Olmesartan Oral
Olmesartan medoxomil is a nonpeptide, benzimidazole derivative angiotensin II type 1 (AT1) receptor antagonist (also referred to as an angiotensin II receptor blocker [ARB]).[1][2][3][16][28][31][44][139]
Brand Name: Benicar
Classes: Angiotensin II Receptor Antagonists (24:32.08), Angiotensin II Receptor Antagonists (24:08.44.08)
Table of Contents
Uses
Hypertension
Olmesartan medoxomil is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.[1][2][3][8][9][28][31][44][139][144][1200]
Angiotensin II receptor antagonists, such as olmesartan medoxomil, are considered one of several preferred antihypertensive drugs for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers, and thiazide diuretics.[501][502][503][504][1200] While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.[501][502][504][1200][1213] (See Uses: Hypertension, in Valsartan 24:32.08.)
Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as diabetes mellitus or chronic kidney disease (CKD); angiotensin II receptor antagonists also may be preferred, generally as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease, and/or following myocardial infarction (MI).[501][502][504][523][524][527][534][535][536][543][1200][1214][1215] (See Uses: Hypertension, in Valsartan 24:32.08.)
In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.[1200][1218] However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).[1200][1218] Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.[1218] Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.[1218]
Efficacy of olmesartan medoxomil in the treatment of hypertension has been established in several placebo-controlled studies of 6-12 weeks' duration in patients with mild to moderate hypertension.[1][2][3][28] In these patients, usual dosages of olmesartan medoxomil (20-40 mg administered once daily) decreased placebo-corrected systolic blood pressure by about 10-12 mm Hg and diastolic blood pressure by about 6-7 mm Hg 24 hours after dosing.[1] There was no evidence of tachyphylaxis during long-term (e.g., 1 year) olmesartan therapy, and rebound hypertension following abrupt withdrawal of the drug has not been reported.[1] Clinical studies have shown that the hypotensive effect of olmesartan in patients with mild to moderate hypertension is greater than that of placebo[1][2][3][12][28] and comparable to or greater than that of captopril, irbesartan, losartan, and valsartan.[2][8][9][28] In addition, olmesartan appears to be as effective as atenolol when used in conjunction with hydrochlorothiazide in the treatment of patients with moderate to severe hypertension.[9][28]
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.[1200] Like ACE inhibitors, angiotensin II receptor antagonists such as olmesartan may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients.[1][5] (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Valsartan 24:32.08.)
For additional information on the management of hypertension, see Uses: Hypertension, in Valsartan 24:32.08. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Diabetic Nephropathy
Both angiotensin II receptor antagonists and ACE inhibitors have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria† , and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion.[535][536][1232] The usual precautions of angiotensin II receptor antagonist or ACE inhibitor therapy in patients with substantial renal impairment should be observed. (See Renal Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) For additional information on the use of angiotensin II receptor antagonists in the treatment of diabetic nephropathy, see Uses: Diabetic Nephropathy, in Losartan 24:32.08 and in Irbesartan 24:32.08.
Heart Failure
Angiotensin II receptor antagonists have been used in the management of heart failure† .[524][528][800]
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-adrenergic blocking agents [β-blockers], aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.[524][701][703][800] Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.[524][800] Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and reduce morbidity and mortality.[524][800] In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.[800] While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction,[524] some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization.[702][800] ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [NYHA] class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.[800] However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised.[800] In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.[800] For additional information on the use of angiotensin II receptor antagonists in the management of heart failure, see Uses: Heart Failure, in Valsartan 24:32.08 and in Candesartan 24:32.08. For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.
While angiotensin II receptor antagonists are considered reasonable alternatives in patients who are unable to tolerate ACE inhibitors (e.g., because of cough or angioedema),[524][528][800] angioedema and anaphylactic reactions have been reported rarely during postmarketing experience in patients receiving olmesartan.[1] (See Sensitivity Reactions under Cautions: Warnings/Precautions.)
Dosage And Administration
Olmesartan medoxomil is administered orally without regard to meals.[1][2] Twice-daily dosing offers no therapeutic advantage over the same total dose given once daily.[1][28]
For pediatric patients unable to swallow tablets, olmesartan may be administered orally as an extemporaneously prepared suspension.[1] An extemporaneous suspension containing olmesartan medoxomil 2 mg/mL can be prepared in the following manner.[1] First, 50 mL of purified water is added to an amber polyethylene terephthalate (PET) bottle containing twenty 20-mg tablets of olmesartan medoxomil, and the contents allowed to stand for a minimum of 5 minutes.[1] The container should then be shaken for at least 1 minute and allowed to stand for at least 1 minute; this step of alternating shaking and standing should be repeated 4 additional times.[1] The concentrated suspension should then be diluted with 100 mL of syrup (Ora-Sweet®) and 50 mL of a suspending vehicle (Ora-Plus®) and the container shaken well for at least 1 minute to disperse the ingredients.[1] The suspension should be shaken well before dispensing each dose.[1] The extemporaneous suspension is stable for up to 4 weeks when stored at 2-8°C.[1] Olmesartan medoxomil tablets and the extemporaneously prepared oral suspension of the drug are bioequivalent.[1]
Dosage
Hypertension
Dosage of olmesartan medoxomil must be individualized[1] and adjusted according to blood pressure response.[29]
Olmesartan Therapy
The usual initial dosage of olmesartan medoxomil as monotherapy is 20 mg once daily in adults without depletion of intravascular volume.[1] If blood pressure response is inadequate with the initial dosage, dosage may be increased as tolerated to 40 mg daily or a diuretic may be added.[1][12] Some experts state that the usual dosage of olmesartan medoxomil in adults is 20-40 mg once daily.[1200] Olmesartan medoxomil dosages exceeding 40 mg daily do not appear to provide additional therapeutic benefit.[1][2][3] The antihypertensive effect of olmesartan medoxomil generally is evident within 2 weeks, with a maximum reduction observed after 4 weeks.[1][3]
Dosage of olmesartan medoxomil in pediatric patients is based on weight.[1][137] For pediatric patients 6-16 years of age weighing 20 to less than 35 kg, the usual initial dosage of olmesartan medoxomil is 10 mg once daily; dosage may be increased to a maximum of 20 mg once daily after 2 weeks if further reduction in blood pressure is needed.[1][137][1150] For pediatric patients 6-16 years of age weighing 35 kg or more, the recommended initial dosage of olmesartan medoxomil is 20 mg once daily; if necessary, dosage may be increased to a maximum of 40 mg once daily after 2 weeks.[1][137][1150]
Olmesartan/Amlodipine Fixed-combination Therapy
In patients who do not respond adequately to monotherapy with olmesartan medoxomil (or another angiotensin II receptor antagonist) or, alternatively, with amlodipine (or another dihydropyridine-derivative calcium-channel blocker), combined therapy with the drugs can be used to provide additional antihypertensive effects.[44] The fixed-combination preparation containing olmesartan medoxomil and amlodipine also can be used as a substitute for the individually titrated drugs.[44] The patient can be switched to the fixed-combination preparation containing the corresponding individual doses of olmesartan medoxomil and amlodipine; alternatively, the dosage of one or both components can be increased for additional antihypertensive effects.[44] If needed, dosage of the fixed combination may be increased after 2 weeks.[44] Dosage adjustments generally should involve one drug at a time, although dosages of both drugs can be increased to achieve more rapid blood pressure control.[44] Daily dosages exceeding 40 mg of olmesartan medoxomil given in fixed combination with 10 mg of amlodipine are not recommended by the manufacturer.[44]
Commercially available preparations containing olmesartan medoxomil in fixed combination with amlodipine may be used for initial treatment of hypertension in patients likely to require combined therapy with multiple antihypertensive drugs to achieve blood pressure control.[144] In such patients, therapy with the fixed-combination preparation usually should be initiated at a dosage of 20 mg of olmesartan medoxomil and 5 mg of amlodipine once daily.[144] If necessary, dosage of the fixed combination may be increased after 1-2 weeks for additional blood pressure control (but should not exceed a maximum dosage of 40 mg of olmesartan medoxomil and 10 mg of amlodipine once daily).[144] In patients whose baseline blood pressure is 160/100 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 48, 46, or 68% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 51, 60, or 85% with olmesartan medoxomil (40 mg daily) alone, amlodipine (10 mg daily) alone, or amlodipine combined with olmesartan medoxomil (at the same dosages), respectively.[144]
Olmesartan/Hydrochlorothiazide Fixed-combination Therapy
In patients who do not respond adequately to monotherapy with olmesartan medoxomil or, alternatively, with hydrochlorothiazide, combined therapy with the drugs can be used.[31] When combination therapy is necessary, the commercially available preparation containing olmesartan medoxomil in fixed combination with hydrochlorothiazide generally should not be used initially.[31] Dosage preferably should first be adjusted by titrating the dosage of each drug separately; if it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, this product may be used.[31] The manufacturer states that combined therapy with the commercially available fixed-combination preparation containing 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide can be used in patients whose blood pressure is not adequately controlled by monotherapy with olmesartan medoxomil or 25 mg daily of hydrochlorothiazide.[31] If needed, dosage of the fixed combination may be increased up to a maximum of 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide daily after 2-4 weeks.[31] Daily dosages exceeding 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide given in combination are not recommended by the manufacturer.[31]
Olmesartan/Amlodipine/Hydrochlorothiazide Fixed-combination Therapy
The fixed-combination preparation containing olmesartan medoxomil, amlodipine, and hydrochlorothiazide may be used to provide additional blood pressure control in patients who do not respond adequately to combination therapy with any 2 of the following classes of antihypertensive agents given at maximally tolerated, labeled, or usual dosages: angiotensin II receptor antagonists, calcium-channel blockers, or diuretics.[139] Patients who experience dose-limiting adverse effects of olmesartan medoxomil, amlodipine, or hydrochlorothiazide while receiving any dual combination of these drugs may be switched to a lower dosage of that drug, given as a fixed-combination preparation containing all 3 of these drugs, to achieve similar blood pressure reductions.[139] The fixed-combination preparation containing olmesartan medoxomil, amlodipine, and hydrochlorothiazide also can be used as a substitute for the individually titrated drugs.[139] If necessary, dosage of the fixed combination preparation may be increased after 2 weeks for additional blood pressure control (but should not exceed a maximum dosage of 40 mg of olmesartan medoxomil, 10 mg of amlodipine, and 25 mg of hydrochlorothiazide daily).[139] The commercially available preparation containing olmesartan medoxomil in fixed combination with amlodipine and hydrochlorothiazide should not be used for the initial management of hypertension.[139]
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.[1200] If an adequate blood pressure response is not achieved with angiotensin II receptor antagonist monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.[1200][1216] (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with olmesartan, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.[1200][1216]
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.[1200] However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.[505][506][507][508][515][523][530][1201][1207][1209][1222] While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,[501][504][536] the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.[1200] Many patients will require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.[1200][1220]
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
Special Populations
The manufacturer recommends that patients with depletion of intravascular volume be monitored closely and consideration be given to administering a lower initial dose of the drug.[1] The manufacturer states that no adjustment in initial olmesartan medoxomil dosage is necessary in geriatric patients or in those with moderate-to-severe hepatic or renal impairment (creatinine clearance less than 40 mL/minute).[1][29][31][44] However, some clinicians state that consideration should be given to administering a lower initial dose of the drug in patients with severe renal impairment (creatinine clearance less than 20 mL/minute) and recommend a maximum dosage of 20 mg once daily in such patients.[10] The appropriate dosage in patients with end-stage renal disease has not been determined.[29]
If concomitant diuretic therapy is required in patients with severe renal impairment (i.e., creatinine clearance of 30 mL/minute or less), a loop diuretic is preferred to a thiazide diuretic.[31][139] Therefore, commercially available preparations containing olmesartan medoxomil in fixed combination with hydrochlorothiazide usually are not recommended for patients with severe renal impairment.[31][139]
The amount of amlodipine in fixed-combination preparations containing olmesartan medoxomil and amlodipine exceeds the recommended initial dosage of amlodipine (2.5 mg daily) in patients 75 years of age or older and in those with hepatic impairment.[44][139]
Cautions
Contraindications
Concomitant therapy with aliskiren in patients with diabetes mellitus.[1][139] (See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)
Warnings/Precautions
Warnings
Fetal/Neonatal Morbidity and Mortality
Drugs that act on the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aliskiren) can reduce fetal renal function and increase fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters.[1][31][43][44] ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.[56][57] Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.[1] Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.[1] Olmesartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving.[1][31][42][43][44] Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.[13] For additional information on the risk during pregnancy of drugs that act on the renin-angiotensin system, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.
Sensitivity Reactions
Facial edema has occurred in patients receiving olmesartan.[1][31] Sensitivity reactions, including various anaphylactoid reactions and/or angioedema have been reported in patients receiving angiotensin II receptor antagonists.[1][2][7][14]
Extreme caution is advised in patients with history of angioedema associated with[2][7][45] or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.[15]
Other Warnings and Precautions
Infant Morbidity
Olmesartan must not be used for the treatment of hypertension in infants younger than 1 year of age because drugs that act on the renin-angiotensin-aldosterone (RAA) system can affect the development of immature kidneys.[1] (See Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
Hypotension
Because symptomatic hypotension may occur in patients with an activated RAA system (e.g., patients with volume or salt depletion secondary to salt restriction or prolonged diuretic therapy), olmesartan should be initiated in such patients under close medical supervision and consideration should be given to administering a lower initial dose of the drug.[1][31][44]
If hypotension occurs in patients receiving olmesartan, the patient should be placed in the supine position;[1][31][44] if hypotension is severe, IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered.[1][31][44] Transient hypotension is not a contraindication to additional doses of olmesartan, and therapy with the drug can be cautiously reinstated after blood pressure has been stabilized (e.g., with volume expansion).[1][31][44]
Malignancies
In July 2010, FDA initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis suggested a possible association between the use of these agents and an increased risk of cancer.[120][121][123][126] The meta-analysis, which combined cancer-related findings from 5 randomized, controlled trials in over 60,000 patients, found a modest but significant increase in the risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist (mostly telmisartan) compared with those in control groups (7.2 versus 6%, respectively; risk ratio 1.08).[120][121][123] However, because of several limitations of the study (e.g., trials included in the meta-analysis were not specifically designed to evaluate cancer outcomes, lack of individual patient data), the validity of these findings has been questioned.[129][130][131]
Subsequent studies, including a larger, more comprehensive meta-analysis conducted by FDA, have not shown an increased risk of cancer in patients receiving angiotensin II receptor antagonists.[126][127][128][129] FDA's meta-analysis, which included trial-level data from 31 randomized studies (total of approximately 156,000 patients), found no evidence of an increased risk of cancer in patients who received an angiotensin II receptor antagonist compared with those who received other treatments (placebo or active control).[126] The overall rate of new cancer occurrence was essentially the same in both groups of patients (1.82 and 1.84 cases per 100 patient-years, respectively).[126] In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups.[126] Based on these results and a review of all currently available data related to this potential safety concern, FDA has concluded that use of angiotensin II receptor antagonists is not associated with an increased risk of cancer.[126]
Renal Effects
Because the RAA system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly (e.g., oliguria, progressive azotemia, renal failure, death) in these patients during therapy with an ACE inhibitor or an angiotensin II receptor antagonist (e.g., olmesartan).[1][31][44] Renal artery stenosis also is a risk factor for renal impairment during therapy with drugs that inhibit the RAA system.[1][31][44] Although reports received to date have involved patients treated with ACE inhibitors, this adverse effect also would be expected to occur when drugs with similar pharmacologic activity (e.g., angiotensin II receptor antagonists) are used in a similar manner.[1][31][44] (See Cautions: Renal Effects, in Enalaprilat/Enalapril 24:32.04.)
Sprue-like Enteropathy
Sprue-like enteropathy, an intestinal condition characterized by severe chronic diarrhea with substantial weight loss, has been reported during postmarketing experience in patients receiving olmesartan; in some cases, intestinal biopsy revealed villous atrophy.[1][133][134][135][139] At least 23 cases of sprue-like enteropathy were identified through the FDA Adverse Event Reporting System, and an additional 22 patients were described as having a similar condition in a published case series.[133][134] Clinical manifestations developed months to years after initiation of olmesartan therapy and sometimes resulted in hospitalization.[1][133][134][135][139] In all of the reported cases, clinical improvement occurred after the drug was discontinued, and a positive rechallenge was observed in some of the patients.[133][134][135] Although the exact mechanism of this adverse effect is not known, certain findings suggest that it may be associated with a localized delayed hypersensitivity or cell-mediated immune response to the prodrug olmesartan medoxomil.[133][134][135]
If symptoms of sprue-like enteropathy develop during olmesartan therapy, the possibility of other etiologies (e.g., celiac disease) should be excluded; if no other causative factor can be identified, discontinuance of the drug should be considered.[1][133][139] Sprue-like enteropathy has not been associated with other angiotensin II receptor antagonists to date and is not considered to be a class effect of the drugs.[133]
Increased Cardiovascular Risk in Patients with Diabetes
Findings from 2 long-term, randomized, double-blind, placebo-controlled trials (the Randomized Olmesartan and Diabetes Microalbuminuria Prevention Study [ROADMAP] and the Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial [ORIENT]) prompted concerns that high-dose olmesartan may be associated with an increased risk of cardiovascular death in patients with diabetes mellitus.[124][132][140] The trials were designed to evaluate the renoprotective effects of olmesartan in patients with type 2 diabetes mellitus over a period of about 4-5 years, but unexpectedly found an increased risk of cardiovascular deaths (e.g., fatal myocardial infarction, sudden cardiac death) associated with olmesartan therapy.[124][125][132][140] However, in the ROADMAP trial, there was a trend toward a lower incidence of nonfatal myocardial infarction in the olmesartan group.[140] The US Food and Drug Administration (FDA) has reviewed the results of these studies in addition to several other studies to further evaluate this safety concern; although some studies appeared to support the initial findings of the ROADMAP trial, results were inconsistent and, in some cases, not statistically significant.[140][141][142][143] In one such study (an observational study conducted in a large [more than 300,000 patient-years of exposure] cohort of patients 65 years of age or older), an increased risk of death was observed in patients receiving olmesartan as compared with other angiotensin II receptor antagonists, but only in the subgroup of patients with diabetes mellitus who received the highest dosage of the drug (40 mg daily) for longer than 6 months; in nondiabetic patients, high-dose olmesartan was associated with a lower incidence of death as compared with other angiotensin II receptor antagonists.[140][141] FDA has concluded after considering all of the available data that the collective evidence to date is insufficient to clearly demonstrate an association between olmesartan and increased cardiovascular risk in diabetic patients.[140] FDA states that the benefits of olmesartan in hypertensive patients continue to outweigh its potential risks when used according to the manufacturer's labeling.[138][140]
Fixed-combination Preparations
When olmesartan is used in fixed combination with hydrochlorothiazide and/or amlodipine, the cautions, precautions, and contraindications associated with the concomitant agent(s) must be considered in addition to those associated with olmesartan.[31][44][139]
Specific Populations
Pregnancy
Category D.[1][139] (See Users Guide.)
Olmesartan may cause fetal and neonatal morbidity and mortality when administered to a pregnant woman.[1] Olmesartan should be discontinued as soon as possible when pregnancy is detected.[1] (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Lactation
Olmesartan is distributed into milk in rats; it is not known whether the drug is distributed into milk in humans.[1][31][44] Because of the potential for serious adverse reactions to olmesartan in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.[1][31][44]
Pediatric Use
If oliguria or hypotension occurs in neonates with a history of in utero exposure to olmesartan, blood pressure and renal function should be supported; exchange transfusions or dialysis may be required.[1] (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Safety and efficacy of olmesartan have been established in a randomized, double-blind, placebo-controlled trial in pediatric patients 6-16 years of age with hypertension.[1][136] Patients in the study were enrolled into 1 of 2 cohorts (an all-black or mixed racial cohort, 18% of whom were black).[1][136] In both groups, olmesartan (given in a weight-adjusted dosage) substantially reduced systolic and diastolic blood pressures from baseline in a dose-dependent manner;[1][136] systolic and diastolic blood pressures were, on average, 3.2 and 2.8 mm Hg lower, respectively, in patients receiving olmesartan than in those receiving placebo.[1] Similar to that observed in the adult population, smaller blood pressure reductions were observed in the black compared with the predominantly nonblack pediatric patient cohort.[1][136] The same pediatric study also included 59 patients who were 1-5 years of age; treatment with olmesartan medoxomil (0.3 mg/kg once daily) in this age group did not result in a statistically significant reduction in blood pressure compared with placebo.[1] Adverse effects reported in the pediatric patients evaluated in this study generally were similar to those observed in adults.[1]
Pharmacokinetics of olmesartan have been evaluated in pediatric patients 1-16 years of age; clearance of the drug (adjusted for body weight) in these pediatric patients was similar to that observed in adults.[1]
The manufacturer states that olmesartan has not been shown to be effective for hypertension in patients younger than 6 years of age.[1]
Olmesartan has not been evaluated in infants younger than 1 year of age; because of the possibility of abnormal kidney development, the drug must not be used in this age group.[1]
Safety and efficacy of olmesartan in fixed combination with hydrochlorothiazide and/or amlodipine in pediatric patients have not been established.[31][44][139]
For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Geriatric Use
No overall differences in safety and efficacy of olmesartan have been observed in geriatric patients 65 years of age or older relative to younger adults, but increased sensitivity to the drug cannot be ruled out.[1][44][139] In general, dosage should be selected 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 in patients with moderate hepatic impairment compared with those with normal hepatic function; however, no initial dosage adjustment is required in patients with moderate or severe hepatic impairment.[1]
Renal Impairment
Serum concentrations of olmesartan may be increased in patients with renal impairment compared with those with normal renal function; however, the manufacturer states that no initial dosage adjustment is required.[1] (See Dosage and Administration: Special Populations.)
Deterioration of renal function may occur during therapy.[1] (See Renal Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)
Black Patients
Blood pressure reduction with olmesartan may be smaller in black patients than in patients of other races.[1]
Common Adverse Effects
Adverse effects occurring in 1% or more of patients receiving olmesartan, but also occurring at about the same or greater incidence in patients receiving placebo, include back pain,[1] bronchitis,[1][2][12] diarrhea,[1] headache,[1][2][3][12] hematuria,[1] hyperglycemia,[1] hypertriglyceridemia,[1] influenza-like symptoms,[1][2][12] pharyngitis,[1] rhinitis,[1] sinusitis,[1] and upper respiratory tract infection.[2][3][12] In placebo-controlled studies, the only adverse effect that occurred in more than 1% of patients receiving olmesartan and at an incidence greater than with placebo was dizziness.[1][2][3] The incidence of adverse effects was not affected by age, gender, or race.[1]
Drug Interactions
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Olmesartan is not metabolized by the cytochrome P-450 (CYP) isoenzyme system and does not alter activity of CYP isoenzymes; pharmacokinetic interactions are unlikely with inhibitors or inducers of CYP isoenzymes or with drugs that are metabolized by these isoenzymes.[1][2]
Drugs that Block the Renin-Angiotensin System
Increased risk of renal impairment, hyperkalemia, and hypotension with concomitant use of other drugs that block the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aliskiren); when olmesartan is used concomitantly with such drugs, blood pressure, renal function, and serum concentrations of electrolytes should be monitored closely.[1] The manufacturer states that most patients do not derive additional benefit from combination therapy with 2 renin-angiotensin system inhibitors compared with monotherapy.[1] Concomitant use of olmesartan and aliskiren is contraindicated in patients with diabetes mellitus; in addition, such concomitant use should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute).[1][2][550] (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings and Precautions, in Cautions in Aliskiren Hemifumarate 24:32.40.)
Antacids
Pharmacokinetic interactions unlikely.[1][2][28]
Colesevelam Hydrochloride
Pharmacokinetic interaction (decreased systemic exposure and peak plasma concentrations of olmesartan).[1] Administration of olmesartan at least 4 hours prior to colesevelam decreases the extent of this interaction and should be considered.[1]
Digoxin
Pharmacokinetic interactions unlikely.[1][2][28]
Lithium
Increased serum lithium concentrations resulting in lithium toxicity have been reported when angiotensin II receptor antagonists are used concomitantly with lithium.[1] Serum lithium concentrations should be carefully monitored. [1]
Nonsteroidal Anti-inflammatory Agents
Potential pharmacologic interaction (attenuated hypotensive effects) when angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors.[1] Possible deterioration of renal function, including possible acute renal failure, in geriatric, volume-depleted (including those receiving concomitant diuretic therapy), or renally impaired patients; renal function should be monitored periodically in patients receiving concomitant therapy with olmesartan and an NSAIA, including selective COX-2 inhibitors.[1]
Warfarin
Pharmacokinetic and pharmacologic interactions unlikely.[1][2][28]
Description
Olmesartan medoxomil is a nonpeptide, benzimidazole-derivative angiotensin II type 1 (AT1) receptor antagonist.[1][2][3][16][28] For additional information on the pharmacology of angiotensin II receptor antagonists, see Description in Irbesartan 24:32.08 and Valsartan 24:32.08.
Olmesartan medoxomil is a prodrug that has little, if any, pharmacologic activity until hydrolyzed during absorption in the GI tract to olmesartan.[1][2] Following rapid and complete ester hydrolysis of olmesartan medoxomil to olmesartan, there is virtually no further metabolism of olmesartan.[1][2][28] Approximately 35-50% of an absorbed dose is recovered in urine while the remainder is excreted in feces via the bile.[1][2] Olmesartan is not metabolized by the cytochrome P-450 (CYP) microsomal enzyme system.[1][2]
Advice To Patients
When olmesartan is used in fixed combination with amlodipine and/or hydrochlorothiazide, importance of advising patients of important precautionary information about the concomitant agent(s).[44][139]
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.[1][31][44]
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.[1][31][44] Importance of advising women of childbearing age about the potential risks to the fetus if the drug is used during pregnancy.[1] All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.[1][31][44] (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
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.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
| 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 |
| 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 10 mg (of amlodipine) | Azor® | Daiichi Sankyo | ||
| 40 mg with Amlodipine Besylate 5 mg (of amlodipine) | Azor® | Daiichi Sankyo | ||
| 40 mg with Amlodipine Besylate 10 mg (of amlodipine) | Azor® | Daiichi Sankyo | ||
| Tablets, film-coated | 20 mg with Amlodipine Besylate 5 mg (of amlodipine) and Hydrochlorothiazide 12.5 mg | Tribenzor® | Daiichi Sankyo | |
| 20 mg with Hydrochlorothiazide 12.5 mg | Benicar® HCT | 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) and Hydrochlorothiazide 12.5 mg | Tribenzor® | Daiichi Sankyo | ||
| 40 mg with Amlodipine Besylate 10 mg (of amlodipine) and Hydrochlorothiazide 25 mg | Tribenzor® | Daiichi Sankyo | ||
| 40 mg with Hydrochlorothiazide 12.5 mg | Benicar® HCT | Daiichi Sankyo | ||
| 40 mg with Hydrochlorothiazide 25 mg | Benicar® HCT | Daiichi Sankyo |
†Use is not currently included in the labeling approved by the US Food and Drug Administration.
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