Instructions for Tiara Trio film-coated tablets 10mg/12.5mg/160mg No. 28
Composition
amlodipine, hydrochlorothiazide, valsartan;
1 tablet of 5 mg/12.5 mg/160 mg contains:
active ingredients: amlodipine besylate equivalent to amlodipine 5 mg, hydrochlorothiazide 12.5 mg, valsartan 160 mg;
excipients: microcrystalline cellulose, croscarmellose sodium, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II 85 F pink.
1 tablet of 10 mg/12.5 mg/160 mg contains:
active ingredients: amlodipine besylate equivalent to amlodipine 10 mg, hydrochlorothiazide 12.5 mg, valsartan 160 mg;
excipients: microcrystalline cellulose, croscarmellose sodium, crospovidone, colloidal anhydrous silica, magnesium stearate, Opadry II 85 F white.
Dosage form
Film-coated tablets.
Main physicochemical properties:
5 mg/12.5 mg/160 mg tablets – round, film-coated, pink, with a biconvex surface;
10 mg/12.5 mg/160 mg tablets – round, film-coated white, with a biconvex surface.
Pharmacotherapeutic group
Angiotensin II receptor blockers, other combinations. Valsartan, amlodipine and hydrochlorothiazide. ATC code C09D X01.
Pharmacological properties
Pharmacodynamics.
Tiara Trio® contains three antihypertensive agents with different mechanisms of blood pressure control in patients with essential hypertension, which complement each other: amlodipine belongs to the class of calcium antagonists, valsartan to the class of angiotensin II receptor antagonists (ARBs), and hydrochlorothiazide to the class of thiazide diuretics. The combination of these three components is characterized by a complementary antihypertensive effect.
Amlodipine
Amlodipine, which is part of the drug Tiara Trio®, inhibits the transmembrane entry of calcium ions into the heart muscle and vascular smooth muscle. The antihypertensive effect of amlodipine occurs through a direct relaxing effect on vascular smooth muscle, which causes a decrease in peripheral vascular resistance and blood pressure. Experimental data confirm that amlodipine binds to dihydropyridine and non-hydropyridine binding sites. Contractility of the heart muscle and vascular smooth muscle depends on the passage of extracellular calcium into the cells through specific ion channels.
Amlodipine at therapeutic doses causes vasodilation in patients with hypertension, resulting in a decrease in supine and standing blood pressure. This decrease in blood pressure is not accompanied by significant changes in heart rate or plasma catecholamine levels with prolonged use.
Amlodipine plasma concentrations correlate with effect in both young and elderly patients.
In patients with hypertension and normal renal function, amlodipine at therapeutic doses causes a decrease in renal vascular resistance and an increase in glomerular filtration rate (GFR) and effective renal plasma flow without changing the filtration fraction or proteinuria.
Valsartan
Valsartan is an orally active, potent and specific ARA II. Valsartan acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II.
In patients with hypertension, valsartan helps reduce blood pressure without affecting pulse rate.
In most patients, after oral administration of a single dose, the onset of the hypotensive effect occurs within 2 hours, and the maximum reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect lasts for 24 hours after administration of the drug. With repeated administration, the maximum reduction in blood pressure (at all dosage regimens) is usually achieved within 2-4 weeks.
Hydrochlorothiazide
The site of action of thiazide diuretics is mainly the distal convoluted tubules of the kidneys. It has been confirmed that high-affinity receptors are present in the renal cortex, which are the main binding site for thiazide diuretics and inhibit NaCl transport into the distal convoluted tubules. The mechanism of action of thiazides is to inhibit Na+Cl– transporters, possibly by competing for Cl– sites, which in turn affects the mechanisms of electrolyte reabsorption: directly increases the excretion of sodium and chlorine to approximately the same extent and indirectly, due to the diuretic effect, reduces plasma volume with subsequent increases in plasma renin activity, aldosterone secretion and urinary potassium excretion, as well as a decrease in serum potassium.
Epidemiological studies have shown a cumulative dose-dependent association between hydrochlorothiazide use and the development of non-melanoma skin cancer. One study included a population of 71,533 basal cell carcinomas and 8,629 squamous cell carcinomas, with a control group of 1,430,833 and 172,462 cases, respectively. High-dose hydrochlorothiazide (total dose ≥ 50,000 mg) was associated with an adjusted odds ratio of 1.29 (95% CI: 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A strong cumulative dose-response relationship was observed for basal cell and squamous cell carcinomas. Another study showed a possible association between lip squamous cell carcinoma and hydrochlorothiazide exposure: 633 cases of lip cancer were found in 63,067 controls (risk-adjusted sampling strategy used). The cumulative dose-response relationship was demonstrated by an adjusted odds ratio of 2.1 (95% CI: 1.7-2.6). This increased to 3.9 (3.0-4.9) at high doses of hydrochlorothiazide (25,000 mg) and to 7.7 (5.7-10.5) at the highest cumulative dose (100,000 mg) (see section 4.4).
Pharmacokinetics.
Linearity
Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.
Amlodipine/valsartan/hydrochlorothiazide
Following oral administration of amlodipine/valsartan/hydrochlorothiazide to adult volunteers, peak plasma concentrations (Cmax) of amlodipine, valsartan and hydrochlorothiazide were achieved within 6–8 hours, 3 hours and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide from the combination were similar to those observed when the components were administered as separate medicinal products.
Amlodipine
Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations were reached within 6–12 hours. Absolute bioavailability ranged from 64% to 80%. Food intake did not affect the bioavailability of amlodipine.
Distribution: The volume of distribution is approximately 21 L/kg. In vitro studies of amlodipine have shown that approximately 97.5% of the drug in the circulating blood is bound to plasma proteins.
Biotransformation: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Elimination: Amlodipine is eliminated from plasma in two phases, with a terminal half-life of approximately 30–50 hours. Steady-state plasma levels are reached after 7–8 days of continuous dosing. 10% of amlodipine and 60% of amlodipine metabolites are excreted in the urine.
Valsartan
Absorption: After oral administration of valsartan alone, peak concentrations are reached within 2–4 hours. The mean absolute bioavailability is 23%. Food intake reduces valsartan exposure by approximately 40% (as determined by the area under the concentration-time curve (AUC)) and Cmax by approximately 50%, although approximately 8 hours after administration, valsartan concentrations are similar in the fasted and fed groups. However, this decrease in AUC is not accompanied by a clinically significant reduction in therapeutic effect, and valsartan can be administered without regard to food intake.
Distribution: The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 liters, indicating that valsartan is not extensively distributed into tissues. Valsartan is extensively bound to serum proteins (94–97%), primarily serum albumin.
Biotransformation: Valsartan is not significantly transformed, with only approximately 20% of the dose excreted as metabolites. A hydroxymetabolite has been identified in plasma at low concentrations (less than 10% of the AUC of valsartan). This metabolite is pharmacologically inactive.
Elimination: Valsartan is excreted primarily in the feces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly as unchanged drug. After intravenous administration, plasma clearance of valsartan is approximately 2 l/h and renal clearance is 0.62 l/h (approximately 30% of total clearance). The elimination half-life of valsartan is 6 hours.
Hydrochlorothiazide
Absorption. Hydrochlorothiazide is rapidly absorbed after oral administration (Tmax is approximately 2 hours). The increase in mean AUC is linear and dose-proportional over the therapeutic dose range. No changes in hydrochlorothiazide kinetics were observed with repeated administration, and accumulation was minimal with once-daily dosing. Both increases and decreases in systemic availability of hydrochlorothiazide were observed with concomitant food administration compared with fasting conditions. The magnitude of these effects is small and of little clinical significance. The absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.
Biotransformation: Hydrochlorothiazide is excreted unchanged.
Excretion: More than 95% of the absorbed dose is excreted unchanged in the urine. Renal clearance consists of passive filtration and active secretion in the renal tubules. The half-life is 6–15 hours.
Certain patient groups
Children (under 18 years of age)
There are no pharmacokinetic data in children.
Elderly patients (aged 65 years and over)
The time to reach Cmax of amlodipine is similar in young and elderly patients. In elderly patients, the clearance of amlodipine tends to decrease, resulting in an increase in AUC and half-life. The mean systemic AUC of valsartan is 70% higher in elderly patients than in young patients, so the dose should be increased with caution in such patients.
Systemic exposure to valsartan is somewhat higher in elderly patients compared to younger patients, but this is not clinically relevant.
Some data indicate that the systemic clearance of hydrochlorothiazide is reduced in both healthy elderly subjects and elderly patients with hypertension compared with younger healthy volunteers.
Since all three components of the medicinal product are equally well tolerated by young and elderly patients, the usual dosing regimen is recommended.
Kidney dysfunction
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. For a drug whose renal clearance accounts for only 30% of total plasma clearance, there was no relationship between renal function and systemic exposure to valsartan. Therefore, patients with mild to moderate renal impairment can use the drug at the usual starting dose.
Liver dysfunction
In patients with impaired liver function, the clearance of amlodipine is reduced, resulting in an increase in AUC by approximately 40-60%. In patients with chronic diseases of mild to moderate severity (determined by AUC), valsartan exposure is on average 2 times higher than in adult volunteers.
The drug should be prescribed with caution to patients with liver disease.
The combination of amlodipine/valsartan/hydrochlorothiazide was not tested for genotoxicity and carcinogenicity, as no evidence of interaction between these drugs was found. However, amlodipine, valsartan and hydrochlorothiazide were each tested separately for genotoxicity and carcinogenicity - the results were negative.
Indication
Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with a combination of amlodipine, valsartan and hydrochlorothiazide, given as three separate medicinal products or as two medicinal products, one of which is a combination.
Contraindication
Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives or to any of the excipients of the medicinal product.
II and III trimesters of pregnancy (see section "Use during pregnancy or breastfeeding").
Liver dysfunction, biliary cirrhosis or cholestasis.
Severe renal impairment (GFR < 30 ml/min/1.73 m2), anuria, and dialysis.
Concomitant use of Tiara Trio® with aliskiren-containing drugs in patients with diabetes mellitus or renal impairment (GFR < 60 mg/min/1.73 m2).
Refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia.
Severe hypotension.
Shock (including cardiogenic shock).
Left ventricular outflow tract obstruction (e.g., hypertrophic obstructive cardiomyopathy and severe aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Interaction with other medicinal products and other types of interactions
No drug interaction studies have been conducted with Tiara Trio®. The following provides only information on the interaction of each individual active ingredient with other drugs.
However, it is important to consider that the drug Tiara Trio® may enhance the hypotensive effect of other antihypertensive drugs.
Concomitant use is not recommended.
Interactions associated with both valsartan and hydrochlorothiazide
Lithium.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of lithium with ACE inhibitors, angiotensin II receptor blockers, including valsartan, or thiazides such as hydrochlorothiazide.
Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is likely to be increased with the use of the drug. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use.
Interactions related to valsartan
Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, and other agents that may increase potassium levels.
If a medicinal product that affects potassium levels is used in combination with valsartan, frequent monitoring of plasma potassium levels is recommended.
Interactions related to amlodipine
The use of amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients this combination increases the blood pressure-lowering effect.
Concomitant use requires caution
Interactions related to amlodipine
CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir).
Studies in elderly patients have shown that diltiazem inhibits the metabolism of amlodipine, possibly through CYP3A4 (plasma concentrations increase by approximately 50% and the effect of amlodipine is enhanced). It cannot be excluded that more potent CYP3A4 inhibitors (such as ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem.
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in a significant increase in amlodipine exposure. The clinical manifestations of these pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required.
CYP3A4 inducers (anticonvulsants (such as carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, St. John's wort).
There are no data on the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (e.g. rifampicin, St. John's wort) may result in decreased plasma concentrations of amlodipine. Clinical monitoring and dose adjustment of amlodipine are indicated during treatment with the inducer and after its withdrawal.
Amlodipine should be used with caution with CYP3A4 inducers.
Simvastatin.
Administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to administration of simvastatin alone. It is recommended that the daily dose of simvastatin be reduced to 20 mg in patients taking amlodipine.
Datrolen (infusion).
Fatal cases of ventricular fibrillation and cardiovascular collapse have been observed in animals due to hyperkalemia after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that concomitant use of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the treatment of malignant hyperthermia.
Interactions associated with both valsartan and hydrochlorothiazide
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and nonselective NSAIDs.
NSAIDs may weaken the antihypertensive effect of both ARA II and hydrochlorothiazide when used simultaneously. In addition, the simultaneous use of Tiara Trio® and NSAIDs may lead to impaired renal function and an increase in serum potassium. Therefore, it is recommended to monitor renal function at the beginning of treatment, as well as to ensure adequate hydration of the patient.
Interactions related to valsartan
Inhibitors of the accumulation transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir).
In vitro studies with human liver tissue have shown that valsartan is a substrate for the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Concomitant use of inhibitors of the uptake transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir) may increase systemic exposure to valsartan.
Interactions related to hydrochlorothiazide
Alcohol, anesthetics and sedative medications.
Concomitant administration of thiazide diuretics with substances that also have a blood pressure-lowering effect (e.g. those that reduce sympathetic activity of the central nervous system or direct vasodilation) may increase orthostatic hypotension.
Amantadine.
Thiazides, including hydrochlorothiazide, increase the risk of adverse reactions caused by amantadine.
Anticholinergic drugs and other drugs that affect gastric motility.
The bioavailability of thiazide-type diuretics may be increased by anticholinergic drugs (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and gastric emptying rate.
Conversely, it is assumed that prokinetic agents such as cisapride may reduce the bioavailability of thiazide diuretics.
Antidiabetic medications (e.g. insulin and oral antidiabetic agents).
Thiazides may alter glucose tolerance. Insulin and oral hypoglycemic agents may need to be re-adjusted.
Metformin.
Metformin should be used with caution because of the risk of lactic acidosis induced by functional renal failure associated with the use of hydrochlorothiazide.
β-blockers and diazoxide.
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers increases the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Therefore, such patients should be warned about the possibility of hyponatremic reactions and monitored.
Cyclosporine.
Concomitant treatment with cyclosporine increases the risk of hyperuricemia and gout-like complications.
Cytotoxic drugs (e.g., cyclophosphamide, methotrexate).
Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effect.
Digitalis glycosides.
Thiazide-induced hypokalemia or hypomagnesemia may occur as adverse effects, contributing to the development of digitalis-induced cardiac arrhythmias.
Iodinated contrast agents.
In case of diuretic-induced dehydration, there is an increased risk of developing acute renal failure, especially with high doses of iodine-containing drugs. Rehydration should be performed before use.
Ion exchange resins.
The absorption of thiazide diuretics, including hydrochlorothiazide, is reduced by cholestyramine or colestipol. This may result in subtherapeutic effects of the thiazide diuretic. However, it is necessary to stagger the administration of hydrochlorothiazide and the resin so that hydrochlorothiazide is taken at least 4 hours before or 4–6 hours after the resin, which would potentially minimize their interaction.
Drugs that affect potassium levels (kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives) and antiarrhythmic drugs.
The hypokalemic effect of hydrochlorothiazide may be enhanced by kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives and antiarrhythmics. If such medicinal products are prescribed with the combination of amlodipine/valsartan/hydrochlorothiazide, monitoring of plasma potassium levels is recommended.
Medications that affect sodium levels.
The hyponatremic effect of diuretics may be enhanced by antidepressants, antipsychotics, antiepileptic drugs, etc. Caution is required with prolonged use of these drugs.
Medications that can cause torsades de pointes.
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution with drugs that can induce torsades de pointes, in particular with class Ia and class III antiarrhythmic drugs, as well as with some antipsychotic drugs.
Medicines used to treat gout (probenecid, sulfinpyrazone and allopurinol).
The dose of uricosuric medicinal products may need to be adjusted as hydrochlorothiazide may increase serum uric acid levels. The dose of probenecid or sulfinpyrazone may need to be increased.
In the case of simultaneous use of thiazide diuretics, including hydrochlorothiazide, the frequency of hypersensitivity reactions to allopurinol increases.
Methyldopa.
There is evidence of the development of hemolytic anemia with the simultaneous use of hydrochlorothiazide and methyldopa.
Non-depolarizing skeletal muscle relaxants (e.g., tubocurarine).
Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
Other antihypertensive drugs.
Thiazides potentiate the antihypertensive effect of other antihypertensive drugs (such as guanethidine, methyldopa, β-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers and direct renin inhibitors).
Pressor amines (e.g., noradrenaline, adrenaline).
Hydrochlorothiazide may reduce the response to pressor amines such as norepinephrine. The clinical significance of this effect is uncertain and insufficient to warrant discontinuation of their use.
Vitamin D and calcium salts.
The use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may increase serum calcium levels. Concomitant use of thiazide diuretics may lead to hypercalcemia in predisposed patients (e.g., hyperparathyroidism, malignancy, or vitamin D-mediated conditions) due to increased tubular calcium reabsorption.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors, or aliskiren.
Clinical data have demonstrated that dual blockade of the RAAS through the concomitant use of ACE inhibitors, ARBs or aliskiren is associated with an increased risk of adverse reactions such as hypotension, hyperkalemia and renal impairment (including acute renal failure) compared with monotherapy with a substance affecting the RAAS.
Application features
The safety and efficacy of amlodipine in hypertensive crisis have not been studied.
Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of Tiara Trio® (10 mg/320 mg/25 mg), compared with 1.8% of patients receiving valsartan/hydrochlorothiazide (320 mg/25 mg), 0.4% of patients receiving amlodipine/valsartan (10 mg/320 mg), and 0.2% of patients receiving hydrochlorothiazide/amlodipine (25 mg/10 mg), in a controlled study in patients with moderate to severe uncomplicated hypertension.
In patients with an activated renin-angiotensin system (salt-depleted and/or dehydrated patients receiving high doses of diuretics) taking ARA II, symptomatic hypotension may occur after starting the drug. It is recommended to correct this condition before using Tiara Trio® or to closely monitor the patient at the beginning of treatment.
If severe hypotension occurs during the use of Tiara Trio®, the patient should be placed in a horizontal position with the legs elevated and, if necessary, intravenous saline should be administered. Treatment can be continued after blood pressure has stabilized.
Changes in serum electrolyte levels
Amlodipine/valsartan/hydrochlorothiazide.
In clinical studies, the opposing effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium levels approximately balance each other in many patients. In other patients, one or the other effect may be dominant.
Serum electrolyte levels should be checked periodically to detect possible electrolyte imbalance.
Periodic determination of serum electrolytes and potassium levels should be performed at appropriate intervals to prevent possible electrolyte imbalance, especially in patients with risk factors such as renal impairment, use of other medications, and a history of electrolyte imbalance.
Valsartan.
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin) is not recommended. Potassium levels should be monitored if necessary.
Hydrochlorothiazide.
Hypokalemia has been reported with thiazide diuretics, including hydrochlorothiazide.
The drug should be initiated only after correction of hypokalemia and any concomitant hypomagnesemia. Thiazide diuretics may induce hypokalemia or exacerbate existing hypokalemia. Thiazide diuretics should be used with caution in patients with conditions involving potassium loss, such as salt-wasting nephropathy and prerenal (cardiogenic) renal impairment. If hypokalemia develops during therapy with hydrochlorothiazide, the drug should be discontinued until stable correction of potassium balance has occurred.
Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with the development of hyponatremia and hypochloremic alkalosis or with exacerbation of existing hyponatremia. Hyponatremia has been observed, accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Treatment with hydrochlorothiazide should be started only after correction of existing hyponatremia. In the event of severe or rapid hyponatremia during therapy with the drug, its administration should be discontinued until normalization of sodium levels.
Thiazides, including hydrochlorothiazide, increase the urinary excretion of magnesium, which may lead to hypomagnesemia. Thiazide diuretics reduce calcium excretion, which may lead to hypercalcemia.
Periodic monitoring of electrolyte levels, especially potassium, sodium and magnesium, is necessary in all patients receiving thiazide diuretics.
Kidney dysfunction
Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease.
There is no need to adjust the dose of Tiara Trio® for patients with mild to moderate renal impairment (GFR > 30 ml/min/1.73m2). When using Tiara Trio®, it is recommended to periodically monitor the level of potassium, creatinine and uric acid in the serum of patients with renal impairment.
Concomitant use of angiotensin receptor antagonists, including valsartan, or ACE inhibitors with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mg/min/1.73 m2).
The drug is contraindicated in patients with severe renal failure, anuria, or patients on dialysis.
Renal artery stenosis
Tiara Trio® should be used with caution for the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation
There is no experience regarding the safety of Tiara Trio® in patients who have recently undergone a kidney transplant.
Valsartan is mainly excreted unchanged in the bile. The half-life of amlodipine is prolonged and the AUC is higher in patients with impaired liver function; dosage recommendations have not been established. For patients with mild to moderate hepatic impairment without cholestasis, the maximum recommended dose of valsartan is 80 mg. For this reason, Tiara Trio® is not indicated in such patients.
Angioedema
Angioedema, including swelling of the larynx and glottis, which may lead to airway obstruction, and/or swelling of the face, lips, pharynx and/or tongue, has been reported in patients taking valsartan. Some of these patients had a history of angioedema with other medicinal products, including ACE inhibitors. The medicinal product should be discontinued immediately if angioedema occurs, and re-administration is not recommended.
Heart failure and coronary artery disease/post-myocardial infarction
Due to inhibition of PAAC in susceptible patients, changes in renal function may be expected. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin receptor antagonists has resulted in oliguria and/or progressive azotemia (rarely) with acute renal failure and/or fatal outcome. Similar results have been reported with valsartan. Evaluation of patients with heart failure or after myocardial infarction should always include assessment of renal function.
In a long-term placebo-controlled study of amlodipine (PRAISE-2) in patients with non-ischemic heart failure of NYHA class III and IV, the incidence of pulmonary edema was higher with amlodipine, despite a small difference in the occurrence or worsening of heart failure compared with placebo.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure as they may increase the risk of cardiovascular events and death.
It is recommended to prescribe the drug with caution to patients with heart failure and coronary artery disease, especially at the maximum dose of 10 mg/25 mg/320 mg, since data on the use of the drug in this group of patients are limited.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other vasodilators, the drug should be administered with extreme caution to patients with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Pregnancy
Treatment with ARA II should not be initiated during pregnancy. If continued ARA II therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy occurs, treatment with ARA II should be stopped immediately, and, if appropriate, alternative therapy should be started.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with ARA II valsartan because they do not have an activated renin-angiotensin system. Therefore, Tiara Trio® is not recommended for this group of patients.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate systemic lupus erythematosus.
Other metabolic disorders
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and increase serum cholesterol, triglycerides, and uric acid. Dosage adjustment of insulin or oral hypoglycemic agents may be necessary in patients with diabetes mellitus.
Since Tiara Trio® contains hydrochlorothiazide, it is contraindicated in systemic hyperuricemia. Hydrochlorothiazide may increase serum uric acid levels due to decreased uric acid clearance and may exacerbate hyperuricemia.
