed combination with hydrochlorothiazide and/or amlodipine, consider contraindications associated with the concomitant agent(s).31 41 139

  • Concomitant use of aliskiren and olmesartan in patients with diabetes mellitus.1 139

Warnings/Precautions

Warnings

Cardiovascular Effects

Possible symptomatic hypotension with olmesartan, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics).1 31 44 (See Volume- and/or Salt-Depleted Patients under Dosage and Administration.)

Transient hypotension is not a contraindication to additional doses; may reinstate olmesartan therapy cautiously after BP is stabilized (e.g., with volume expansion).1 31 44

Results of 2 randomized controlled trials in patients with type 2 diabetes mellitus showed an increased risk of death from cardiovascular causes (e.g., MI, sudden death, stroke) in patients receiving olmesartan compared with placebo.124 Following review of the data, FDA has concluded that benefits of olmesartan in hypertensive patients continue to outweigh potential risks.124 138

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when drugs that act on the renin-angiotensin system (e.g., angiotensin II receptor antagonists, ACE inhibitors, aliskiren) are used during the second and third trimesters of pregnancy.1 4 31 43 44 (See Boxed Warning.) Most epidemiologic studies assessing fetal abnormalities following exposure to antihypertensive agents during the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.1

Discontinue olmesartan as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.1 31 42 43 44 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.13

Malignancies

In July 2010, FDA initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis found a modest but statistically significant increase in risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist compared with control.120 121 123 126 However, subsequent studies, including a larger meta-analysis conducted by FDA, have not shown such risk.126 127 128 129 Based on currently available data, FDA has concluded that angiotensin II receptor antagonists do not increase the risk of cancer.126

Sprue-like Enteropathy

Risk of sprue-like enteropathy, an intestinal condition characterized by severe chronic diarrhea with substantial weight loss; intestinal biopsy may reveal villous atrophy.1 133 134 135 139 Can occur months to years after initiating olmesartan.1 133 134 139 Clinical improvement is expected after the drug is discontinued.133 134 135

Not associated with other angiotensin II receptor antagonists to date; not considered to be a class effect of the drugs.133

If symptoms of sprue-like enteropathy develop, exclude other etiologies (e.g., celiac disease); if no other causative factor can be identified, consider drug discontinuance.1 133 139

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible with angiotensin II receptor antagonists;1 2 7 14 extreme caution in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.7 15 45

General Precautions

Use of Fixed Combinations

When olmesartan is used in fixed combination with amlodipine and/or hydrochlorothiazide, consider cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).31 44 139 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.31 44 139

Renal Effects

Possible oliguria, progressive azotemia and, rarely, acute renal failure and/or death in patients with severe CHF.1 31 44

Increases in BUN and Scr possible in patients with unilateral or bilateral renal artery stenosis.1 31 44

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Olmesartan is distributed into milk in rats; not known whether olmesartan is distributed into human milk.1 31 44 Discontinue nursing or the drug.1 31 44

Pediatric Use

Safety and efficacy of olmesartan in fixed combination with amlodipine and/or hydrochlorothiazide not established.31 44 139

Safety and efficacy of olmesartan established in pediatric patients 6–16 years of age with hypertension.1 136 Although evaluated in pediatric patients 1–5 years of age, statistically significant reductions in BP were not observed.1

Not evaluated in infants <1 year of age; because of the possibility of abnormal kidney development, do not use in this age group.1 If oliguria or hypotension occurs in a neonate with a history of in utero exposure to olmesartan, support BP and renal function; exchange transfusions or dialysis may be required.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Adverse effects in pediatric patients appear to be similar to those observed in adults.1

Geriatric Use

No overall differences in safety or efficacy of olmesartan alone or in fixed combination with amlodipine and/or hydrochlorothiazide relative to younger adults, but increased sensitivity cannot be ruled out.1 44 139 In general, select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.31

Hepatic Impairment

Systemic exposure to olmesartan may be increased.1 31 44 (See Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Systemic exposure to olmesartan may be increased.1 31 44 (See Absorption: Special Populations, under Pharmacokinetics and also see Renal Impairment under Dosage and Administration.)

Use of olmesartan in fixed combination with hydrochlorothiazide is not recommended in patients with Clcr ≤30 mL/minute.31 139

Deterioration of renal function may occur.1 31 44 (See Renal Effects under Cautions.)

Blacks

BP reduction with olmesartan may be smaller in black patients compared with nonblack patients; use in combination with a diuretic.1 5 30 31

Common Adverse Effects

Olmesartan: Dizziness,1 2 3 back pain,1 bronchitis,1 2 12 diarrhea1 , headache,1 2 3 12 hematuria,1 hyperglycemia,1 hypertriglyceridemia,1 influenza-like symptoms,1 2 12 pharyngitis,1 rhinitis,1 sinusitis,1 upper respiratory tract infection.2 3 12

Interactions for Olmesartan Medoxomil

The following information addresses potential interactions with olmesartan. When olmesartan is used in fixed combination with hydrochlorothiazide or amlodipine, consider interactions associated with the concomitant agent.31 44

Olmesartan is not metabolized by and does not inhibit or induce CYP isoenzymes.1 2

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Increased risk of renal impairment, hyperkalemia, and hypotension1

Closely monitor BP, renal function, and serum electrolytes1

Aliskiren

Increased risk of renal impairment, hyperkalemia, and hypotension1

Closely monitor BP, renal function, and serum electrolytes1

Concomitant use contraindicated in patients with diabetes mellitus1

Avoid concomitant use in patients with GFR <60 mL/minute1

Antacids

Pharmacokinetic interactions unlikely1 2 28

Colesevelam

Decreased AUC and peak plasma concentrations of olmesartan1

Consider administering olmesartan at least 4 hours before colesevelam1

Digoxin

Pharmacokinetic interactions unlikely1 2 28

Hydrochlorothiazide

Pharmacokinetic interactions unlikely1 2 28

Additive hypotensive effects1 31

NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors

Possible deterioration of renal function, including possible acute renal failure, in geriatric, volume-depleted, or renally impaired patients1

Possible decreased hypotensive effect1

Monitor renal function periodically1

Warfarin

Pharmacokinetic interaction unlikely1 2 28

Olmesartan Medoxomil Pharmacokinetics

Absorption

Bioavailability

Olmesartan medoxomil (prodrug) is rapidly and completely hydrolyzed to olmesartan during absorption in the GI tract.1 31 44

Absolute bioavailability of olmesartan is about 26%.1 31 44 Bioavailability of the extemporaneously prepared suspension (see Reconstitution under Dosage and Administration) is similar to that of olmesartan tablets.1

Peak plasma olmesartan concentration generally reached 1–2 hours following oral administration.1 31 44

Onset

Antihypertensive effect of olmesartan is evident within 2 weeks, with maximum BP reduction after 4–6 weeks.1 3

Food

Food does not affect bioavailability of olmesartan.1 31 44

Special Populations

In patients with moderate hepatic impairment, peak plasma concentration of olmesartan is increased; AUC increased by about 60%.1 31 44

In patients with severe renal impairment (Clcr <20 mL/minute), plasma concentrations and AUC of olmesartan are increased.1 31 44 After repeated dosing, AUC values are approximately triple those in patients with normal renal function.1 31 44

In women, peak plasma concentration and AUC of olmesartan are about 10–15% higher than values in men.1 31 44

Distribution

Extent

Olmesartan crosses the placenta and is distributed in the fetus in animals.1 31 44

Olmesartan crosses the blood-brain barrier poorly, if at all, in animals.1 31 44

Olmesartan is distributed into milk in rats; not known whether olmesartan is distributed into human milk.1 31 44

Plasma Protein Binding

Olmesartan: 99%.1 31 44

Elimination

Metabolism

Olmesartan medoxomil undergoes rapid and complete ester hydrolysis to olmesartan.1 2 28 31 44 Virtually no further metabolism of olmesartan occurs; not metabolized by CYP isoenzymes.1 2 28 31 44

Elimination Route

Olmesartan is eliminated mainly in urine (35–50%) and feces (via bile).1 2 31 44

Half-life

Biphasic; terminal half-life of olmesartan is approximately 13 hours.1 31 44

Special Populations

Clearance (adjusted for body weight) in pediatric patients 1–16 years of age is similar to that in adults.1

In geriatric patients, renal clearance of olmesartan is decreased by approximately 30%.1 31 44

Stability

Storage

Oral

Extemporaneous Suspension

2-mg/mL preparation of olmesartan medoxomil in a mixture of syrup (Ora-Sweet) and suspending vehicle (Ora-Plus) (see Reconstitution under Dosage and Administration): Up to 4 weeks at 2–8°C.1

Tablets

Olmesartan or olmesartan/hydrochlorothiazide fixed combination: 20–25°C.1 31

Olmesartan/amlodipine or olmesartan/amlodipine/hydrochlorothiazide fixed combination: 25ºC (may be exposed to 15–30ºC).44 139

Actions

  • Olmesartan medoxomil (prodrug) has little pharmacologic activity until hydrolyzed to olmesartan during absorption.1 2 31 44

  • Olmesartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.1 31 44

  • Olmesartan does not interfere with response to bradykinins and substance P.1 31 44

  • Olmesartan does not share the ACE inhibitor common adverse effect of dry cough.1

Advice to Patients

  • When olmesartan is used in fixed combination with hydrochlorothiazide and/or amlodipine, importance of advising patients of important precautionary information about the concomitant agent(s).31 44 139

  • Importance of advising women of childbearing age about the risks of use during pregnancy.1 31 42 43 44

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 31 44

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 31 44

  • Importance of informing patients of other important precautionary information.1 31 44 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Olmesartan Medoxomil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg

Benicar

Daiichi Sankyo

20 mg

Benicar

Daiichi Sankyo

40 mg

Benicar

Daiichi Sankyo

Olmesartan Medoxomil Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

20 mg with Amlodipine Besylate 5 mg (of amlodipine)

Azor

Daiichi Sankyo

20 mg with Amlodipine Besylate 5 mg (of amlodipine) and Hydrochlorothiazide 12.5 mg

Tribenzor

Daiichi Sankyo

20 mg with Amlodipine Besylate 10 mg (of amlodipine)

Azor

Daiichi Sankyo

40 mg with Amlodipine Besylate 5 mg (of amlodipine)

Azor

Daiichi Sankyo

40 mg with Amlodipine Besylate 5 mg (of amlodipine) and Hydrochlorothiazide 12.5 mg

Tribenzor

Daiichi Sankyo

40 mg with Amlodipine Besylate 5 mg (of amlodipine) and Hydrochlorothiazide 25 mg

Tribenzor

Daiichi Sankyo

40 mg with Amlodipine Besylate 10 mg (of amlodipine)

Azor

Daiichi Sankyo

40 mg with Amlodipine Besylate 10 mg (of amlodipine) and Hydrochlorothiazide 12.5 mg

Tribenzor

Daiichi Sankyo

40 mg with Amlodipine Besylate 10 mg (of amlodipine) and Hydrochlorothiazide 25 mg

Tribenzor

Daiichi Sankyo

Tablets, film-coated

20 mg with Hydrochlorothiazide 12.5 mg

Benicar HCT

Daiichi Sankyo

40 mg with Hydrochlorothiazide 12.5 mg

Benicar HCT

Daiichi Sankyo

40 mg with Hydrochlorothiazide 25 mg

Benicar HCT

Daiichi Sankyo

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 12/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Azor 10-20MG Tablets (SANKYO): 30/$117.76 or 90/$340.05

Azor 10-40MG Tablets (SANKYO): 90/$442.99 or 270/$1,299.02

Azor 5-20MG Tablets (SANKYO): 30/$121.06 or 90/$349.97

Azor 5-40MG Tablets (SANKYO): 30/$154.35 or 90/$450.93

Benicar 20MG Tablets (SANKYO): 30/$95.99 or 90/$276.96

Benicar 40MG Tablets (SANKYO): 30/$134.99 or 90/$387.95

Benicar 5MG Tablets (SANKYO): 30/$78.99 or 90/$225.97

Benicar HCT 20-12.5MG Tablets (SANKYO): 30/$96.99 or 90/$275.96

Benicar HCT 40-12.5MG Tablets (SANKYO): 30/$135.99 or 90/$391.96

Benicar HCT 40-25MG Tablets (SANKYO): 30/$135.99 or 90/$376.98

Tribenzor 20-5-12.5MG Tablets (SANKYO): 30/$119.99 or 90/$335.95

Tribenzor 40-10-25MG Tablets (SANKYO): 30/$152.14 or 90/$433.29

Tribenzor 40-5-12.5MG Tablets (SANKYO): 30/$152.14 or 60/$304.27

Tribenzor 40-5-25MG Tablets (SANKYO): 30/$154.49 or 90/$444.01

AHFS DI Essentials. © Copyright, 2004-2013, Selected Revisions November 5, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Daiichi Sankyo, Inc. Benicar (olmesartan medoxomil) tablets prescribing information. Parsippany, NJ; 2013 Jul.

2. Song JC, White CM. Olmesartan medoxomil (CS-866): an angiotensin II receptor blocker for treatment of hypertension. Formulary. 2001; 36:487-99.

3. Neutel JM. Clinical studies of CS-866, the newest angiotensin II receptor antagonist. Am J Cardiol. 2001; 87(Suppl):37-43C.

4. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98?4080.)

5. Anon. Drugs for hypertension. Med Lett Drugs Ther. 2001; 43:17-22. [PubMed 11242494]

6. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol. 1999; 83:9-38A.

7. Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother. 2000; 34:526-8. [IDIS 443518] [PubMed 10772441]

8. Oparil S, Williams D, Chrysant SG et al. Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. J Clin Hypertens (Greenwich). 2001; 3:283-91, 318. [PubMed 11588406]

9. Ball KJ, Williams PA, Stumpe KO. Relative efficacy of an angiotensin II antagonist compared with other antihypertensive agents. Olmesartan medoxomil versus antihypertensives. J Hypertens. 2001; 19(Suppl 1):S49-56.

10. von Bergmann K, Laeis P, Puchler K et al. Olmesartan medoxomil: influence of age, renal and hepatic function on the pharmacokinetics of olmesartan medoxomil. J Hypertens. 2001; 19(Suppl 1):S33-40.

11. Walser M. Angiotensin-Receptor Blockers, Type 2 Diabetes, and Renoprotection. N Engl J Med. 2002; 346:706.

12. Puchler K, Laeis P, Stumpe KO. Blood pressure response, but not adverse event incidence, correlates with dose of angiotensin II antagonist. J Hypertens. 2001; 19(Suppl 1):S41-8.

13. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull. 1992; 22:2.

14. Mazzolai L, Burnier M. Comparative safety and tolerability of angiotensin II receptor antagonists. Drug Safety. 1999; 21:23-33. [PubMed 10433351]

15. Kirk JK. Therapy with angiotensin II receptor antagonists. Clin Geriatrics. From the MultiMedia Health Care website.

16. Sankyo Pharma, New York, NY: Personal communication.

17. AstraZeneca, Wayne, PA: personal communication on Candesartan 24:32.08.

18. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002; 25(Suppl 1):S71-73.

19. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345:861-9. [IDIS 469607] [PubMed 11565518]

20. Lewis EJ, Hunsicker LG, Claarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345:851-60. [IDIS 469606] [PubMed 11565517]

21. DA, Bakris GL. Type 2 diabetes: RENAAL and IDNT-the emergence of new treatment options. J Clin Hypertens (Greenwich). 2002; 4:52-7. [PubMed 11821641]

22. Parving HH, Brenner BM, Cooper ME et al. [Effect of losartan on renal and cardiovascular complications of patients with type 2 diabetes and nephropathy.] (Danish; with English abstract.) Ugeskr Laeger. 2001; 163:5514-9.

23. Weekers L, Krzesinski JM. [Clinical study of the month. Nephroprotective role of angiotensin II receptor antagonists in type 2 diabetes: results of IDNT and RENAAL trials.] (French with English abstract.) Rev Med Liege. 2001; 56:723-6.

24. Parving HH, Lehnert H, Brochner-Mortensen J et al and the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001; 345:870-8. [IDIS 469608] [PubMed 11565519]

25. Walser M. Angiotensin-Receptor Blockers, Type 2 Diabetes, and Renoprotection. N Engl J Med. 2002; 346:706.

26. Unger T. Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different? Am J Cardiol. 1999; 84:9-15S.

27. Martineau P, Goulet J. New competition in the realm of renin-angiotensin axis inhibition; the angiotensin II receptor antagonists in congestive heart failure. Ann Pharmacother. 2001; 35:71-84. [IDIS 457649] [PubMed 11197588]

28. Warner GT, Jarvis B. Olmesartan medoxomil. Drugs. 2002; 62:1345-53. [PubMed 12076183]

29. Sankyo Pharma, New York, NY: Personal communication.

30. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (Also published in JAMA. 2003; 289.

31. Daiichi Sankyo, Inc. Benicar HCT (olmesartan medoxomil and hydrochlorothiazide) tablets prescribing information. Parsippany, NJ; 2007 Jul.

32. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med. 1993; 153:154-83. [IDIS 309043] [PubMed 8422206]

33. Joint National Committee on Detection, Evaluation. The 1984 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1984; 144:1045-57. [IDIS 184763] [PubMed 6143542]

34. Joint National Committee on Detection, Evaluation. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988; 148:1023-38. [IDIS 242588] [PubMed 3365073]

35. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA. 2002; 288:3039-60. [IDIS 490723] [PubMed 12479770]

36. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981-97. [IDIS 490721] [PubMed 12479763]

37. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

38. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

39. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. [IDIS 452007] [PubMed 10977801]

40. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003; 26(Suppl 1):S80-2.

41. Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension. 2003; 21:1011-53.

42. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006; 354:2443-51. [PubMed 16760444]

43. Food and Drug Administration. FDA public health advisory: angiotensin-converting enzyme inhibitor (ACE inhibitor) drugs and pregnancy. From FDA website.

44. Daiichi Sankyo, Inc. Azor (amlodipine and olmesartan medoxomil) tablets prescribing information. Parsippany, NJ; 2008 Oct.

45. Howes LG, Tran D. Can angiotensin receptor antagonists be used safely in patients with previous ACE inhibitor-induced angioedema? Drug Saf. 2002; 25:73-6.

120. Food and Drug Administration. FDA drug safety communication: ongoing safety review of the angiotensin receptor blockers and cancer. Rockville, MD; 2010 Jul 15. From FDA website ().

121. Sipahi I, Debanne SM, Rowland DY et al. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010; 11:627-36. [PubMed 20542468]

122. Nissen SE. Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Lancet Oncol. 2010; 11:605-6. [PubMed 20542469]

123. Sica DA. Angiotensin receptor blockers and the risk of malignancy: a note of caution. Drug Saf. 2010; 33:709-12. [PubMed 20701404]

124. Food and Drug Administration. FDA drug safety communication: ongoing safety review of Benicar and cardiovascular events. Rockville, MD; 2010 June 11. From FDA website ().

125. Imai E, Ito S, Haneda M et al. Olmesartan reducing incidence of endstage renal disease in diabetic nephropathy trial (ORIENT): rationale and study design. Hypertens Res. 2006; 29:703-9. [PubMed 17249526]

126. Food and Drug Administration. FDA drug safety communication: No increase in risk of cancer with certain blood pressure drugs-angiotensin receptor blockers (ARBs). Rockville, MD; 2011 Jun 2. Available from FDA website. Accessed 2011 Jun 15.

127. Bangalore S, Kumar S, Kjeldsen SE et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol. 2011; 12:65-82. [PubMed 21123111]

128. ARB Trialists Collaboration. Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138,769 individuals. J Hypertens. 2011; 29:623-35. [PubMed 21358417]

129. Pasternak B, Svanström H, Callréus T et al. Use of angiotensin receptor blockers and the risk of cancer. Circulation. 2011; 123:1729-36. [PubMed 21482967]

130. Volpe M, Morganti A. 2010 Position Paper of the Italian Society of Hypertension (SIIA): Angiotensin Receptor Blockers and Risk of Cancer. High Blood Press Cardiovasc Prev. 2011; 18:37-40. [PubMed 21612311]

131. Siragy HM. A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors. Vasc Health Risk Manag. 2011; 7:297-313. [PubMed 21633727]

132. Haller H, Viberti GC, Mimran A et al. Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study. J Hypertens. 2006; 24:403-8. [PubMed 16508590]

133. Food and Drug Administration. FDA drug safety communication: FDA approves label changes to include intestinal problems (sprue-like enteropathy) linked to blood pressure medicine olmesartan medoxomil. Rockville, MD; 2013 July 3. From FDA website.

134. Rubio-Tapia A, Herman ML, Ludvigsson JF et al. Severe spruelike enteropathy associated with olmesartan. Mayo Clin Proc. 2012; 87:732-8. [PubMed 22728033]

135. Dreifuss SE, Tomizawa Y, Farber NJ et al. Spruelike enteropathy associated with olmesartan: an unusual case of severe diarrhea. Case Rep Gastrointest Med. 2013; 2013:618071. [PubMed 23573432]

136. Hazan L, Hernández 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; 55:1323-30. [PubMed 20385971]

137. Salazar DE, Song SH, Shi J et al. The use of modeling and simulation to guide clinical development of olmesartan medoxomil in pediatric subjects. Clin Pharmacol Ther. 2012; 91:250-6. [PubMed 22205195]

138. Food and Drug Administration. FDA drug safety communication: Safety review update of Benicar (olmesartan) and cardiovascular events. Rockville, MD; 2011 April 14. From FDA website.

139. Daiichi Sankyo, Inc. Tribenzor (olmesartan medoxomil, amlodipine, hydrochlorothiazide) tablets prescribing information. Parsippany, NJ; 2013 Jul.

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