Drug: Benicar

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. Olmesartan medoxomil is described chemically as 2,3-dihydroxy-2-butenyl 4(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C29H30N6O6 and its structural formula is: Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.59. It is practically insoluble in water and sparingly soluble in methanol. Benicar is available for oral use as film-coated tablets containing 5 mg, 20 mg, or 40 mg of olmesartan medoxomil and the following inactive ingredients: hydroxypropyl cellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, talc, titanium dioxide, and (5 mg only) yellow iron oxide.

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Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adult Hypertension Benicar has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with Benicar was well tolerated, with an incidence of adverse reactions similar to placebo. Events generally were mild, transient and had no relationship to the dose of Benicar. The overall frequency of adverse reactions was not dose-related. Analysis of gender, age and race groups demonstrated no differences between Benicar and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with Benicar and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with Benicar and at a higher incidence versus placebo was dizziness (3% vs. 1%). The following adverse reactions occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with Benicar, but also occurred at about the same or greater incidence in patients receiving placebo: back pain, bronchitis, creatine phosphokinase increased, diarrhea, headache, hematuria, hyperglycemia, hypertriglyceridemia, influenza-like symptoms, pharyngitis, rhinitis and sinusitis. The incidence of cough was similar in placebo (0.7%) and Benicar (0.9%) patients. Other potentially important adverse reactions that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive patients treated with Benicar monotherapy in controlled or open-label trials are listed below. Body as a Whole: chest pain, peripheral edema Central and Peripheral Nervous System: vertigo Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, nausea Heart Rate and Rhythm Disorders: tachycardia Metabolic and Nutritional Disorders: hypercholesterolemia, hyperlipemia, hyperuricemia Musculoskeletal: arthralgia, arthritis, myalgia Skin and Appendages: rash Facial edema was reported in five patients receiving Benicar. Angioedema has been reported with angiotensin II antagonists. Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Benicar. Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g/dL and 0.3 volume percent, respectively) were observed. Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients (0.1%) assigned to Benicar and one patient (0.2%) assigned to placebo in clinical trials were withdrawn because of abnormal liver chemistries (transaminases or total bilirubin). Of the five Benicar patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued. Pediatric Hypertension No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to 16 years and that previously reported for adult patients. Post-Marketing Experience The following adverse reactions have been reported in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Asthenia, angioedema, anaphylactic reactions Gastrointestinal: Vomiting, sprue-like enteropathy [see WARNINGS AND PRECAUTIONS] Metabolic and Nutritional Disorders: Hyperkalemia Musculoskeletal: Rhabdomyolysis Urogenital System: Acute renal failure, increased blood creatinine levels Skin and Appendages: Alopecia, pruritus, urticaria Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, decrease in time-to-onset of microalbuminuria, but olmesartan had no beneficial effect on decline in GFR. There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18). The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months. Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics. Read the Benicar (olmesartan medoxomil) Side Effects Center for a complete guide to possible side effectsLearn More »

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Adult Hypertension Dosage must be individualized. The usual recommended starting dose of Benicar is 20 mg once daily when used as monotherapy in patients who are not volume-contracted. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Benicar may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect. Twice-daily dosing offers no advantage over the same total dose given once daily. No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked renal impairment (creatinine clearance < 40 mL/min) or with moderate to marked hepatic dysfunction [see WARNINGS AND PRECAUTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY] . For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Benicar under close medical supervision and give consideration to use of a lower starting dose [see WARNINGS AND PRECAUTIONS]. Benicar may be administered with or without food. If blood pressure is not controlled by Benicar alone, a diuretic may be added. Benicar may be administered with other antihypertensive agents. Pediatric Hypertension (6 to 16 years of age) Dosage must be individualized. For children who can swallow tablets, the usual recommended starting dose of Benicar is 10 mg once daily for patients who weigh 20 to < 35 kg (44 to 77 lb), or 20 mg once daily for patients who weigh ≥ 35 kg. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of Benicar may be increased to a maximum of 20 mg once daily for patients who weigh < 35 kg or 40 mg once daily for patients who weigh ≥ 35 kg. Children < 1 year of age must not receive Benicar for hypertension. For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below [see CLINICAL PHARMACOLOGY] . Follow the suspension preparation instructions below to administer Benicar as a suspension. Preparation of Suspension (for 200 mL of a 2 mg/mL suspension) Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty Benicar 20 mg tablets and allow to stand for a minimum of 5 minutes. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1-minute standing for four additional times. Add 100 mL of Ora-Sweet® and 50 mL of Ora-Plusto® the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return promptly to the refrigerator.

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No significant drug interactions were reported in studies in which Benicar was coadministered with digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2]. Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected. Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors. Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on Benicar and other agents that affect the RAS. Do not co-administer aliskiren with Benicar in patients with diabetes [see CONTRAINDICATIONS] . Avoid use of aliskiren with Benicar in patients with renal impairment (GFR < 60 ml/min). Colesevelam hydrochloride Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see CLINICAL PHARMACOLOGY] . Read the Benicar Drug Interactions Center for a complete guide to possible interactions Learn More »

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Benicar is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Benicar. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. It may be used alone or in combination with other antihypertensive agents.

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Do not co-administer aliskiren with Benicar in patients with diabetes [See DRUG INTERACTIONS]. Last reviewed on RxList: 6/27/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension occurs, initiate supportive treatment. The dialyzability of olmesartan is unknown.

Source: http://www.rxlist.com

Dosage Forms And Strengths
  • 5 mg yellow, round, film-coated, non-scored tablets debossed with Sankyo on one side and C12 on the other side
  • 20 mg white, round, film-coated, non-scored tablets debossed with Sankyo on one side and C14 on the other side
  • 40 mg white, oval-shaped, film-coated, non-scored tablets debossed with Sankyo on one side and C15 on the other side
Storage And Handling Benicar is supplied as yellow, round, film-coated, non-scored tablets containing 5 mg of olmesartan medoxomil, as white, round, film-coated, non-scored tablets containing 20 mg of olmesartan medoxomil, and as white, oval-shaped, film-coated, non-scored tablets containing 40 mg of olmesartan medoxomil. Tablets are debossed with Sankyo on one side and C12, C14, or C15 on the other side of the 5, 20, and 40 mg tablets, respectively. Tablets are supplied as follows:   5 mg 20 mg 40 mg Bottle of 30 NDC 65597-101-30 NDC 65597-103-30 NDC 65597-104-30 Bottle of 90 Not available NDC 65597-103-90 NDC 65597-104-90 Blister 10 cards x 10 Not available NDC 65597-103-10 NDC 65597-104-10 Blister 1 card x 30 Not available NDC 65597-103-03 NDC 65597-104-03 Carton 6 cards x 30 Not available NDC 65597-103-06 NDC 65597-104-06 Storage Store at 20-25°C (68-77°F) [see USP Controlled Room Temperature] . Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey 07054. Revised: May 2014 Last reviewed on RxList: 6/27/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Fetal toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benicar as soon as possible [see Use In Specific Populations]. Morbidity in Infants Children < 1 year of age must not receive Benicar for hypertension. Drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of immature kidneys [see Use in Specific Populations] . Hypotension In Volume-Or Salt-Depleted Patients In patients with an activated renin-angiotensin aldosterone system, such as volumeand/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with Benicar. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline [see DOSAGE AND ADMINISTRATION] . A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Benicar. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with Benicar [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY] . In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Benicar in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. Sprue-like Enteropathy Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Benicar in cases where no other etiology is identified. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m² basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil. Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested). Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. Use In Specific Populations Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Benicar as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benicar, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Benicar for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations] . Nursing Mothers It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Neonates with a history of in utero exposure to Benicar: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. The antihypertensive effects of Benicar were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see Clinical Studies] . The pharmacokinetics of Benicar were evaluated in pediatric patients 1 to 16 years of age [see CLINICAL PHARMACOLOGY] . Benicar was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults. Benicar has not been shown to be effective for hypertension in children < 6 years of age. Children < 1 year of age must not receive Benicar for hypertension [see WARNINGS AND PRECAUTIONS] . The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development. RAAS blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the reninangiotensin aldosterone system (RAAS) can alter normal renal development. Geriatric Use Of the total number of hypertensive patients receiving Benicar in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] . Hepatic Impairment Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] . Renal Impairment Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance < 20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance < 40 mL/min) [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] . Black Patients The antihypertensive effect of Benicar was smaller in black patients (usually a low-renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers. Last reviewed on RxList: 6/27/2014
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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