Teveten^® plus (Tablets) Instructions for Use

ATC Code

C09DA02 (Eprosartan and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Eprosartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Antihypertensive combination agent (diuretic + angiotensin II receptor antagonist)

Pharmacological Action

A combined antihypertensive drug containing the angiotensin II receptor antagonist eprosartan and the diuretic Hydrochlorothiazide.

Eprosartan– an angiotensin II receptor antagonist, selectively acts on AT₁ receptors located in the vessels, heart, kidneys, and adrenal cortex, forming a strong bond with them followed by slow dissociation.

It prevents the development or weakens the effects of angiotensin II and suppresses the activity of the RAAS. It has a vasodilating, antihypertensive, and mediated diuretic effect. It reduces arterial vasoconstriction, total peripheral resistance, pressure in the pulmonary circulation, reabsorption of water and sodium in the proximal segment of the renal tubules, and the secretion of aldosterone.

With long-term use, it suppresses the proliferative effect of angiotensin II on vascular smooth muscle cells and myocardium. The antihypertensive effect after a single oral dose develops within 24 hours, and a stable therapeutic effect develops with regular oral administration after 2-3 weeks without affecting heart rate.

It does not cause the development of orthostatic hypotension in response to the first dose of the drug.

It increases renal blood flow and glomerular filtration rate, reduces albumin excretion (nephroprotective action), while maintaining renal autoregulation regardless of the degree of renal failure.

It does not affect lipid, carbohydrate, and purine metabolism. Upon discontinuation of treatment, it does not cause withdrawal syndrome.

It causes effects associated with bradykinin activity (including persistent dry cough) less frequently than ACE inhibitors.

Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chloride, potassium, magnesium ions, and water in the distal part of the nephron; it delays the excretion of calcium ions and uric acid.

It has antihypertensive properties; the hypotensive effect develops due to the expansion of arterioles. It has practically no effect on normal blood pressure levels.

The diuretic effect develops approximately within 2 hours after administration, the maximum effect is reached in 3-6 hours and lasts for 6-12 hours.

The antihypertensive effect is achieved in 3-4 days of treatment and lasts for 1 week after completion of the drug intake. With long-term treatment, blood pressure reduction is achieved with lower doses than those required for a diuretic effect.

Blood pressure reduction is accompanied by a slight increase in glomerular filtration rate, vascular resistance of the renal bed, and plasma renin activity.

Hydrochlorothiazide, when taken once in high doses, leads to a decrease in plasma volume, glomerular filtration rate, renal blood flow, and mean blood pressure.

With long-term use in low doses, plasma volume remains reduced, while minute volume and glomerular filtration rate return to the baseline level preceding the start of treatment.

Mean blood pressure and systemic vascular resistance remain reduced. Thiazide diuretics can interfere with breast milk production.

Eprosartan+Hydrochlorothiazide. In patients with elevated systolic blood pressure, eprosartan provides a statistically significant reduction.

The addition of 12.5 mg of hydrochlorothiazide to a single daily dose (600 mg or 1200 mg) of eprosartan provides an additional statistically significant reduction in systolic blood pressure compared to daily intake of eprosartan alone.

Combined intake of eprosartan with hydrochlorothiazide reduces potassium loss associated with the diuretic effect of hydrochlorothiazide.

The diuretic effect when using this combination develops within the first 2 hours and reaches a maximum 4 hours after oral administration. A stable antihypertensive effect usually develops after 2-3 weeks of treatment.

Pharmacokinetics

Eprosartan

When taken orally, the absolute bioavailability is about 13%.

C_max of eprosartan is determined 1-2 hours after oral administration. The binding of eprosartan to plasma proteins is high (98%) and remains constant after reaching therapeutic concentration in plasma.

V_d of eprosartan is 13 L. Eprosartan practically does not accumulate. T_1/2 is usually 5-9 hours. The total clearance of eprosartan is 130 ml/min.

When taken orally, it is excreted mainly unchanged through the intestine (90%) and by the kidneys (7%). A small part (less than 2%) is excreted by the kidneys in the form of glucuronides.

Hydrochlorothiazide

Hydrochlorothiazide does not penetrate the BBB but penetrates the placental barrier and is excreted in breast milk.

It is not metabolized. It is rapidly excreted by the kidneys. After oral administration, at least 61% of the dose is excreted unchanged within 24 hours.

Eprosartan+Hydrochlorothiazide

Simultaneous administration of eprosartan and hydrochlorothiazide from a clinical point of view does not have a significant impact on the pharmacokinetics of both components.

Food intake does not affect the bioavailability of eprosartan and hydrochlorothiazide but delays their absorption.

C_max in plasma is reached 4 hours after taking eprosartan and 3 hours after taking hydrochlorothiazide orally.

Indications

Arterial hypertension (when combination therapy with eprosartan and hydrochlorothiazide is necessary).

ICD codes

Dosage Regimen

Take the fixed-dose combination tablet orally once daily.

The standard adult dose is 600 mg eprosartan / 12.5 mg hydrochlorothiazide.

Take the tablet with a sufficient amount of water, with or without food.

Dose titration should be based on individual patient response and tolerability.

If blood pressure control is insufficient, consider increasing the dose after several weeks of therapy.

Do not exceed the maximum recommended daily dose.

For patients with severe renal impairment (creatinine clearance <30 mL/min), this combination is contraindicated.

Use with caution in patients with mild to moderate hepatic impairment; it is contraindicated in severe hepatic impairment.

In elderly patients, no initial dose adjustment is typically required, but initiate therapy with caution.

Monitor blood pressure, renal function, and serum electrolytes periodically during treatment.

This medication is not indicated for use in children and adolescents under 18 years of age.

Adverse Reactions

From the hematopoietic system: infrequently – leukopenia; very rarely – hemolytic anemia; frequency unknown – agranulocytosis, thrombocytopenia, aplastic anemia.

From the immune system: infrequently – hypersensitivity reactions; frequency unknown – anaphylactic reactions.

From metabolism and nutrition: frequently – hyperglycemia; infrequently – hyperuricemia, exacerbation of gout, hyponatremia, hypokalemia, hypochloremia, hypercholesterolemia; frequency unknown – hypercalcemia, hypomagnesemia, hypertriglyceridemia, anorexia.

From the psyche: infrequently – depression, anxiety, insomnia, nervousness, libido disorders; frequency unknown – restlessness.

From the nervous system: very frequently – headache (11%); frequently – dizziness, paresthesia.

From the organ of vision: frequency unknown – acute myopia, secondary angle-closure glaucoma.

From the organ of hearing and balance: infrequently – vertigo.

From the cardiovascular system: frequently – pronounced decrease in blood pressure, orthostatic hypotension; frequency unknown – necrotizing angiitis.

From the respiratory system: frequently – rhinitis; rarely – respiratory distress syndrome (including pneumonitis and non-cardiogenic pulmonary edema).

From the digestive system: frequently – nonspecific gastrointestinal disorders (nausea, vomiting, diarrhea); infrequently – constipation; rarely – pancreatitis.

From the liver and biliary tract: frequency unknown – jaundice, including intrahepatic cholestatic jaundice.

From the skin and subcutaneous tissues: frequently – allergic skin reactions (skin rash, itching); infrequently – angioedema; frequency unknown – toxic epidermal necrolysis, photosensitivity reactions.

From the musculoskeletal system: infrequently – muscle spasms; frequency unknown – systemic lupus erythematosus.

From the urinary system: frequency unknown – interstitial nephritis, renal failure, impaired renal function in patients at risk (renal artery stenosis), glucosuria.

From the reproductive organs: infrequently – sexual dysfunction.

General disorders: frequently – asthenia; infrequently – hyperthermia.

Contraindications

Severe renal failure (creatinine clearance <30 ml/min); severe hepatic failure (more than 9 points on the Child-Pugh scale); cholestasis and obstruction of the biliary tract; hemodynamically significant bilateral renal artery stenosis or severe stenosis of the artery of a single functioning kidney; treatment-resistant hypokalemia or hypercalcemia; refractory hyponatremia; symptomatic hyperuricemia or gout; simultaneous use with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (creatinine clearance less than 60 ml/min); pregnancy, lactation period (breastfeeding); age under 18 years; hypersensitivity to eprosartan, hydrochlorothiazide, other sulfonamide derivatives.

With caution: severe and chronic heart failure (NYHA class IV), bilateral renal artery stenosis, stenosis of the artery of a single kidney, reduced circulating blood volume, impaired water-electrolyte balance of the blood (due to taking diuretics in high doses, repeated vomiting, prolonged diarrhea, salt-free diet), mild or moderate hepatic failure (less than 9 points on the Child-Pugh scale without a history of cholestasis), diabetes mellitus, stenosis of the aortic and mitral valves, hypertrophic obstructive cardiomyopathy, primary hyperaldosteronism, coronary artery disease (experience of use is limited), acute myopathy, secondary angle-closure glaucoma, systemic lupus erythematosus.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during the lactation period (breastfeeding).

Special Precautions

In patients whose renal function depends on the activity of the RAAS (for example, in severe chronic heart failure of functional class IV according to the NYHA classification), during treatment with ACE inhibitors, oliguria and/or progressive azotemia may develop, and, in rare cases, acute renal failure.

These phenomena are most likely in patients simultaneously taking diuretics. Due to insufficient experience with the use of angiotensin II receptor antagonists in patients with severe chronic heart failure of NYHA class IV, impaired renal function during the use of the combination eprosartan+Hydrochlorothiazide due to suppression of RAAS activity cannot be ruled out.

Due to the increased risk of developing severe arterial hypotension and renal failure in such patients, renal function should be carefully monitored.

Before starting treatment with the combination eprosartan+Hydrochlorothiazide in patients with renal failure and, periodically, during treatment, renal function, serum potassium and uric acid levels should be monitored.

If during this period a deterioration in renal function is observed, treatment with the combination should be discontinued.

In patients with impaired renal function, Hydrochlorothiazide-associated azotemia may be observed.

Eprosartan should be used with caution for the treatment of patients with mild and moderate hepatic impairment due to limited clinical experience with the drug in such patients.

Due to the possibility of developing intrahepatic cholestasis, Hydrochlorothiazide should be used with caution for the treatment of mild and moderate hepatic impairment.

Changes in water-electrolyte balance can cause hepatic coma.

Hydrochlorothiazide can reduce glucose tolerance, which may require adjustment of the dose of hypoglycemic agents and insulin.

Latent diabetes mellitus may manifest during treatment with this combination.

The use of hydrochlorothiazide can lead to an imbalance in the water-electrolyte balance of the blood (hypokalemia, hyponatremia, hypercalcemia, hypomagnesemia, and hypochloremic alkalosis).

All patients receiving diuretics, including Hydrochlorothiazide, need to periodically monitor the serum electrolyte levels.

In case of severe hyponatremia or reduced circulating blood volume (for example, during treatment with diuretics in high doses, repeated vomiting, prolonged diarrhea, salt-free and low-salt diet), taking this combination can cause a sharp decrease in blood pressure.

Correction of hyponatremia and/or circulating blood volume and, if possible, discontinuation of diuretics before starting treatment with this combination is necessary.

Hydrochlorothiazide, being a sulfonamide, can cause idiosyncrasy, expressed as acute transient myopia and an attack of acute angle-closure glaucoma.

Symptoms, including a sharp decrease in visual acuity or eye pain, usually develop within a few hours to several weeks after starting the drug.

Lack of treatment for acute angle-closure glaucoma can lead to irreversible vision loss. Primary treatment consists of discontinuing hydrochlorothiazide as soon as possible.

Urgent medical or surgical treatment may be required if intraocular pressure remains uncontrolled. Risk factors for the development of an acute angle-closure glaucoma attack may include a history of allergic reactions to sulfonamide or penicillin.

In patients with primary hyperaldosteronism, the use of antihypertensive agents that inhibit the RAAS is usually ineffective.

In this regard, the use of this combination in this category of patients is not recommended.

Hypersensitivity reactions to hydrochlorothiazide are most likely for patients with a history of allergies, including those with hypersensitivity to sulfonamide derivatives.

Hydrochlorothiazide may give a positive result when conducting a doping control test.

Concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) compared to the separate use of agents acting on the RAAS.

Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended.

If dual blockade is necessary, it should be carried out strictly under the supervision of a specialist and with constant monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended for patients with diabetic nephropathy.

Effect on the ability to drive vehicles and mechanisms

During treatment with this combination, the patient should exercise caution when driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions, due to the possibility of dizziness and weakness.

Drug Interactions

Concomitant use of ACE inhibitors and angiotensin II receptor antagonists is not recommended for patients with diabetic nephropathy.

Concomitant use of aliskiren with an ACE inhibitor or angiotensin receptor blocker is contraindicated in patients with type 2 diabetes or renal impairment (creatinine clearance less than 60 ml/min).

Eprosartan+Hydrochlorothiazide

A reversible increase in serum lithium concentration and increased toxicity have been noted with the concomitant use of lithium preparations with ACE inhibitors and, in rare cases, with angiotensin II receptor antagonists.

In addition, thiazides reduce the renal clearance of lithium and therefore may increase the risk of its toxic effects.

In this regard, this combination together with lithium preparations is not recommended. If combination therapy is necessary, regular monitoring of serum lithium concentration should be carried out.

Baclofen – possible enhancement of the antihypertensive effect.

Concomitant use of angiotensin II receptor antagonists and NSAIDs may increase the risk of renal dysfunction, including the possibility of acute renal failure and increased serum potassium levels, especially in patients with pre-existing reduced renal function.

Such combinations should be used with caution, especially in elderly patients.

Amifostine – possible enhancement of the antihypertensive effect.

Other antihypertensive drugs – the antihypertensive effect of this combination may be enhanced when used simultaneously with other antihypertensive agents.

Ethanol, barbiturates, anesthetics, or antidepressants – possible occurrence of orthostatic hypotension.

Eprosartan

Clinical study data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased frequency of adverse events such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) compared to the separate use of agents acting on the RAAS.

Hydrochlorothiazide

The hypokalemic effect of hydrochlorothiazide may be enhanced by the simultaneous administration of other drugs that lead to potassium excretion and hypokalemia (for example, other potassium-wasting diuretics, laxatives, corticosteroids, glycyrrhizic acid (contained in licorice root), adrenocorticotropic hormone, amphotericin B (for intravenous administration), carbenoxolone, penicillin G (sodium salt) or salicylic acid derivatives).

In this regard, the use of this combination is not recommended.

Thiazide diuretics may increase serum calcium levels due to decreased excretion.

If it is necessary to use calcium preparations or calcium-sparing drugs (for example, vitamin D), it is necessary to monitor serum calcium levels and adjust its dose accordingly.

The absorption of hydrochlorothiazide is reduced with the simultaneous use of anion exchange resins, including cholestyramine or colestipol.

Cardiac glycosides – hypokalemia or hypomagnesemia caused by thiazide diuretics contributes to the development of arrhythmia.

Drugs whose effects are affected by hypokalemia – cardiac glycosides and antiarrhythmic drugs, as well as drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type (ventricular tachycardia) – class IA antiarrhythmic drugs (for example, quinidine, hydroquinidine, disopyramide); class III antiarrhythmic drugs (for example, amiodarone, dofetilide, ibutilide) and sotalol; some antipsychotics (for example, thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol); other drugs (for example, bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

Non-depolarizing muscle relaxants (e.g., tubocurarine) – Hydrochlorothiazide may enhance the effect of non-depolarizing muscle relaxants.

Anticholinergic drugs (e.g., atropine, biperiden) – increased bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Drugs for the treatment of diabetes mellitus (hypoglycemic drugs and insulin) – use of thiazide may affect glucose tolerance, which may require dose adjustment of hypoglycemic agents.

Metformin – metformin should be used with caution due to the risk of lactic acidosis due to possible functional renal failure caused by hydrochlorothiazide.

Beta-blockers and diazoxide – thiazides may enhance the hyperglycemic effect of beta-blockers and diazoxide.

Pressor amines (e.g., norepinephrine) – a decrease in the effect of pressor amines is possible.

Antigout drugs (probenecid, sulfinpyrazone and allopurinol) – dose adjustment of antigout drugs is necessary, since Hydrochlorothiazide may increase serum uric acid concentration. An increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant use with thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadine – thiazides may increase the risk of adverse reactions caused by amantadine.

Cytostatic drugs (e.g., cyclophosphamide, methotrexate) – thiazides can reduce the renal excretion of cytostatic drugs and enhance their myelosuppressive effect.

Tetracyclines – when tetracyclines and thiazides are used concomitantly, the risk of an increase in the level of the latter in the urine caused by tetracycline increases. This interaction most likely does not apply to doxycycline.

Drugs that reduce serum sodium levels, – when used concomitantly with antidepressants, antipsychotics and antiepileptic drugs, the hyponatremic effect of hydrochlorothiazide may be enhanced.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.