Instructions for use Corsar Trio film-coated tablets 160 mg + 5 mg + 12.5 mg blister No. 30
Composition
active ingredients: valsartan, amlodipine, hydrochlorothiazide;
1 tablet contains:
160 mg valsartan, amlodipine besylate equivalent to 5 mg amlodipine, and 12.5 mg hydrochlorothiazide
or 160 mg of valsartan, amlodipine besylate equivalent to 10 mg of amlodipine, and 12.5 mg of hydrochlorothiazide;
excipients: microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silicon dioxide, magnesium stearate, polyethylene glycol 6000 (macrogol 6000), hypromellose, titanium dioxide (E 171), talc.
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex tablets, white to almost white in color, film-coated.
Pharmacotherapeutic group
Drugs affecting the cardiovascular system. Drugs acting on the renin-angiotensin system. Combinations of angiotensin II inhibitors. Angiotensin II antagonists, other combinations. Valsartan, amlodipine and hydrochlorothiazide.
ATX code C09D X01.
Pharmacological properties
Pharmacodynamics.
ADENIZ-Trio contains three antihypertensive agents with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the class of calcium antagonists, valsartan to the class of angiotensin II antagonists, 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 ADENIZ-Trio, inhibits the transmembrane entry of calcium ions into the heart muscle and vascular smooth muscle. The antihypertensive effect of amlodipine is carried out by a direct relaxing effect on vascular smooth muscle, causing a decrease in peripheral vascular resistance and blood pressure.
Amlodipine at therapeutic doses in patients with arterial hypertension causes vasodilation, leading to a decrease in blood pressure in the supine and standing positions. This decrease in blood pressure is not accompanied by pronounced changes in heart rate or plasma catecholamine levels with prolonged use.
Plasma concentration correlates with effect in both young and elderly patients.
In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses leads to 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 angiotensin II receptor antagonist. Valsartan acts selectively on the AT1 receptor subtype, which is responsible for the known effects of angiotensin II.
Taking valsartan by patients with arterial hypertension 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 there are high-affinity receptors 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 an approximately equivalent 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.
Non-melanoma skin cancer
The results of two pharmacoepidemiological studies based on data from the Danish National Cancer Registry demonstrated a cumulative dose-dependent association between hydrochlorothiazide and the occurrence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).
Another study showed a possible association between lip cancer (LC) and hydrochlorothiazide use: cases of lip cancer (LC) were compared with patients in a control population using a random sampling strategy. A cumulative dose-dependent association was demonstrated with an adjusted hazard ratio of 2.1 (95% CI: 1.7–2.6), increasing to a hazard ratio of 3.9 (3.0–4.9) for high doses (25,000 mg) and a hazard ratio of 7.7 (5.7–10.5) for the highest cumulative dose (100,000 mg) (see section 4.4).
Pharmacokinetics.
Linearity
Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.
Amlodipine/valsartan/hydrochlorothiazide
After oral administration of amlodipine, valsartan and hydrochlorothiazide, peak plasma concentrations were reached within 6–8 hours, 3 hours and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and hydrochlorothiazide when administered in combination are similar to those observed when administered as individual drugs.
Amlodipine
Absorption
After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations (Cmax) are reached within 6–12 hours. Absolute bioavailability is 64–80%. Food intake does not affect the bioavailability of amlodipine.
Distribution
The volume of distribution is approximately 21 l/kg. Approximately 97.5% of the drug in the circulating blood is bound to plasma proteins.
Biotransformation
Amlodipine is actively (approximately 90%) metabolized in the liver to inactive metabolites.
Breeding
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 the parent amlodipine and 60% of the 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 the area under the pharmacokinetic curve (AUC) of valsartan by approximately 40% and Cmax by approximately 50%, although approximately 8 hours after administration, valsartan concentrations are similar in the fasting and fed groups. However, this decrease in AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so valsartan can be used regardless of food intake.
Distribution
The volume of distribution of valsartan at steady state after intravenous administration is approximately 17 liters, indicating that it is not extensively distributed into tissues. Valsartan is highly bound to serum proteins (94–97%), mainly 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.
Breeding
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. There is no change in the kinetics of hydrochlorothiazide upon repeated administration, and accumulation was minimal with once-daily dosing. When taken with food, both an increase and a decrease in the systemic availability of hydrochlorothiazide were observed compared with fasting. The magnitude of these effects is insignificant and of little clinical significance. The absolute bioavailability of hydrochlorothiazide is 60–80% after oral administration.
Distribution
The apparent volume of distribution is 4–8 l/kg. Hydrochlorothiazide in the circulating blood binds to plasma proteins (40–70%), mainly albumin. Hydrochlorothiazide also accumulates in erythrocytes in an amount 1.8 times higher than in plasma.
Biotransformation
Hydrochlorothiazide is excreted unchanged.
Breeding.
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 younger patients, so the dose should be increased with caution in such patients.
Limited data indicate that the systemic clearance of hydrochlorothiazide is reduced in both healthy elderly volunteers and elderly patients with hypertension compared to younger healthy volunteers.
Since the three components of the drug are equally well tolerated by young and elderly patients, the usual dosage regimen is recommended for elderly patients.
Kidney dysfunction
Renal impairment does not significantly affect the pharmacokinetics of amlodipine. As expected, 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.
In the presence of renal insufficiency, the mean peak plasma levels of hydrochlorothiazide and AUC values increase, and the rate of its excretion in the urine decreases. In patients with mild and moderate renal impairment, a 3-fold increase in the AUC of hydrochlorothiazide is observed. In patients with severe renal impairment, an 8-fold increase in AUC was observed. The drug ADENIZ-Trio is contraindicated in patients with severe renal impairment, anuria or dialysis.
Liver dysfunction
There are very limited clinical data on the use of amlodipine in patients with impaired hepatic function. In patients with impaired hepatic function, the clearance of amlodipine is reduced, resulting in an increase in AUC by approximately 40-60%. On average, in patients with mild to moderate chronic diseases, the AUC of valsartan is 2 times higher than in adult volunteers (grouped by age, sex and body weight).
The drug ADENIZ-Trio is contraindicated in patients with liver failure due to the presence of valsartan in its composition.
Indication
Treatment of essential hypertension in adult patients whose blood pressure is adequately controlled with a combination of amlodipine, valsartan and hydrochlorothiazide, who are taking three separate drugs or two drugs, one of which is a combination.
Contraindication
- Hypersensitivity to the active substances, other sulfonamides, dihydropyridine derivatives or to any of the excipients of the drug;
- pregnancy or planning a pregnancy (see section "Use during pregnancy or breastfeeding");
- liver failure, biliary cirrhosis or cholestasis;
- severe renal dysfunction (GFR 1.73 m2), anuria, as well as dialysis;
- concomitant use of angiotensin receptor antagonists (ARBs), including valsartan, or angiotensin-converting enzyme (ACE) inhibitors with aliskiren in the case of diabetes mellitus or impaired renal function (GFR 2);
- refractory hypokalemia, hyponatremia, hypercalcemia, symptomatic hyperuricemia;
- severe hypotension;
- shock (including cardiogenic shock);
- obstruction of the left ventricular outflow tract (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
Interaction studies with valsartan/amlodipine/hydrochlorothiazide have not been conducted. Only information on interactions with other medicinal products known for each individual active substance is presented below.
However, it is important to consider that the drug ADENIZ-Trio may enhance the hypotensive effect of other antihypertensive drugs.
Concomitant use is not recommended.
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 antagonists 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 ADENIZ-Trio. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use.
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 required in combination with valsartan, frequent monitoring of plasma potassium levels is recommended.
Amlodipine
Grapefruit or grapefruit juice
The use of amlodipine with grapefruit or grapefruit juice is not recommended, as it may lead to an increased blood pressure-lowering effect in some patients.
Concomitant use requires caution
Amlodipine
Studies in elderly patients have shown that diltiazem inhibits the metabolism of amlodipine, possibly with the participation of CYP3A4 (plasma concentration increases 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 concentration 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 lead to a decrease in plasma concentrations of amlodipine. Clinical monitoring with possible dose adjustment of amlodipine is 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.
Dantrolene (infusion)
Fatalities due to ventricular fibrillation and cardiovascular collapse have been observed in animals due to hyperkalemia following 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.
Valsartan and hydrochlorothiazide
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and nonselective NSAIDs
NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when used concomitantly. In addition, concomitant use of ADENIZ-Trio with NSAIDs may lead to impaired renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of treatment and appropriate hydration of the patient are recommended.
Inhibitors of the accumulation transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir)
Concomitant use of inhibitors of the accumulation transporter (rifampicin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure of valsartan.
Hydrochlorothiazide
Alcohol, barbiturates, or narcotics
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, may 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-type diuretics.
Antidiabetic medications (e.g., insulin and oral antidiabetic agents)
Thiazide diuretics may alter glucose tolerance, which may necessitate re-adjustment of insulin and oral hypoglycemic agents.
Metformin
Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure associated with the use of hydrochlorothiazide.
β-blockers and diazoxide
Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide.
Carbamazepine
Hyponatremia may develop in patients receiving hydrochlorothiazide concomitantly with carbamazepine. Therefore, patients should be warned about the possibility of hyponatremic reactions and monitored.
Cyclosporine
Concomitant treatment with cyclosporine may increase 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.
Thiazide-induced hypokalemia or hypomagnesemia may occur as undesirable effects, leading to the development of digitalis-induced cardiac arrhythmias.
Iodine-containing contrast agents
In case of diuretic-induced dehydration, there is an increased risk of developing acute renal failure, especially with high doses of iodine preparations. 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 diuretics. However, the effective dose of hydrochlorothiazide and the resin is such that hydrochlorothiazide should be administered at least 4 hours before or 4 to 6 hours after the resin, potentially minimizing the interaction.
Drugs that affect potassium levels (kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G, salicylic acid derivatives), and antiarrhythmics
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 drugs 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 concomitant use of such drugs as antidepressants, neuroleptics, and antiepileptic drugs. Caution should be exercised when prescribing ADENIZ-Trio during long-term treatment with the above drugs.
Drugs that can cause torsades de pointes
Due to the risk of hypokalemia, hydrochlorothiazide should be used with caution simultaneously with drugs that can cause torsades de pointes, in particular with class Ia and class III antiarrhythmics and some neuroleptics.
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.
Concomitant use of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.
Methyldopa
There have been isolated reports of the development of hemolytic anemia with the simultaneous use of hydrochlorothiazide and methyldopa.
Nondepolarizing skeletal muscle relaxants (e.g., tubocurarine)
Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
Other antihypertensive drugs
Thiazide diuretics potentiate the antihypertensive effect of other antihypertensive drugs (e.g. guanethidine, methyldopa, β-blockers, vasodilators, calcium channel blockers, ACE inhibitors, angiotensin II receptor blockers and direct renin inhibitors).
Pressor amines (e.g., noradrenaline, adrenaline)
The effect of pressor amines may be attenuated.
The clinical significance of this effect is uncertain and insufficient to rule out their use.
Vitamin D and calcium salts
The use of thiazide diuretics, including hydrochlorothiazide, with vitamin D or calcium salts may potentiate increases in serum calcium levels.
Concomitant use of thiazide diuretics may lead to hypercalcemia (e.g. hyperparathyroidism, malignancy or vitamin D-mediated conditions) in predisposed patients by increasing 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, angiotensin II receptor antagonists or aliskiren is associated with an increased risk of adverse reactions such as hypotension, hyperkalemia and renal dysfunction (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.
Patients with sodium deficiency and/or dehydration
Excessive hypotension, including orthostatic hypotension, was observed in 1.7% of patients receiving the maximum dose of the amlodipine/valsartan/hydrochlorothiazide combination (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.
If severe hypotension occurs during the use of ADENIZ-Trio, the patient should be placed in a horizontal position with the lower extremities elevated and, if necessary, an intravenous infusion of saline should be administered. Treatment can be continued after blood pressure has stabilized.
Changes in serum electrolyte levels
Amlodipine/valsartan/hydrochlorothiazide
In a controlled study of the combination of amlodipine/valsartan/hydrochlorothiazide, the opposing effects of valsartan 320 mg and hydrochlorothiazide 25 mg on serum potassium approximately balanced each other in many patients. In other patients, one effect may be dominant.
Serum electrolyte levels should be checked periodically at appropriate intervals to identify 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, treatment with other drugs and a history of electrolyte imbalance.
Valsartan
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs 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.
Treatment with ADENIZ-Trio should only be initiated after correction of hypokalemia and any concomitant hypomagnesemia. Thiazide diuretics may induce hypokalemia or exacerbate existing hypokalemia and 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, ADENIZ-Trio should be discontinued until potassium balance is stable.
Treatment with thiazide diuretics, including hydrochlorothiazide, is associated with the development of hyponatremia and hypochloremic alkalosis or with exacerbation of existing hyponatremia. Hyponatremia is observed, accompanied by neurological symptoms (nausea, progressive disorientation, apathy). Treatment with hydrochlorothiazide should be started only after correction of existing hyponatremia. In case of severe or rapid hyponatremia during treatment with ADENIZ-Trio, the drug should be discontinued until normalization of sodium. Thiazides, including hydrochlorothiazide, increase the excretion of magnesium in the urine, which can lead to hypomagnesemia. When using thiazide diuretics, calcium excretion is reduced, which can lead to hypercalcemia.
All patients receiving thiazide diuretics should have periodic monitoring of electrolyte levels, especially potassium, sodium, and magnesium.
Non-melanoma skin cancer
An increased risk of non-melanoma skin cancer with increasing cumulative dose of hydrochlorothiazide has been found in two pharmacoepidemiological studies. The photosensitizing effect of hydrochlorothiazide may be a mechanism for the development of this pathology.
Patients taking hydrochlorothiazide alone or in combination with other drugs should be informed of the risk of developing non-melanoma skin cancer, especially with long-term use, of the need to regularly examine the skin and immediately report to the doctor any new lesions or any suspicious skin growths, changes in skin lesions or moles.
To reduce the risk of skin cancer, patients should be informed about possible preventive measures, such as limiting exposure to sunlight and UV radiation, and in case of exposure, about the need for adequate skin protection. Suspicious skin lesions should be examined as soon as possible, including histological examination of biopsy material.
Patients with a history of non-melanoma skin cancer may also need to reconsider the use of hydrochlorothiazide.
Kidney dysfunction
Thiazide diuretics may precipitate azotemia in patients with chronic kidney disease.
There is no need to adjust the dose of ADENIZ-Trio in patients with mild to moderate renal impairment (GFR ≥ 30 ml/min/1.73 m2).
The drug is contraindicated in patients with severe renal failure, anuria, and patients on dialysis.
It is recommended to periodically monitor serum potassium, creatinine, and uric acid levels in patients with renal impairment when using the drug ADENIZ-Trio.
Renal artery stenosis
The drug ADENIZ-Trio should be used with caution for the treatment of hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of a solitary kidney, as serum urea and creatinine levels may increase.
Kidney transplantation
There is currently no information on the safety of using the drug ADENIZ-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 AUC is higher in patients with impaired hepatic 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, ADENIZ-Trio is not indicated in this group of 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 treated with valsartan. Some of these patients had a history of angioedema while taking other drugs, including ACE inhibitors. ADENIZ-Trio should be discontinued immediately if angioedema occurs; re-administration is not recommended.
Heart failure and coronary artery disease/post-myocardial infarction
Due to inhibition of the RAAS, renal function may be expected to deteriorate in susceptible patients. 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 may be fatal.
It is recommended to prescribe the drug with caution to patients with heart failure and coronary artery disease, especially at the maximum dose of the drug ADENIZ-Trio - 320 mg/10 mg/25 mg, since data on the use of the drug in this group of patients is limited.
Aortic and mitral valve stenosis
As with other vasodilators, the drug should be prescribed with extreme caution to patients with mild aortic and mitral valve stenosis.
Pregnancy
Angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. Unless continued ARB 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 is diagnosed, ARB treatment should be stopped immediately, and, if appropriate, alternative therapy should be started.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan, as they do not have an activated renin-angiotensin system. Therefore, ADENIZ-Trio is not recommended for this group of patients.
Systemic lupus erythematosus
Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.
Other metabolic disorders
Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and increase cholesterol, triglycerides, and uric acid levels in
