Tribenzor

Description

Tribenzor provided as a tablet for oral administration, is a fixed combination of olmesartan medoxomil (ARB), amlodipine (CCB), and hydrochlorothiazide (thiazide diuretic).

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.

The olmesartan medoxomil component of Tribenzor is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C₂₉H₃₀N₆O₆.

The amlodipine besylate component of Tribenzor is chemically described as 3-ethyl-5methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C₂₀H₂₅CIN₂O₅•C₆H₆O₃S.

The hydrochlorothiazide component of Tribenzor is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzo-thiazidiazine-7-sulfonamide 1,1-dioxide. Its  empirical formula is C₇H₈CIN₃O₄S₂.

The structural formula for olmesartan medoxomil is:

 

 

The structural formula for amlodipine besylate is:

 

 

The structural formula for hydrochlorothiazide is:

 

 

Tribenzor contains olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder, amlodipine besylate, a white to off-white crystalline powder, and hydrochlorothiazide, a white or practically white, crystalline powder. The molecular weights of olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide are 558.6, 567.1, and 297.7, respectively. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Each tablet of Tribenzor also contains the following inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coating contains polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (20 /5 /12.5 mg, 40 /5 /12.5 mg, 40 /5 /25 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), iron oxide red (20 /5 /12.5 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg tablets), and iron oxide black (20 /5 /12.5 mg tablets).

Tribenzor is indicated for the treatment of hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure reduces the riskof fatal and nonfatal cardiovascular (CV) 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 riskreduction with Tribenzor.

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. Forspecific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committeeon 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 toreduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, thatis largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions inmyocardial 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 evenmodest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations withvarying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes orhyperlipidemia), 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 approvedindications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Limitations Of Use

This fixed combination drug is not indicated for the initial therapy of hypertension.

Dosage And Administration

Dose once daily. Dosage may be increased in 2-week intervals, as needed. The maximum recommended dose of Tribenzor is 40/10/25 mg.

Dose selection should be individualized based on previous therapy.

How Supplied

Dosage Forms And Strengths

Tribenzor tablets are available in the following strength combinations:

 

	20/5/12.5	40/5/12.5	40/5/25	40/10/12.5	40/10/25
Olmesartan medoxomil (mg)	20	40	40	40	40
Amlodipine equivalent (mg)	5	5	5	10	10
Hydrochlorothiazide (mg)	12.5	12.5	25	12.5	25

 

Storage And Handling

Tribenzor tablets contain olmesartan medoxomil, amlodipine besylate at a dose equivalent to 5 or 10 mg amlodipine, and hydrochlorothiazide in the strengths describedbelow.

Tribenzor tablets are differentiated by tablet color/size and are debossed with an individual product tablet code on one side. Tribenzor tablets are supplied for oraladministration in the following strength and package configurations:

 

Tablet Strength (OM/AML equivalent/HCTZ)	Package Configuration	NDC#	Product Code	Tablet Color
20 /5 /12.5 mg	Bottle of 30	0713-0874-30	C51	Orange white
	Bottle of 90	Not available
	10 blisters of 10	Not available
40 /5 /12.5 mg	Bottle of 30	0713-0875-30	C53	Light yellow
	Bottle of 90	Not available
	10 blisters of 10	Not available
40 /5 /25 mg	Bottle of 30	0713-0876-30	C54	Light yellow
	Bottle of 90	Not available
	10 blisters of 10	Not available
40 /10 /12.5 mg	Bottle of 30	0713-0877-30	C55	Grayish red
	Bottle of 90	Not available
	10 blisters of 10	Not available
40 /10 /25 mg	Bottle of 30	0713-0878-30	C57	Grayish red
	Bottle of 90	Not available
	10 blisters of 10	Not available

 

Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].

Marketed by Cosette Pharmaceuticals, Inc., South Plainfield, NJ 07080. Revised: Feb 2022

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 torates in the clinical studies of another drug and may not reflect the rates observed in practice.

Tribenzor

In the controlled trial of Tribenzor, patients were randomized to Tribenzor (olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg), olmesartanmedoxomil/amlodipine 40/10 mg, olmesartan medoxomil/hydrochlorothiazide 40/25 mg, or amlodipine/hydrochlorothiazide 10/25 mg. Subjects who received triplecombination therapy were treated between two and four weeks with one of the three dual combination therapies. Safety data from this study were obtained in 574patients with hypertension who received Tribenzor for 8 weeks.

The frequency of adverse reactions was similar between men and women, patients <65 years of age and patients ≥65 years of age, patients with and without diabetes,and Black and non-Black patients. Discontinuations because of adverse events occurred in 4% of patients treated with Tribenzor 40/10/25 mg compared to 1% ofpatients treated with olmesartan medoxomil/amlodipine 40/10 mg, 2% of patients treated with olmesartan medoxomil/hydrochlorothiazide 40/25 mg, and 2% of patientstreated with amlodipine/hydrochlorothiazide 10/25 mg. The most common reason for discontinuation with Tribenzor was dizziness (1%).

Dizziness was one of the most frequently reported adverse reactions with incidence of 1.4% to 3.6% in subjects continuing on dual combination therapy compared to5.8% to 8.9% in subjects who switched to Tribenzor.

The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below:

Table 1

Adverse Reaction	0M40/ AML10/ HCTZ25 mg (N = 574) n (%)	OM40/ AML10 mg (N = 596) n (%)	OM40/ HCTZ25mg (N = 580) n (%)	AML10/ HCTZ25 mg (N = 552) n (%)
Edema peripheral	44 (7.7)	42 (7.0)	6 (1.0)	46 (8.3)
Headache	37 (6.4)	42 (7.0)	38 (6.6)	33 (6.0)
Fatigue	24 (4.2)	34 (5.7)	31 (5.3)	36 (6.5)
Nasopharyngitis	20 (3.5)	11 (1.8)	20 (3.4)	16 (2.9)
Muscle spasms	18 (3.1)	12 (2.0)	14 (2.4)	13 (2.4)
Nausea	17 (3.0)	12 (2.0)	22 (3.8)	12 (2.2)
Upper respiratory tract infection	16 (2.8)	26 (4.4)	18 (3.1)	14 (2.5)
Diarrhea	15 (2.6)	14 (2.3)	12 (2.1)	9 (1.6)
Urinary tract infection	14 (2.4)	8 (1.3)	6 (1.0)	7 (1.3)
Joint swelling	12 (2.1)	17 (2.9)	2 (0.3)	16 (2.9)

 

Syncope was reported by 1% of Tribenzor subjects compared to 0.5% or less for the other treatment groups.

Olmesartan Medoxomil

Olmesartan medoxomil 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 treated for at least 1 year. Treatment with olmesartan medoxomil was welltolerated, with an incidence of adverse reactions similar to that seen with placebo. Adverse reactions were generally mild, transient, and without relationship to the doseof olmesartan medoxomil.

Amlodipine

Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of the individual components of Tribenzor. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:

Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema

Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy [see WARNINGS AND PRECAUTIONS]

Metabolic and Nutritional Disorders: hyperkalemia

Musculoskeletal: rhabdomyolysis

Urogenital System: acute renal failure, increased blood creatinine

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 theoverall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuriaPrevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least oneadditional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline inglomerular filtration rate (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 therisk 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-doseolmesartan (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 angiotensinreceptor 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 olmesartancompared 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, concernswith 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 magnitudesimilar to the adverse finding in diabetics.

Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing experience,jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported inassociation with use of amlodipine. Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine.

Hydrochlorothiazide

Non-melanoma Skin Cancer

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantlyfor squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC casefor every 6,700 patients per year.

Drug Interactions With Olmesartan Medoxomil

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (includingthose on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptorantagonists, 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-2inhibitors.

Dual Blockade Of The Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated withincreased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving thecombination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closelymonitor blood pressure, renal function and electrolytes in patients on Tribenzor and other agents that affect the RAS.

Do not co-administer aliskiren with Tribenzor in patients with diabetes [See CONTRAINDICATIONS]. Avoid use of aliskiren with Tribenzor in patients with renalimpairment (GFR <60 ml/min).

Use With Colesevelam Hydrochloride

Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peakplasma 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].

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of olmesartan or thiazide diuretics. Monitor lithiumlevels in patients receiving Tribenzor and lithium.

Drug Interactions With Amlodipine

Simvastatin

Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipineto 20 mg daily. [see CLINICAL PHARMACOLOGY].

Immunosuppressants

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levelsof cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see CLINICAL PHARMACOLOGY].

CYP3A Inhibitors

Co-administration of amlodipine with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may requiredose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for doseadjustment.

CYP3A Inducers

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored whenamlodipine is co-administered with CYP3A inducers.

Drug Interactions With Hydrochlorothiazide

When administered concurrently the following drugs may interact with thiazide diuretics:

Antidiabetic Drugs (oral agents and insulin)

Dosage adjustment of the antidiabetic drug may be required.

Cholestyramine And Colestipol Resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single dose of either cholestyramineor colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalemia.

Non-steroidal Anti-inflammatory Drugs

In some patients the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, andantihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when hydrochlorothiazide tablets and non-steroidal anti-inflammatory agents areused concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.

WarningS

Included as part of the PRECAUTIONS section.

Precautions

Fetal Toxicity

Olmesartan Medoxomil

Tribenzor can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during thesecond and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associatedwith fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Whenpregnancy is detected, discontinue Tribenzor as soon as possible [see Use In Specific Populations].

Hydrochlorothiazide

Thiazides cross the placental barrier and appear in cord blood.

Adverse reactions include fetal or neonatal jaundice and thrombocytopenia [see Use In Specific Populations].

Hypotension In Volume- Or Salt-Depleted Patients

Olmesartan Medoxomil

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high dosesof diuretics) symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment with Tribenzor under closemedical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transienthypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Amlodipine

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension isunlikely.

Increased Angina And/Or Myocardial Infarction

Amlodipine

Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acutemyocardial infarction upon starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Impaired Renal Function

Tribenzor

Impaired renal function was reported in 2.1% of subjects receiving Tribenzor compared to 0.2% to 1.3% of subjects receiving dual combination therapy of olmesartanmedoxomil and amlodipine, olmesartan medoxomil and hydrochlorothiazide or amlodipine and hydrochlorothiazide.

If progressive renal impairment becomes evident consider withholding or discontinuing Tribenzor.

Olmesartan Medoxomil

Changes in renal function occur in some individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestiveheart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acuterenal failure and/or death. Similar effects may occur in patients treated with Tribenzor due to the olmesartan medoxomil component [see DRUG INTERACTIONS 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 olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected withTribenzor because of the olmesartan medoxomil component.

Hydrochlorothiazide

Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renalfunction.

Patients With Hepatic Impairment

Amlodipine

Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t) is 56 hours in patients with severely impaired hepaticfunction, titrate slowly when administering to patients with severe hepatic impairment.

Electrolyte And Metabolic Imbalances

Tribenzor contains hydrochlorothiazide which can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may bedifficult to treat despite potassium repletion. Tribenzor also contains olmesartan, a drug that affects the RAS. Drugs that inhibit the RAS can also cause hyperkalemia.

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.

Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels.

Postsympathectomy Patients

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

Systemic Lupus Erythematosus

Hydrochlorothiazide

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 acuteonset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead topermanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to beconsidered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillinallergy.

Sprue-like Enteropathy

Olmesartan medoxomil. 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 Tribenzor in cases where no other etiology is identified.

Nonclinical Toxicology

The rationale for no or limited new toxicity from the triple combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide has already been established onthe basis of the safety profile of the individual compounds or the dual combinations. To clarify the toxicological profile for Tribenzor, a 3-month repeated dose toxicitystudy was conducted in rats, and the results demonstrated that the combined administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide neitheraugment any existing toxicities of the individual agents nor induce any new toxicities and there were no toxicologically synergistic effects observed in the study.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide.However, these studies have been conducted for olmesartan medoxomil, amlodipine and hydrochlorothiazide alone.

Olmesartan Medoxomil

Olmesartan 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 MRHD of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in thep53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (on a mg/m² basis, about 120 timesthe MRHD of 40 mg/day), revealed no evidence of a carcinogenic effect of olmesartan.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicityin the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and testedpositive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestineand 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 at dose levels as high as 1000 mg/kg/day (240 times the MRHD of 40 mg/day on a mg/m² basis) in astudy in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. (Calculations based on a 60 kg patient.)

Amlodipine

Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5,1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m² basis, similar to the MRHD ofamlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m² basis, about two times the MRHD (calculations based on a 60 kg patient).

Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine upto 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of acarcinogenic 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 toapproximately 100 mg/kg/day). These doses in mice and rats are about 117 and 39 times, respectively, the MRHD of 25 mg/day on a mg/m² basis. (Calculations basedon a 60 kg patient.) The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, orin the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. It was also not genotoxic in vivo in assays using mouse germinal cell chromosomes, ChineseHamster bone marrow chromosomes, or in Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) assay, the Mouse Lymphoma Cell (mutagenicity) assay and the Aspergillus nidulans nondisjunction 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 to100 and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses in mice and rats are about 19 and 1.5 times, respectively, the MRHD of 25 mg/dayon a mg/m² basis. (Calculations based on a 60 kg patient.)

 

Use In Specific Populations

Pregnancy

Risk Summary

Tribenzor can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters ofpregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death [see Clinical Considerations].Most epidemiologic studies examining fetalabnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from otherantihypertensive agents.

When pregnancy is detected, discontinue Tribenzor as soon as possible. Consider alternative antihypertensive therapy during pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect,loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognizedpregnancies is 2%–4% and 15%–20%, respectively.

Clinical Considerations

Disease-Associated Maternal And/Or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesareansection and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertensionshould be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Olmesartan medoxomil

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following:reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death.

Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients andphysicians 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 olmesartan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure toolmesartan, if oliguria or hypotension occur, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may berequired as a means of reversing hypotension and supporting renal function [see Use In Specific Populations].

Hydrochlorothiazide

Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, cancause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times that in umbilical vein plasma. Use of thiazides duringpregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of preeclampsia, these drugs shouldnot be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided.

Data

Animal Data

No reproductive studies have been conducted with the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide. However, these studies have beenconducted for olmesartan medoxomil, amlodipine and hydrochlorothiazide alone, and olmesartan medoxomil and hydrochlorothiazide together.

Olmesartan medoxomil

No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximumrecommended human dose [MRHD] on a mg/m 2basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m 2basis; higher doses could notbe evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effectdose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

Olmesartan medoxomil And Hydrochlorothiazide

No teratogenic effects were observed when 1.6:1 combinations of olmesartan medoxomil and hydrochlorothiazide were administered to pregnant mice at oral doses upto 1625 mg/kg/day (122 times the MRHD on a mg/m 2basis) or pregnant rats up to 1625 mg/kg/day (243 times the MRHD on a mg/m 2basis) or pregnant rabbits atoral doses up to 1 mg/kg/day (0.3 times the MRHD on a mg/m 2basis). In rats, however, fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in thedams) were significantly lower than control. The no observed effect dose for developmental toxicity in rats is 162.5 mg/kg/day, about 24 times, on a mg/m 2basis, theMRHD of 40 mg olmesartan medoxomil/25 mg hydrochlorothiazide/day. (Calculations based on a 60 kg patient.)

Amlodipine

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m 2basis) during their respectiveperiods of major organogenesis (calculations based on a patient weight of 60 kg). However, litter size was significantly decreased (by about 50%), and the number ofintrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days beforemating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose.

Hydrochlorothiazide

No teratogenic effects were observed when hydrochlorothiazide was administered to mice and rats via gavage at doses up to 3000 and 1000 mg/kg/day, respectively(about 600 and 400 times the MRHD), on gestation days 6 through 15.

Lactation

Risk Summary

There is limited information regarding the presence Tribenzor in human milk, the effects on the breastfed infant, or the effects on milk production. Amlodipine andhydrochlorothiazide are present in human milk. Olmesartan is present in rat milk [see Data]. Because of the potential for adverse effects on the nursing infant, advise anursing woman that breastfeeding is not recommended during treatment with Tribenzor.

Data

Presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [14C] olmesartan medoxomil to lactating rats.

Pediatric Use

The safety and effectiveness of Tribenzor in pediatric patients have not been established.

Geriatric Use

Tribenzor

In a controlled clinical trial, 123 hypertensive patients treated with Tribenzor were ≥65 years of age and 18 patients were ≥75 years of age. No overalldifferences in the efficacy or safety of Tribenzor were observed in these patient populations; however, greater sensitivity of some older individuals cannot be ruled out.The recommended initial dose of amlodipine in patients ≥ 75 years of age is 2.5 mg, a dose not available with Tribenzor.

Hepatic Impairment

There are no studies of Tribenzor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patientswith severe hepatic impairment. The recommended initial dose of amlodipine in patients with severe hepatic impairment is 2.5 mg, a dose not available with Tribenzor[see WARNINGS AND PRECAUTIONS].

Amlodipine

Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepaticfunction.

Olmesartan Medoxomil

Increases in AUC 0-∞and peak plasma concentration (Cmax) for olmesartan were observed with moderate hepatic impairment compared tothose in matched controls with an increase in AUC of about 60%.

Hydrochlorothiazide

In patients with impaired hepatic function or progressive liver disease, minor alterations of fluid and electrolyte balance may precipitate hepaticcoma.

Renal Impairment

There are no studies of Tribenzor in patients with renal impairment. Avoid use in patients with severe renal impairment (creatinine clearance <30 mL/min).

Olmesartan Medoxomil

Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. Afterrepeated dosing, AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment isrecommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min). The pharmacokinetics of olmesartan in patients undergoinghemodialysis has not been studied.

Amlodipine

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.

Hydrochlorothiazide

Thiazide should be used with caution in patients with 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.

Black Patients

Of the total number of patients who received Tribenzor in a randomized trial, 29% (184/627) were black. Tribenzor was effective in lowering both systolic and diastolicblood pressure in black patients (usually a low-renin population) to the same extent as in non-black patients.

Overdose

There is no information on overdosage with Tribenzor in humans.

Olmesartan Medoxomil

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

Amlodipine

Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Singleoral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m² basis) caused a marked peripheral vasodilation and hypotension.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience withintentional overdosage of amlodipine is limited.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Shouldhypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remainsunresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume andurine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likelyto be of benefit.

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 degreeto which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats,more than 1000-fold the highest recommended human dose.

Contraindications

Because of the hydrochlorothiazide component, Tribenzor is contraindicated in patients with anuria, hypersensitivity to any component, or hypersensitivity to othersulfonamide-derived drugs.

Do not co-administer aliskiren with Tribenzor in patients with diabetes [See DRUG INTERACTIONS].

Mechanism Of Action

The active ingredients of Tribenzor target three separate mechanisms involved in blood pressure regulation. Specifically, amlodipine blocks the contractile effects ofcalcium on cardiac and vascular smooth muscle cells; olmesartan medoxomil blocks the vasoconstriction and sodium retaining effects of angiotensin II on cardiac,vascular smooth muscle, adrenal and renal cells; and hydrochlorothiazide directly promotes the excretion of sodium and chloride in the kidney leading to reductions inintravascular volume. For a more detailed description of the mechanisms of action for each individual component, see below.

Olmesartan Medoxomil

Angiotensin II is formed from angiotensin I in a reaction catalyzed by ACE, kininase II. Angiotensin II is the principal pressor agent of therenin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption ofsodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1receptor in vascular smoothmuscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

An AT2 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-foldgreater affinity for the AT1 receptor than for the AT2 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 usedto treat hypertension. Angiotensin-converting enzyme inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan doesnot 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 activityand circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

Amlodipine

Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiacmuscle. Experimental data suggests that amlodipine binds to both dihydropyridine and nonhydropyridine binding sites. The contractile processes of cardiac muscle andvascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ioninflux across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detectedin vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pHrange, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association anddissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in bloodpressure.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretionof sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases inplasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediatedby 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.

Pharmacodynamics

Tribenzor has been shown to be effective in lowering blood pressure. The three components of Tribenzor (olmesartan medoxomil, amlodipine, and hydrochlorothiazide)lower the blood pressure through complementary mechanisms, each working at a separate site and blocking different effects or pathways. The pharmacodynamics ofeach individual component is described below.

Olmesartan Medoxomil

Olmesartan medoxomil doses of 2.5 to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect wasrelated to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.

Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil tohealthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect onserum potassium.

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine andstanding blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronicdosing.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both youngand elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals withmoderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg).Normotensive patients experienced no clinically significant change in blood pressures (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerularfiltration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricularfunction treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolicpressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range tointact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patientswith heart failure with agents possessing significant negative inotropic effects.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In clinical studies in which amlodipine was administeredin combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.

Drug Interactions

Alcohol, Barbiturates, Or Narcotics

Potentiation of orthostatic hypotension may occur.

Skeletal Muscle Relaxants, Non-Depolarizing (e.g., tubocurarine)

Possible increased responsiveness to the muscle relaxant.

Pharmacokinetics

Tribenzor

After oral administration of Tribenzor in normal healthy adults, peak plasma concentrations of olmesartan, amlodipine, and hydrochlorothiazide are reachedin about 1.5 to 3 hours, 6 to 8 hours, and 1.5 to 2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine, and hydrochlorothiazidefrom Tribenzor are the same as when administered as individual dosage forms. Food does not affect the bioavailability of Tribenzor.

Olmesartan Medoxomil

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinaltract. The absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral administration, the C maxof olmesartan is reached after 1 to 2 hours. Fooddoes not affect the bioavailability of olmesartan medoxomil.

Amlodipine

After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolutebioavailability is estimated between 64% and 90%.

Hydrochlorothiazide

When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.

Distribution

Olmesartan Medoxomil

The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetratered blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.

In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan wasdistributed to milk at low levels in rats.

Amlodipine

Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levelsof amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Metabolism And Excretion

Olmesartan Medoxomil

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no furthermetabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose isrecovered in urine while the remainder is eliminated in feces via the bile.

Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokineticsfollowing single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and noaccumulation in plasma occurs with once-daily dosing.

Amlodipine

Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Elimination from the plasma is biphasic with a terminalelimination half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of the metabolites are excreted in the urine.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24hours.

Specific Populations

Geriatric Patients

Olmesartan Medoxomil

The pharmacokinetics of olmesartan medoxomil were studied in the elderly (≥65 years). Overall, maximum plasma concentrations ofolmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUC ss, τwas 33%higher in elderly patients, corresponding to an approximate 30% reduction in CLR.

Amlodipine

Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%, and a lower initial dose may berequired.

Male And Female Patients

Population pharmacokinetic analysis indicated that gender had no effect on the clearance of olmesartan and amlodipine. Female patients had approximately 20%smaller clearances of hydrochlorothiazide than male patients.

Olmesartan Medoxomil

Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. Area under the curve and C maxwere 10% to 15% higher in women than in men.

Patients With Renal Impairment

Olmesartan Medoxomil

In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. Afterrepeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartanmedoxomil in patients undergoing hemodialysis has not been studied.

Amlodipine

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.

Patients With Hepatic Impairment

Olmesartan Medoxomil

Increases in AUC 0-∞and C maxwere observed in patients with moderate hepatic impairment compared to those in matched controls, with anincrease in AUC of about 60%.

Amlodipine

Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.

Heart Failure

Amlodipine

Patients with heart failure have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.

Drug Interaction Studies

Simvastatin

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared tosimvastatin alone. [see DRUG INTERACTIONS].

CYP3A Inhibitors

Co-administration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase inamlodipine systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure. However, stronginhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see DRUG INTERACTIONS].

Cyclosporine

In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was observed in the presence of amlodipine. [see DRUG INTERACTIONS].

Colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction inCmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomilwas administered 4 hours prior to colesevelam hydrochloride [see DRUG INTERACTIONS].

Cimetidine

Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit Juice

Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on thepharmacokinetics of amlodipine.

Maalox ®(antacid)

Co-administration of the antacid Maalox ®with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil

A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipineand sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin

Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokineticparameters of atorvastatin.

Digoxin

Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

No significant drug interactions were reported in studies in which olmesartan medoxomil was coadministered with digoxin in healthy volunteers.

Ethanol (alcohol)

Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin

Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time. No significant drug interactions were reported instudies in which olmesartan medoxomil was coadministered with warfarin in healthy volunteers.

Antacids

The bioavailability of olmesartan medoxomil was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2].

Clinical Studies

Tribenzor

The antihypertensive efficacy of Tribenzor was studied in a double-blind, active-controlled study in hypertensive patients. A total of 2492 patients with hypertension(mean baseline blood pressure 169/101 mmHg) received olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg (627 patients), olmesartanmedoxomil/amlodipine 40/10 mg (628 patients), olmesartan medoxomil/hydrochlorothiazide 40/25 mg (637 patients), or amlodipine/hydrochlorothiazide 10/25 mg(600 patients). Each subject was randomized to one of the three dual therapy combinations for two to four weeks. Patients were then randomized to continue on the dualtherapy they were receiving or to receive triple therapy. A total of 53% of patients were male, 19% were 65 years or older, 67% were white, 30% were black, and 15%were diabetic.

After 8 weeks of treatment, the triple combination therapy produced greater reductions in both systolic and diastolic blood pressures (p< 0.0001) compared to each ofthe 3 dual combination therapies. The full blood pressure lowering effects were attained within 2 weeks after a change in dose.

The seated blood pressure reductions attributable to the addition of a single high-dose drug to each high-dose dual drug combination are shown in Table 2.

Table 2 : Additional blood pressure reductions on high-dose Tribenzorcompared to high doses of dual combination drugs

Start on	Adding	BP reduction*
Olmesartan medoxomil 40 / amlodipine 10 mg	HCTZ 25 mg	8.4/4.5 mmHg
Olmesartan medoxomil 40 / HCTZ 25 mg	Amlodipine 10 mg	7.6/5.4 mmHg
Amlodipine 10 / HCTZ 25 mg	Olmesartan medoxomil 40 mg	8.1/5.4 mmHg
*all highly statistically significant.

 

There were no apparent differences in terms of seated diastolic blood pressure (SeDBP) or seated systolic blood pressure (SeSBP) reductions in black and non-blackpatients treated with Tribenzor [see Use In Specific Populations].

There were no apparent differences in terms of SeDBP or SeSBP reductions in diabetic and non-diabetic patients treated with Tribenzor.

A total of 440 patients participated in the ambulatory blood pressure monitoring portion of the study. Over the 24-hour period, there was a greater reduction in diastolicand systolic ambulatory blood pressure for olmesartan medoxomil/amlodipine/hydrochlorothiazide 40/10/25 mg compared to each of the dual combination therapies(see Figure 1 and Figure 2).

Figure 1: Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Hour

 

Figure 2: Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Hour

 

The blood pressure lowering effects of lower dose strengths of Tribenzor (olmesartan medoxomil/amlodipine/hydrochlorothiazide 20/5/12.5 mg, 40/5/12.5 mg,40/10/12.5 mg, and 40/5/25 mg) have not been studied.

All of the dose strengths of the triple combination are expected to provide superior blood pressure lowering effects compared to their respective mono and dualcombination components. The order of the blood pressure lowering effects among the different dose strengths of Tribenzor (olmesartanmedoxomil /amlodipine /hydrochlorothiazide) is expected to be 20/5/12.5 mg < 40/5/12.5 mg < (40/10/12.5 mg ≈ 40/5/25 mg) < 40/10/25 mg.

There are no trials of Tribenzor demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug hasdemonstrated such benefits.