Tribenzor Information
Tribenzor (Olmesartan) Warning: Avoid Use In Pregnancy
Tribenzor (Olmesartan) Indications And Usage
Tribenzor (Olmesartan) (olmesartan medoxomil, amlodipine, hydrochlorothiazide) is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Tribenzor (Olmesartan) .
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
Tribenzor (Olmesartan) Dosage And Administration
Dosage may be increased after 2 weeks. The full blood pressure lowering effects are attained within 2 weeks after a change in dose. The maximum recommended dose of Tribenzor (Olmesartan) is 40/10/25 mg. Tribenzor (Olmesartan) may be taken with or without food.
A patient who experiences dose-limiting adverse reactions to an individual component while on any dual combination of the components of Tribenzor (Olmesartan) may be switched to Tribenzor (Olmesartan) containing a lower dose of that component to achieve similar blood pressure reductions.
Tribenzor (Olmesartan) Dosage Forms And Strengths
Tribenzor (Olmesartan) tablets are formulated for oral administration in the following strength combinations: (olmesartan medoxomil/amlodipine/hydrochlorothiazide) 20 /5 /12.5 mg, 40 /5 / 12.5 mg, 40 /5 /25 mg, 40 /10 /12.5 mg, and 40 /10 /25 mg.
Tribenzor (Olmesartan) Contraindications
Because of the hydrochlorothiazide component, Tribenzor (Olmesartan) is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Tribenzor (Olmesartan) Warnings And Precautions
Drugs that act directly on the renin-angiotensin system like olmesartan medoxomil can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking angiotensin converting enzyme (ACE) inhibitors. When pregnancy is detected, discontinue Tribenzor (Olmesartan) as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Tribenzor (Olmesartan) as soon as possible .
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system is available. In these rare cases, the mother should be apprised of the potential hazards to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, Tribenzor (Olmesartan) should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function.
Olmesartan medoxomil.
Amlodipine.
An adverse event of impaired renal function was reported in 2.1% of subjects receiving Tribenzor (Olmesartan) compared to 0.2% to 1.3% of subjects receiving dual combination therapy.
If progressive renal impairment becomes evident consider withholding or discontinuing either diuretic or angiotensin receptor blocker therapies.
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 with Tribenzor (Olmesartan) because of the olmesartan medoxomil component.
Hydrochlorothiazide.
1/2
Hydrochlorothiazide.
Hydrochlorothiazide.
Hypokalemia may develop, especially during 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).
Metabolic acidosis may occur. Although a chloride deficit in a particular patient 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.
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. Tribenzor (Olmesartan) should be discontinued before carrying out tests for parathyroid function.
Hydrochlorothiazide.
Hydrochlorothiazide.
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.
Amlodipine.
Tribenzor (Olmesartan) .
Amlodipine.
Hydrochlorothiazide.
[see Drug Interactions ()]
Olmesartan medoxomil.
Hydrochlorothiazide.
Tribenzor (Olmesartan) Adverse Reactions
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Tribenzor (Olmesartan)
The frequency of adverse reactions was similar between men and women, patients
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 to 5.8% to 8.9% in subjects who switched to Tribenzor (Olmesartan) .
The other most frequent adverse reactions that occurred in at least 2% of subjects are presented in the table below:
Table 1
Syncope was reported by 1% of Tribenzor (Olmesartan) subjects compared to 0.5% or less for the other treatment groups.
Olmesartan medoxomil
Amlodipine
The following adverse reactions occurred in 0.1% of patients in controlled clinical trials under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert physicians to a possible relationship: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension, vasculitis hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo anorexia, constipation, dyspepsia*, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia allergic reaction, asthenia*, back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease arthralgia, arthrosis, muscle cramps*, myalgia sexual dysfunction (male* and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization dyspnea*, epistaxis angioedema, erythema multiforme, pruritus*, rash*, rash erythematous, rash maculopapular abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus micturition frequency, micturition disorder, nocturia dry mouth, sweating increased hyperglycemia, thirst leukopenia, purpura, thrombocytopenia * = events that occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.
The following adverse reactions occurred in
The following adverse reactions have been identified during post-approval use of the individual components of Tribenzor (Olmesartan) . Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Amlodipine.
Tribenzor (Olmesartan) Drug Interactions
The pharmacokinetics of olmesartan medoxomil, amlodipine, and hydrochlorothiazide are not altered when the drugs are co-administered.
No drug interaction studies have been conducted with other drugs and Tribenzor (Olmesartan) , although studies have been conducted with the olmesartan medoxomil, amlodipine, and hydrochlorothiazide components of Tribenzor (Olmesartan) , as described below.
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers.
The bioavailability of olmesartan medoxomil 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.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may be attenuated by NSAIDs including selective COX-2 inhibitors.
In vitro
Effect of Other Agents on Amlodipine Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine. 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 the pharmacokinetics of amlodipine. Co-administration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine. A single 100 mg dose of sildenafil in patients with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Effect of Amlodipine on Other Agents Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady state pharmacokinetic parameters of atorvastatin. Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers. Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol. Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
Tribenzor (Olmesartan) Use In Specific Populations
Drugs that act directly on the renin-angiotensin system like olmesartan medoxomil can cause fetal and neonatal morbidity and death when administered to pregnant women. There have been several dozen cases reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue Tribenzor (Olmesartan) as soon as possible.
Healthcare professionals who prescribe drugs acting directly on the renin angiotensin aldosterone system should counsel women of childbearing potential about the risks of these agents during pregnancy .
Tribenzor (Olmesartan) .
There are no studies of Tribenzor (Olmesartan) in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with severe hepatic impairment. Initiate amlodipine at 2.5 mg in patients with severe hepatic impairment.
Olmesartan medoxomil.
Hydrochlorothiazide.
There are no studies of Tribenzor (Olmesartan) in patients with renal impairment. Avoid use in patients with severe renal impairment (creatinine clearance
Olmesartan medoxomil.
Amlodipine.
Hydrochlorothiazide.
Tribenzor (Olmesartan) Overdosage
There is no information on overdosage with Tribenzor (Olmesartan) in humans.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Tribenzor (Olmesartan) Description
Tribenzor (Olmesartan) 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 (Olmesartan) is chemically described as 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.
The amlodipine besylate component of Tribenzor (Olmesartan) is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is CHCINO•CHOS.
The hydrochlorothiazide component of Tribenzor (Olmesartan) is chemically described as 6-chloro-3,4-dihydro-2-1,2,4-benzo-thiazidiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is CHCINOS.
The structural formula for olmesartan medoxomil is:
The structural formula for amlodipine besylate is:
The structural formula for hydrochlorothiazide is:
Tribenzor (Olmesartan) 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 (Olmesartan) 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 (Olmesartan) Clinical Pharmacology
The active ingredients of Tribenzor (Olmesartan) target three separate mechanisms involved in blood pressure regulation. Specifically, amlodipine blocks the contractile effects of calcium 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 in intravascular volume. For a more detailed description of the mechanisms of action for each individual component, see below.
Olmesartan medoxomil.
1
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. Angiotensin-converting enzyme inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan 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.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Hydrochlorothiazide.
The mechanism of the antihypertensive effect of thiazides is not fully understood.
Tribenzor (Olmesartan) has been shown to be effective in lowering blood pressure. The three components of Tribenzor (Olmesartan) (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 of each individual component is described below.
Olmesartan medoxomil.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.
Amlodipine.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate 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 glomerular filtration 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 ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with 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 administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
Hydrochlorothiazide.
Tribenzor (Olmesartan) .
Olmesartan medoxomil.
max
Amlodipine.
Hydrochlorothiazide.
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 was distributed to milk at low levels in rats.
Hydrochlorothiazide.
Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following 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 no accumulation in plasma occurs with once-daily dosing.
Amlodipine.
Hydrochlorothiazide.
Amlodipine.
Gender
Olmesartan medoxomil.
max
Amlodipine.
Amlodipine.
Tribenzor (Olmesartan) Nonclinical Toxicology
The rationale for no or limited new toxicity from the triple combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide has already been established on the basis of the safety profile of the individual compounds or the dual combinations. To clarify the toxicological profile for Tribenzor (Olmesartan) , a 3-month repeated dose toxicity study was conducted in rats, and the results demonstrated that the combined administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide neither augment any existing toxicities of the individual agents nor induce any new toxicities and there were no toxicologically synergistic effects observed in the study.
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.
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 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 at dose levels as high as 1000 mg/kg/day (240 times the MRHD of 40 mg/day on a mg/m basis) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating. (Calculations based on a 60 kg patient.)
Amlodipine.
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 up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m basis).
Hydrochlorothiazide.
2
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 in 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 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 to 100 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/day on a mg/m basis. (Calculations based on a 60 kg patient.)
No reproductive 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, and olmesartan medoxomil and hydrochlorothiazide together.
Olmesartan medoxomil.
Olmesartan medoxomil and Hydrochlorothiazide.
Amlodipine.
2
Hydrochlorothiazide.
Tribenzor (Olmesartan) Clinical Studies
Tribenzor (Olmesartan) How Supplied/storage And Handling
Tribenzor (Olmesartan) tablets contain olmesartan medoxomil, amlodipine besylate at a dose equivalent to 5 or 10 mg amlodipine, and hydrochlorothiazide in the strengths described below.
Tribenzor (Olmesartan) tablets are differentiated by tablet color/size and are debossed with an individual product tablet code on one side. Tribenzor (Olmesartan) tablets are supplied for oral administration in the following strength and package configurations:
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].
Tribenzor (Olmesartan) Patient Counseling Information
Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope .
Tribenzor (Olmesartan)
Tribenzor (Olmesartan)
Tribenzor (Olmesartan)
Tribenzor (Olmesartan)
Tribenzor (Olmesartan)
Tribenzor (Olmesartan)
