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olmesartan medoxomil and hydrochlorothiazide
Overview
What is BENICAR HCT?
BENICAR HCT (olmesartan medoxomil-hydrochlorothiazide) is a combination of an angiotensin II receptor antagonist (AT subtype), olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide (HCTZ).
Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
Olmesartan medoxomil is 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[-(-1-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.
Its empirical formula is CHNO and its structural formula is:
Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.6. It is practically insoluble in water and sparingly soluble in methanol.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2-1,2,4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is CHClNOS and its structural formula is:
Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.7. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.
BENICAR HCT is available for oral administration in tablets containing 20 mg or 40 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, or 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide. Inactive ingredients include: hydroxypropylcellulose, hypromellose, lactose, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide and yellow iron oxide.
What does BENICAR HCT look like?
What are the available doses of BENICAR HCT?
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What should I talk to my health care provider before I take BENICAR HCT?
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How should I use BENICAR HCT?
The usual recommended starting dose of BENICAR (olmesartan medoxomil) 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 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 <40mL/min) or with moderate to marked hepatic dysfunction (see ). For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), BENICAR should be initiated under close medical supervision and consideration should be given to use of a lower starting dose (see ).
Hydrochlorothiazide is effective in doses between 12.5 mg and 50 mg once daily.
The side effects (see ) of BENICAR are generally rare and independent of dose; those of hydrochlorothiazide are most typically dose-dependent (primarily hypokalemia). Some dose-independent phenomena (e.g., pancreatitis) do occur with hydrochlorothiazide. Therapy with any combination of olmesartan medoxomil and hydrochlorothiazide will be associated with both sets of dose-independent side effects.
To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
What interacts with BENICAR HCT?
BENICAR HCT is contraindicated in patients who are hypersensitive to any component of this product.
Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with BENICAR HCT in patients with diabetes.
What are the warnings of BENICAR HCT?
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 HCT 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 HCT , 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 HCT for hypotension, oliguria, and hyperkalemia(see
).
There is no clinical experience with the use of BENICAR HCT in pregnant women. No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the maximum recommended human dose [MRHD] on a mg/m basis) or pregnant rats at oral doses up to 1625 mg/kg/day (280 times the MRHD on a mg/m basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the dams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats, 162.5 mg/kg/day, is about 28 times, on a mg/m basis, the MRHD of BENICAR HCT (40 mg olmesartan medoxomil /25 mg hydrochlorothiazide/day).
Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.
Hypotension in Volume- or Salt-Depleted Patients
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients ( those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with BENICAR HCT, as with any angiotensin receptor blocker. Treatment should start under close medical supervision. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline (See ). When electrolyte and fluid imbalances have been corrected, therapy usually can be continued without difficulty. A transient hypotensive response is not a contraindication to further treatment.
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 HCTwhere no other etiology is identified.
Hydrochlorothiazide
Hepatic Impairment
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Hypersensitivity Reaction
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Acute Myopia and Secondary Angle-Closure Glaucoma
Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
What are the precautions of BENICAR HCT?
General
Olmesartan medoxomil-hydrochlorothiazide
In a double-blind clinical trial of various doses of olmesartan medoxomil and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.4 mEq/L) was 2.1%; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%. In this trial, no patient discontinued due to increases or decreases in serum potassium.
Hydrochlorothiazide
Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis and hypokalemia. Serum and urine electrolyte determinations are important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
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 olmesartan medoxomil. 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 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 olmesartan medoxomil. (See , )
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 olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Information for Patients
Pregnancy:
Symptomatic Hypotension:
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea or vomiting can lead to an excessive fall in blood pressure, with the same consequences of light-headedness and possible syncope.
Drug Interactions
Olmesartan medoxomil
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with hydrochlorothiazide, digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)/Mg(OH)]. 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.
Dual Blockade of the Renin- Angiotensin System (RAS)
Do not co-administer aliskiren with Benicar HCT in patients with diabetes (see ). Avoid use of aliskiren with Benicar HCT in patients with renal impairment (GFR <60ml/min).
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.
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 ).
Lithium
Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of olmesartan or thiazide diuretics. Monitor lithium levels in patients receiving BENICAR HCT and lithium.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, Barbiturates, Or Narcotics
Antidiabetic Drugs (oral agents and insulin)
Other Antihypertensive Drugs
Cholestyramine and Colestipol Resins
Corticosteroids, ACTH
Pressor Amines (e.g. Norepinephrine)
Skeletal Muscle Relaxants, Non depolarizing (e.g. Tubocurarine)
Non-steroidal Anti-inflammatory Drugs
Carcinogenesis, Mutagenesis, Impairment of Fertility
Olmesartan medoxomil-hydrochlorothiazide
No carcinogenicity studies with olmesartan medoxomil-hydrochlorothiazide have been conducted.
Olmesartan medoxomil-hydrochlorothiazide in a ratio of 20:12.5 was negative in the /mammalian microsome reverse mutation test up to the maximum recommended plate concentration for the standard assays. Olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20:12.5 and 10:12.5, for clastogenic activity in the Chinese hamster lung (CHL) chromosomal aberration assay. A positive response was seen for each component and combination ratio. However, no synergism in clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio. Olmesartan medoxomil-hydrochlorothiazide in a ratio of 20:12.5, administered orally, tested negative in the mouse bone marrow erythrocyte micronucleus assay at administered doses of up to 3144 mg/kg.
No studies of impairment of fertility with olmesartan medoxomil-hydrochlorothiazide have been conducted.
Olmesartan medoxomil
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/m 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 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 (Chinese hamster lung) and both tested positive for thymidine kinase mutations in the mouse lymphoma assay. Olmesartan medoxomil tested negative 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.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in the Ames mutagenicity assay of strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538, or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. It was also not genotoxic in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, or the sex-linked recessive lethal trait gene. Positive test results were obtained in the CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay and the non-disjunction assay.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation.
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.
Thiazides appear in human milk. 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 HCT:
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Clinical studies of BENICAR HCT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.
Olmesartan and hydrochlorothiazide are substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
What are the side effects of BENICAR HCT?
Sorry No records found
What should I look out for while using BENICAR HCT?
BENICAR HCT is contraindicated in patients who are hypersensitive to any component of this product.
Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with BENICAR HCT in patients with diabetes.
What might happen if I take too much BENICAR HCT?
Olmesartan medoxomil
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 should occur, supportive treatment should be initiated. The dialyzability of olmesartan is unknown.
No lethality was observed in acute toxicity studies in mice and rats given single oral doses up to 2000 mg/kg olmesartan medoxomil. The minimum lethal oral dose of olmesartan medoxomil in dogs was greater than 1500 mg/kg.
Hydrochlorothiazide
The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.
How should I store and handle BENICAR HCT?
StorageStore at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] and protect from light.StorageStore at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] and protect from light.BENICAR HCT is supplied as 20 mg/12.5 mg: reddish-yellow, circular, film-coated tablets, approximately 8.5 mm in diameter, with "Sankyo" debossed on one side and “C22” on the other side. Each tablet contains 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/12.5 mg: reddish-yellow, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and “C23” on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/25 mg: pink, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and "C25" on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide.Tablets are supplied as follows:BENICAR HCT is supplied as 20 mg/12.5 mg: reddish-yellow, circular, film-coated tablets, approximately 8.5 mm in diameter, with "Sankyo" debossed on one side and “C22” on the other side. Each tablet contains 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/12.5 mg: reddish-yellow, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and “C23” on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/25 mg: pink, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and "C25" on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide.Tablets are supplied as follows:BENICAR HCT is supplied as 20 mg/12.5 mg: reddish-yellow, circular, film-coated tablets, approximately 8.5 mm in diameter, with "Sankyo" debossed on one side and “C22” on the other side. Each tablet contains 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/12.5 mg: reddish-yellow, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and “C23” on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/25 mg: pink, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and "C25" on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide.Tablets are supplied as follows:BENICAR HCT is supplied as 20 mg/12.5 mg: reddish-yellow, circular, film-coated tablets, approximately 8.5 mm in diameter, with "Sankyo" debossed on one side and “C22” on the other side. Each tablet contains 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/12.5 mg: reddish-yellow, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and “C23” on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.40 mg/25 mg: pink, oval, film-coated tablets, approximately 15 x 7 mm, with "Sankyo" debossed on one side and "C25" on the other side. Each tablet contains 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide.Tablets are supplied as follows:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Olmesartan medoxomil
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An AT receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT receptor than for the AT receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.
Hydrochlorothiazide
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
Non-Clinical Toxicology
BENICAR HCT is contraindicated in patients who are hypersensitive to any component of this product.Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with BENICAR HCT in patients with diabetes.
Olmesartan medoxomil
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with hydrochlorothiazide, digoxin or warfarin in healthy volunteers. The bioavailability of olmesartan was not significantly altered by the co-administration of antacids [Al(OH)/Mg(OH)]. 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.
Dual Blockade of the Renin- Angiotensin System (RAS)
Do not co-administer aliskiren with Benicar HCT in patients with diabetes (see ). Avoid use of aliskiren with Benicar HCT in patients with renal impairment (GFR <60ml/min).
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.
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 ).
Lithium
Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of olmesartan or thiazide diuretics. Monitor lithium levels in patients receiving BENICAR HCT and lithium.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, Barbiturates, Or Narcotics
Antidiabetic Drugs (oral agents and insulin)
Other Antihypertensive Drugs
Cholestyramine and Colestipol Resins
Corticosteroids, ACTH
Pressor Amines (e.g. Norepinephrine)
Skeletal Muscle Relaxants, Non depolarizing (e.g. Tubocurarine)
Non-steroidal Anti-inflammatory Drugs
Olmesartan medoxomil-hydrochlorothiazide
In a double-blind clinical trial of various doses of olmesartan medoxomil and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.4 mEq/L) was 2.1%; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%. In this trial, no patient discontinued due to increases or decreases in serum potassium.
Hydrochlorothiazide
Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis and hypokalemia. Serum and urine electrolyte determinations are important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.
If progressive renal impairment becomes evident consider withholding or discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Olmesartan medoxomil-hydrochlorothiazide
Olmesartan medoxomil-hydrochlorothiazide has been evaluated for safety in 1243 hypertensive patients. Treatment with olmesartan medoxomil-hydrochlorothiazide was well tolerated, with an incidence of adverse events similar to placebo. Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil-hydrochlorothiazide.
In the clinical trials, the overall frequency of adverse events was not dose-related. Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil-hydrochlorothiazide and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.0% (25/1243) of patients treated with olmesartan medoxomil-hydrochlorothiazide and 2.0% (7/342) of patients treated with placebo.
In a placebo-controlled clinical trial, the following adverse events reported with olmesartan medoxomil-hydrochlorothiazide occurred in >2% of patients, and more often on the olmesartan medoxomil-hydrochlorothiazide combination than on placebo, regardless of drug relationship:
The following adverse events were also reported at a rate of >2%, but were as, or more, common in the placebo group: headache and urinary tract infection.
Other adverse events that have been reported with an incidence of greater than 1.0%, whether or not attributed to treatment, in the more than 1200 hypertensive patients treated with olmesartan medoxomil-hydrochlorothiazide in controlled or open-label trials are listed below.
Body as a Whole:
Central and Peripheral Nervous System:
Gastrointestinal:
Liver and Biliary System:
Metabolic and Nutritional:
Musculoskeletal:
Respiratory System:
Skin and Appendages Disorders:
Urinary System:
Facial edema was reported in 2/1243 patients receiving olmesartan medoxomil-hydrochlorothiazide. Angioedema has been reported with angiotensin II receptor antagonists.
Olmesartan medoxomil
Other adverse events that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in more than 3100 hypertensive patients treated with olmesartan medoxomil monotherapy in controlled or open-label trials are tachycardia and hypercholesterolemia.
Hydrochlorothiazide
Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below:
Body as a Whole:
Digestive:
Hematologic:
Hypersensitivity:
Metabolic:
Musculoskeletal:
Nervous System/Psychiatric:
Renal:
Skin:
Special Senses:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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