Teveten, 600 mg, film-coated tablets, 28 pcs.

Pharmacological properties of the drug Teveten plus

Pharmacodynamics . Eprosartan Eprosartan is a potent, non-peptide, orally active, non-biphenyl, non-tetrazole angiotensin II receptor antagonist that selectively binds to AT1 receptors. Angiotensin II plays an important role in the pathogenesis of hypertension (arterial hypertension) and is the main active hormone of the renin-angiotensin-aldosterone system. In addition, eprosartan blocks the direct vasoconstrictor effect of angiotensin, and its indirect effects associated with increased nerve impulse transmission indicate a potential ability to counteract increased activity of the sympathetic nervous system. Eprosartan interferes with the effects of angiotensin II on blood pressure, renal blood flow and aldosterone release in healthy volunteers. The therapeutic effect lasts for 24 hours without the appearance of postural hypotension or reflex tachycardia after taking the first dose. Discontinuation of treatment with eprosartan does not lead to a sharp rebound rise in blood pressure. Eprosartan does not interfere with the mechanisms of self-regulation of renal function. In healthy individuals, eprosartan improves effective renal blood flow. Eprosartan supports renal function in patients with essential hypertension and in those with renal failure. Unlike ACE inhibitors, eprosartan does not potentiate the effects associated with increased bradykinin levels, such as cough. Hydrochlorothiazide Hydrochlorothiazide is a well-known thiazide diuretic. Thiazides affect the mechanisms of electrolyte reabsorption in the renal tubules, causing a direct increase in the excretion of fluid, sodium and chloride. The diuretic effect of hydrochlorothiazide leads to a decrease in blood plasma volume, an increase in plasma renin activity and aldosterone secretion with a further increase in urinary excretion of potassium and bicarbonate and a decrease in serum potassium levels. The antihypertensive effect of hydrochlorothiazide is due to a combination of a diuretic effect and a direct effect on blood vessels (reducing vascular resistance). Teveten plus Combined intravenous administration of eprosartan and hydrochlorothiazide to rats with spontaneous hypertension demonstrated a pronounced antihypertensive effect. In patients with isolated systolic hypertension, eprosartan produces a statistically significant reduction in systolic blood pressure compared to placebo. The addition of hydrochlorothiazide once daily (12.5 mg) to eprosartan once daily (600 or 1200 mg) resulted in an even greater, statistically significant decrease in systolic blood pressure compared to taking eprosartan only once daily (600 or 1200 mg). Concomitant use of eprosartan eliminates potassium losses associated with the diuretic effect of hydrochlorothiazide, possibly by blocking the renin-angiotensin-aldosterone system. The diuretic effect occurs within 2 hours with a peak after 4 hours. Pharmacokinetics. Eprosartan After oral administration, the absolute bioavailability of eprosartan is 13%. The maximum concentration in the blood plasma is observed after 1–2 hours. The half-life of eprosartan is 5–9 hours. Eprosartan has a slight accumulation with prolonged use. Plasma protein binding is 98% and is independent of gender, age, liver dysfunction and the presence of mild/moderate renal failure. The volume of distribution of eprosartan is 13 l. Total plasma clearance is 130 ml/min. After oral administration, 90% of 14C-eprosartan is excreted in feces and 7% in urine, of which 80% is eprosartan. The AUC value and maximum plasma concentration of eprosartan increase in elderly people (on average 2 times), but this does not require dosage changes. The AUC value of eprosartan increases in patients with liver failure (by an average of 40%), which also does not require dosage changes. The AUC value and maximum plasma concentration of eprosartan were 30% higher in patients with moderate renal failure (creatinine clearance - 30-59 ml/min) and 50% higher in patients with severe renal failure (creatinine clearance - 5-29 ml /min) compared with those in individuals with normal renal function. The pharmacokinetics of eprosartan are no different in women and men. Hydrochlorothiazide Hydrochlorothiazide is not metabolized but is rapidly eliminated by the kidneys. At least 61% of an oral dose is excreted unchanged within 24 hours. Hydrochlorothiazide crosses the placenta and is excreted into breast milk. It does not penetrate the BBB. The half-life is 6–8 hours. Teveten plus The simultaneous use of hydrochlorothiazide and eprosartan did not significantly affect the pharmacokinetics of either drug. The bioavailability of eprosartan and hydrochlorothiazide is not affected by food intake, but their absorption is slowed down. The maximum concentration of eprosartan in the blood plasma is achieved 4 hours after administration, and hydrochlorothiazide - after 3 hours.

TEVETEN

Antihypertensive therapy: a new strategy to protect the brain

Specialization in medicine has become increasingly distinct in recent years. A striking example of this is cardiology. However, experience shows that it is rare that a cardiology scientific forum today goes without mentioning related problems. This is understandable: the pathogenesis of many diseases contains identical or similar aspects. To confirm this, I would like to cite the example of the recently completed Russian National Congress of Cardiologists, within the framework of which an extremely interesting and extremely relevant symposium “Antihypertensive therapy: a new strategy for protecting the brain” was held. The symposium took place on October 12, 2006 and was organized by the pharmaceutical company Solvay Pharma, .

It was also very significant that the first report was presented by Academician of the Russian Academy of Medical Sciences, Chairman of the All-Russian Scientific and Scientific Committee, R.G. Oganov. At the very beginning of his report “Secondary prevention of stroke - new data,” the academician noted that primary and secondary prevention of strokes are similar, which only increases interest in the problem. The risk factors for strokes, as well as cerebrovascular complications, are similar:

• Age, gender
• Arterial hypertension
• Diabetes
• Previous stroke
• IHD, atrial fibrillation, heart failure
• Obesity, alcohol abuse, smoking

Atrial fibrillation has the greatest strength, but the main quantitative contribution to the development of cerebral stroke in Russia is made by hypertension. Recently, against the backdrop of an increase in the number of people with hypertension, the number of not only strokes, but also vascular dementia is increasing. “The problem of controlling hypertension in our country is purely organizational, and if we do not take measures, then our incidence will be the highest in the world,” noted academician R.G. Oganov.

The relationship of hypertension with stroke and cardiovascular diseases is straightforward: the higher the level of hypertension, the higher the risk of primary and recurrent stroke. Risk stratification tables are built on this principle. The higher the blood pressure, the higher the individual risk. At SBP 120 the risk is 7%, at 180 – 23%.

The pattern of development of cognitive impairment in most cases is simple and develops according to the following pattern: hypertension-stroke-dementia. The PROGRESS study once showed that it is possible to reduce the risk of stroke, as well as influence the cognitive function and capacity of patients with the help of drugs that lower blood pressure. Then there was the MOSES study, which showed that the highly effective nitrendipine was significantly inferior to the drug eprosartan in the primary and endpoint: a reduction in overall mortality and cerebrovascular disorders. Eprosartan ( Teveten ) was 21% more effective in reducing the primary outcome (mortality and the number of cases of cerebrovascular and cardiovascular complications). Effect on all vascular events 25% (significantly reduced the incidence of fatal and non-fatal cerebrovascular events). The best result was achieved at a pressure of 120 to 140 mm Hg. The risk of recurrent strokes was significantly reduced and, of course, a cardioprotective effect was observed.

Academician R.G. Oganov drew the audience's attention to a simple fact: reducing risk in a population is more effective than treating individual patients, and lifelong prevention of risk in a population is even more effective. In other words, a drug reduction of a patient’s blood pressure to normal does not mean a reduction in risks to the level of healthy people; therefore, preventive measures and timely identification of risks are necessary. The task of doctors is to increase public awareness and adherence to treatment. Only in this case can we expect a significant reduction in cerebrovascular and cardiovascular risks, emphasized Academician R.G. at the end of his speech. Oganov.

The next report, “Features of blood supply to the brain in arterial hypertension,” was presented by senior researcher. Laboratory of Cardioneurology, Department of Cerebrovascular Disorders Lyudmila Aleksandrovna Geraskina. At the beginning of the report, it was noted that neurological complications in hypertension are not uncommon. With hypertension, the following changes occur:

• Adaptive: media hypertrophy, hyperelastosis, myoelastofibrosis, sclerosis;
• Destructive: primary necrosis of medial myocytes, plasmorrhagia, fibrinoid necrosis of the vessel wall
• Reparative: hyalinosis.

And if adaptive changes can undergo reverse development during the treatment process, then destructive changes are irreversible. Reparative changes are aimed at stabilizing the process at a new level. They occur in both large and small arteries, but the most serious changes occur in the microvasculature, which is not available in routine patient examination. A damaged vessel wall, increased blood pressure, and changes in trophism lead to plasmorrhagia. The patency of these arteries changes. As a result, there is an accumulation of organic changes in the blood vessels of the brain - hypertensive angioencephalopathy. On neuroimaging they look like small infarcts and diffuse changes - leukoaraiosis. And only then follows the clinical picture of atherosclerosis: decreased attention, memory, headaches. In the absence of adequate treatment, more severe chronic damage occurs and discirculatory encephalopathy occurs.

Every second patient with hypertension has the mildest initial manifestation of insufficient blood supply to the brain. No signs. A neurologist can detect only a set of small manifestations. Deformation of the carotid arteries and minor stenoses can be detected, but brain damage will be more pronounced, despite the silent course. In patients with minimal symptoms, there is a failure of perfusion and additional brain stealing.

As it progresses, changes in the vascular wall and rheological properties of the blood worsen. Focal and diffuse changes worsen. Cerebral symptoms increase - sensitive, coordination, and cognitive impairments appear (attention, memory, social, professional adaptation). There is a clear decrease in blood flow and an increase in the rigidity of the walls of large vessels. Multiple heart attacks and leukoaraiosis appear. If small focal changes are described, blood flow is already reduced.

Only a third of patients respond adequately to vasodilator stimuli. In most patients, blood flow is reduced, a perverted or exactly the opposite response. Factors that influence changes in the reactivity of the vascular wall: age, characteristics of the circadian rhythm. We find the greatest changes in patients with an additional increase in blood pressure at night, or with its excessive decrease. Reactivity is worse in patients with hemodynamically significant changes in the vessels of the neck or intracranial vessels and the presence of previous antihypertensive therapy.

The sooner we begin to treat hypertension, the more intact the vessels and their reactivity will remain with adequate treatment with modern drugs. Poor treatment (course, short-lived drugs) only aggravates the deterioration of vascular reactivity. How to recognize patients who have the least adaptation to changes in blood pressure during antihypertensive therapy? Usually this:

• persons over 60 years old,
• patients with diffuse damage to brain tissue: pyramidal syndrome, pseudobulbar syndrome, subcortical syndrome;
• patients who have markers of changes in brain matter: leukoaraiosis, cerebral infarction;
• patients with occlusive lesions of the vessels supplying the brain.
• persons with cardiac markers: left ventricular hypertrophy, coronary pathology.

Patients who already have neurological complications of hypertension and the lower limit of autoregulation of cerebral blood flow can be shifted to a mean pressure level of 120 mm Hg, then a disaster can occur. Moreover, this catastrophe may not necessarily be clinically obvious. He does not faint, does not pass out, nothing happens, but the trouble is that the patient may develop focal symptoms with a relatively moderate decrease in blood pressure, but loss of consciousness and global cerebral ischemia will not occur. It will occur if the level of cerebral blood flow drops to critical levels - 20 ml per 100 g of brain matter per minute. Here is a clinical example of the treatment of hypertensive crisis. It is recommended to reduce blood pressure by 25% of the initial value during the first 2 hours and to a level of 160/100 mmHg over the next 6 hours. But in case of chronic cerebral pathology, only a decrease in blood pressure to 20% of the initial value is tolerated normally. Those. preferably no more than 20% within 2 hours.

In terms of cerebroprotection, the MOSES study is indicative. Ca antagonists are considered the drugs of choice in the prevention of cerebral stroke. Eprosartan ( Teveten ) belongs to a new class of antihypertensive drugs. 2 advanced drugs collided. The result is a 25% reduction in the risk of recurrent stroke on eprosartan. Mechanism of cerebroprotection: improvement of endothelial properties, reverse remodeling, reduction of vascular stiffness, antiplatelet effect. Blockade of type 1 angiotensin receptors leaves no room for angiotensin to circulate in the vessels. But there remains room for receptors of the second type, which leads to a revival of blood flow: cerebroprotection due to activation of collateral blood flow. This is an additional positive non-antihypertensive effect that must be taken into account when treating patients with cerebrovascular pathologies. The conclusion is simple: in the presence of hypertension and cerebrovascular pathology, it is necessary to include Teveten with its strong cerebroprotective effect.

Professor Evgeniy Vladimirovich Shlyakhto continued the symposium. The topic of his report: “Cognitive impairment in patients with arterial hypertension: results of the OSCAR study” also turned out to be relevant and interesting. The professor noted that the fate of a patient with cardiovascular pathology is determined, among other things, by the development of cognitive impairment. The patient management strategy is based on risk factors:

• Preventing progression of the cardiovascular continuum
• Impact on risk factors (insulin resistance, cardiovascular remodeling, atherogenesis, prevention of MI, stroke, heart and kidney failure)
• Prevention of cognitive impairment

In Europe, older age groups have seen an increase in the number of people with cognitive impairment. More and more attention is being paid to mild cognitive impairment, when memory suffers, but self-care is at the proper level. 2% of mild to moderate dementia occurs before age 65, about 9% over age 65, and 20% over age 80. “We underestimate the importance of mild cognitive impairment,” said Professor E.V. Nobles. Prevention of cognitive impairment is the treatment of the underlying disease (atherosclerosis, hypertension, heart failure), elimination of neurological syndromes, improvement of cerebral circulation and metabolism in the brain.

Studies on primary and secondary prevention of strokes, as well as effects on cognitive function, showed that a decrease in blood pressure by 11% did not significantly improve cognitive function. However, in relation to angiotensin receptor blockers, improvement in the prevention of dementia has been shown, which is associated with a decrease in the amount of ischemia in brain tissue. A drug that increases the level of angiotensin II improves the prognosis of cognitive impairment. In this regard, the MOSES study is indicative, which for the first time highlighted the significant benefits of eprosartan ( Teveten ):

• the number of brain events decreased by 25%
• cardiac events - by 30%, even compared with calcium antagonists, the effectiveness of which on cerebral blood flow is considered proven.
• There were no differences in stroke prevention for these drugs.

Experimental data also fully confirm clinical studies of eprosartan. At the next stage of research, the multicenter OSCAR study showed extremely interesting results on the use of the drug Teveten . The first global analysis showed that the dynamics of blood pressure normalization for the majority of patients was positive and in more than 60% of cases it decreased to normal. At the same time, the decrease in SBP averaged 26 mm Hg, and DBP – 12.6 mm Hg. The dynamics of changes in cognitive functions were also positive. The most radical changes were typical for people over 60 years of age. Obese patients showed less improvement in cognitive function compared to those with normal BMI. However, with concomitant atherosclerosis, the increase in the MMSE (Mini - Mental State Examination) index was greater.

Side effects were observed in only 0.1% of cases, and good tolerability was noted on average in 94% of cases. High effectiveness of treatment with Teveten is observed in approximately 95% of cases.

Conclusions:

• Hypertension is the most important risk factor for the development of stroke and loss of cognitive function
• The results of multicenter randomized trials on the treatment and prevention of strokes showed the possibility of preventing strokes and dementia with antihypertensive drugs
• Teveten appears to be the most effective drug for preventing cerebral strokes (MOSES) in patients with hypertension and improving cognitive impairment (OSCAR).

The final message of the symposium was presented by Professor S.A. Boytsov: “Combination therapy of arterial hypertension.” He noted that in a real clinic there is a well-known rule: it is necessary not only to correct blood pressure levels, but also to influence risk factors. The reason is simple - today organ protection is needed - a relatively new and not always clear goal of therapy. The basis of vascular protection is the influence on their remodeling. Cerebrovascular pathology is 5.8 cases per 1000 people and in 92% of cases cerebral stroke is associated with hypertension. Therefore, neurologists, cardiologists and therapists should remember about the prevention of stroke and chronic stroke, including dementia. An indicative risk factor is an increase in pulse pressure and a decrease in the elasticity of large arteries.

It should be taken into account that 77% of patients with hypertension are over 55 years of age. According to a 10-year observation, in people over 60 years of age, isolated hypertension with high pulse pressure is observed in 8% of cases. Therefore, a separate consideration of this problem is necessary.

In young and middle-aged people, a proportional reduction in SBP and DBP is required, but in people over 60 years of age, it is more necessary to reduce SBP in order to reduce pulse pressure. Ensuring adequate cerebral perfusion also requires reducing systemic SBP and pulse pressure while maintaining DBP. The evolution of ideas and blood pressure control is interesting:

• Before 1990, DBP control prevailed
• Until the end of the 90s - SBP control
• Before 2004 – PD in the brachial artery
• Today – PD in the aorta

What are the current recommendations? The results of numerous studies provide a clear answer: Angiotensin II receptor blockade is the method of choice for organ protection in antihypertensive therapy. Returning to the MOSES study, I would like to note that the effect on SBP and DBP of nitrendipine and eprosartan was similar, however, the protective effect of eprosartan was significantly higher. Consequently, eprosartan ( Teveten ), other things being equal, has a special effect on hemodynamic characteristics. Why should hypertension therapy, according to the recommendations, be combined? There are several reasons:

• Possibility of simultaneous influence on several links of pathogenesis
• Possibility of enhancing the effect by acting on one mechanism using different means
• Inhibition of counter-regulatory mechanisms
• Reduced incidence of side effects

Rational combinations of antihypertensive therapy today include:

• Diuretic + ACE inhibitor (ARA)
• Ca antagonist + ACE inhibitor (ARA)
• Beta blocker + calcium antagonist
• Diuretic + beta blocker
• Alpha blocker + beta blocker

If we consider the main blocks of the pathogenesis of arterial hypertension, then the combination of an ACE inhibitor (ARB) + diuretic will have an optimal and universal effect on these blocks. Is there a ready-made drug? Yes, this is Teveten plus . It is extremely easy to use, and therefore is doomed to success. Teveten Plus is a combination of eprosartan and hydrochlorothiazide. Teveten Plus was registered in Russia only this year. The drug is not only highly effective, but also safe. At the end of the report, Professor S.A. Boytsov I once again reminded that organ protection and cerebroprotection are the most important goals of hypertension therapy, which are achieved mainly by controlling pulse blood pressure and carried out through combination therapy, and the most effective is the combination of ACE inhibitors or ARBs with diuretics. We can only hope that the advanced scientific achievements in the field of cardiology and neurology, presented at the symposium, will be picked up by doctors and transferred into practice.

Internet project "RMS-Expo" E-mail Web: Expo.rusmedserv.com

Use of the drug Teveten plus

The recommended dose for adults is 1 Teveten tablet plus 1 time per day, in the morning. Teveten plus can be used in monotherapy or in combination with other antihypertensive drugs. The drug can be taken regardless of meals. No dosage changes are required for the elderly. Since the safety and effectiveness of treatment with Teveten plus in children have not been established, prescribing the drug to children is not recommended. No dosage changes are required for patients with liver failure. No dosage change is required for patients with renal failure whose creatinine clearance is 30 ml/min.

Side effects of the drug Teveten plus

In placebo-controlled clinical trials, the overall incidence of adverse effects with eprosartan did not differ from placebo. These effects were mild, transient, and required discontinuation of treatment in 4.1% of patients treated with eprosartan (6.5% of those treated with placebo). Hydrochlorothiazide does not increase the incidence of side effects. Nervous system disorders Rare: headache, dizziness. Cardiovascular disorders Very rare: arterial hypotension, including orthostatic hypotension. Skin and subcutaneous tissue disorders Rare: skin reactions (rash, itching, urticaria). Very rare: facial edema, angioedema. General symptoms and reactions at the injection site Rare: asthenia. Hydrochlorothiazide: Blood system and lymphatic system : leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia. Immune system : anaphylactic reactions. Metabolism and nutrition : anorexia, hyperglycemia, hyperuricemia, gout, hyponatremia, hypokalemia, hypochloremia, hypercalcemia, hypomagnesemia, hypercholesterolemia, hypertriglyceridemia. Mental disorders : changes in libido. Nervous system : dizziness, paresthesia, headache. Vestibular apparatus : vertigo. Cardiovascular system : arterial hypotension, including orthostatic hypotension, vasculitis. Respiratory system : pulmonary edema, pneumonitis. Gastrointestinal tract : irritation of the gastric mucosa, nausea, vomiting, cramps, diarrhea, constipation, pancreatitis. Hepatobiliary system : intrahepatic cholestatic jaundice. Skin and subcutaneous tissues : photosensitivity, rash, toxic epidermal necrolysis. Musculoskeletal system : systemic lupus erythematosus, muscle spasms. Urinary system : renal dysfunction, interstitial nephritis, renal failure. Reproductive system : sexual dysfunction. General symptoms: weakness, fever.

Special instructions for the use of Teveten plus

Renal failure Careful examination of renal function is necessary in patients in whom vascular tone and renal function depend primarily on the renin-angiotensin-aldosterone system, for example in patients with bilateral renal artery stenosis or renal artery stenosis of a single kidney. Hydrochlorothiazide-associated azotemia may occur in patients with impaired renal function. Hepatic impairment Hydrochlorothiazide should be used with caution in patients with moderate to severe hepatic impairment. There is no clinical experience in treating patients with severe liver failure with Teveten plus. Metabolic and endocrine effects Hydrochlorothiazide may impair glucose tolerance, which may require dosage adjustments of antidiabetic agents. Latent diabetes mellitus may manifest itself during treatment with Teveten Plus. Since the dose of hydrochlorothiazide in Teveten Plus is 12.5 mg, only minor metabolic or endocrine effects have been reported. Electrolyte Imbalances Hydrochlorothiazide may cause fluid and electrolyte imbalances (hypokalemia, hyponatremia, hypercalcemia, hypomagnesemia and hypochloremic alkalosis). As with other patients taking diuretics, periodic monitoring of serum electrolytes is necessary. Caution should be used when prescribing Teveten plus potassium-sparing diuretics and drugs containing potassium. Arterial hypotension Symptomatic arterial hypotension may occur, especially in patients with fluid and/or electrolyte deficiency, for example, after treatment with diuretics, when limiting dietary salt intake, during diarrhea or vomiting. Fluid and/or electrolyte deficiency must be corrected before starting treatment with Teveten Plus. Other conditions Patients with single hereditary diseases such as galactose intolerance, lactase deficiency, Lapp syndrome or glucose/galactose malabsorption syndrome should not take this drug. During pregnancy and lactation Like other drugs that affect the renin-angiotensin-aldosterone system, eprosartan should not be used during pregnancy, and if pregnancy is detected during treatment with Teveten Plus, treatment should be discontinued as soon as possible. Hydrochlorothiazide is excreted into breast milk. During breastfeeding, treatment with Teveten Plus is contraindicated. Ability to drive or operate machinery The effect of Teveten plus on the ability to drive or operate machinery has not been studied, but based on its pharmacodynamic properties, it is unlikely that eprosartan would affect this. However, caution should be exercised as fatigue and dizziness may sometimes occur during treatment of hypertension (arterial hypertension).

Teveten Plus 12.5 mg+ 600 mg 28 film-coated tablets

Registration Certificate Holder

ABBOTT PRODUCTS (Germany)

Dosage form

Medicine - Teveten® Plus (Teveten® Plus)

Description

Film-coated tablets

yellow-brown, oval, biconvex, with “5147” engraved on one side; The tablet is white on the break.

1 tab.

eprosartan mesylate 735.8 mg, which corresponds to the content of eprosartan 600 mg hydrochlorothiazide 12.5 mg

Excipients

: microcrystalline cellulose - 43.3 mg, lactose monohydrate - 43.3 mg, pregelatinized corn starch - 43.3 mg, crospovidone - 38.5 mg, magnesium stearate - 7.2 mg, purified water - 50.9 mg.

Film shell composition:

Opadry II Butterscotch 85F27320 - 39 mg (polyvinyl alcohol - 15.6 mg, macrogol 3350 - 7.88 mg, talc - 5.77 mg, titanium dioxide (E171) - 9.41 mg, iron oxide yellow (E172) - 0.33 mg, iron oxide black (E172) - 0.004 mg).

14 pcs. - blisters (1) - cardboard packs. 14 pcs. - blisters (2) - cardboard packs. 14 pcs. - blisters (4) - cardboard packs.

Indications

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

Contraindications for use

Severe renal failure (creatinine clearance <30 ml/min); severe liver failure (more than 9 points on the Child-Pugh scale); cholestasis and bile duct obstruction; hemodynamically significant bilateral renal artery stenosis or severe stenosis of the artery of the only 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 (breastfeeding); age under 18 years; hypersensitivity to eprosartan, hydrochlorothiazide, and other sulfonamide derivatives.

Carefully:

severe and chronic heart failure (IV FC according to the NYHA classification), bilateral renal artery stenosis, stenosis of the artery of a single kidney, decreased 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 liver failure (less than 9 points on the Child-Pugh scale without a history of cholestasis), diabetes mellitus, aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy, primary hyperaldosteronism, coronary artery disease (experience is limited), acute myopathy, secondary angle-closure glaucoma , SCV.

pharmachologic effect

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

Eprosartan
is
an angiotensin II receptor antagonist, selectively acts on AT1 receptors located in the blood vessels, heart, kidneys and adrenal cortex, forms a strong bond with them followed by slow dissociation. Prevents the development or weakens the effects of angiotensin II, inhibits the activity of the RAAS. It has a vasodilating, hypotensive and indirect diuretic effect. Reduces arterial vasoconstriction, peripheral vascular resistance, pressure in the pulmonary circulation, reabsorption of water and sodium in the proximal segment of the renal tubules, and aldosterone secretion. With long-term use, it suppresses the proliferative effect of angiotensin II on vascular and myocardial smooth muscle cells. The antihypertensive effect after taking a single dose orally develops within 24 hours, and a stable therapeutic effect develops with regular oral administration after 2-3 weeks without affecting heart rate. Does not cause the development of orthostatic hypotension in response to the first dose of the drug.

Increases renal blood flow and glomerular filtration rate, reduces the excretion of albumin (nephroprotective effect), while maintaining renal self-regulation, regardless of the severity of renal failure. Does not affect lipid, carbohydrate and purine metabolism. When stopping treatment, it does not cause withdrawal syndrome.

Less common than ACE inhibitors, it causes effects associated with bradykinin activity (including dry persistent cough).

Hydrochlorothiazide

- a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chlorine, potassium, magnesium, and water ions in the distal nephron; delays the excretion of calcium ions and uric acid. Has antihypertensive properties; the hypotensive effect develops due to the expansion of arterioles. It has virtually no effect on normal blood pressure levels.

The diuretic effect develops within approximately 2 hours after administration, the maximum effect is achieved within 3-6 hours and persists for 6-12 hours. The antihypertensive effect is achieved within 3-4 days of treatment and lasts for 1 week after completion of the drug. With long-term treatment, a decrease in blood pressure is achieved by using lower doses than those required for a diuretic effect. The decrease in blood pressure is accompanied by a slight increase in glomerular filtration rate, renal vascular resistance and renin activity in the blood plasma.

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 small doses, blood plasma volume remains reduced, while minute volume and glomerular filtration rate return to the initial level prior to the start of treatment. Mean blood pressure and systemic vascular resistance remain reduced. Thiazide diuretics may interfere with breast milk production.

Eprosartan + hydrochlorothiazide.

In patients with elevated systolic blood pressure, eprosartan provides a statistically significant reduction in blood pressure. The addition of 12.5 mg 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 administration of eprosartan alone. The combined use of eprosartan with hydrochlorothiazide reduces the loss of potassium associated with the diuretic effect of hydrochlorothiazide. The diuretic effect when using this combination develops during 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.

Drug interactions

The combined use of ACE inhibitors and angiotensin II receptor antagonists in patients with diabetic nephropathy is not recommended.

Concomitant use of aliskiren

with an ACE inhibitor or angiotensin II receptor blocker is contraindicated in patients with type 2 diabetes mellitus or renal failure (creatinine clearance less than 60 ml/min).

Eprosartan+hydrochlorothiazide

A reversible increase in serum lithium levels and increased toxicity have been observed with 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 lithium toxicity. In this regard, this combination together with lithium preparations is not recommended. If combination therapy is necessary, serum lithium concentrations should be regularly monitored.

Baclofen

- may enhance the antihypertensive effect.

Concomitant use of angiotensin II receptor antagonists and NSAIDs

may increase the risk of developing renal impairment, 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.

Amifostin

- may enhance the antihypertensive effect.

Other antihypertensive drugs

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

Ethanol, barbiturates, anesthetics or antidepressants

- orthostatic hypotension may occur.

Eprosartan

Data from a clinical trial have shown that dual blockade of the RAAS through concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of adverse events such as hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared with individual use. , acting on the RAAS.

Hydrochlorothiazide

The hypokalemic effect of hydrochlorothiazide may be enhanced by concomitant administration of other drugs that lead to potassium depletion and hypokalemia (for example, other non-potassium sparing diuretics

,
laxatives, corticosteroids, glycyrrhizic acid (found in licorice root), adrenocorticotropic hormone, amphotericin B (for IV 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 by reducing calcium excretion. If necessary, use calcium supplements or calcium-sparing medications

(eg, vitamin D), serum calcium levels should be monitored and the dosage adjusted accordingly.

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

Cardiac glycosides -

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

Medicines whose effects are affected by hypokalemia

- cardiac glycosides and antiarrhythmic drugs, as well as drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type (ventricular tachycardia) - class IA antiarrhythmic drugs (for example, quinidine, hydroquinidine, disopyramide); class III antiarrhythmic drugs (eg, amiodarone, dofetilide, ibutilide) and sotalol; some antipsychotics (eg, thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol); other drugs (eg, bepridil, cisapride, difemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, terfenadine, vincamine IV).

Non-depolarizing muscle relaxants (for example, tubocurarine) -

hydrochlorothiazide may enhance the effect of non-depolarizing muscle relaxants.

Anticholinergic drugs (eg, atropine, biperiden) -

increasing the bioavailability of thiazide diuretics by reducing gastrointestinal motility and the rate of gastric emptying.

Medicines for the treatment of diabetes mellitus (hypoglycemic drugs and insulin) -

the use of a 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 developing lactic acidosis due to possible functional renal failure under the influence of hydrochlorothiazide.

Beta blockers and diazoxide -

Thiazides may enhance the hyperglycemic effect of beta-blockers and diazoxide.

Pressor amines (eg, norepinephrine) -

the effect of pressor amines may be reduced.

Anti-gout drugs (probenecid, sulfinpyrazone and allopurinol) -

dose adjustment of anti-gout drugs is necessary, since hydrochlorothiazide can increase the concentration of uric acid in the blood serum. The dose of probenecid or sulfinpyrazone may need to be increased. 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 (for example, cyclophosphamide, methotrexate) -

Thiazides can reduce the excretion of cytotoxic drugs by the kidneys and enhance their myelosuppressive effect.
Tetracyclines -
when tetracyclines and thiazides are used together, the risk of increased levels of the latter in the urine caused by tetracycline increases. This interaction does not appear to apply to doxycycline.

Drugs that reduce serum sodium levels

- when used together with antidepressants, neuroleptics and antiepileptic drugs, the hyponatremic effect of hydrochlorothiazide may be enhanced.

Dosage regimen

The oral dose of the fixed combination of eprosartan + hydrochlorothiazide is 600 mg/12.5 mg 1 time/day.

Side effect

From the hematopoietic system:

uncommon - leukopenia; very rarely - hemolytic anemia; frequency unknown - agranulocytosis, thrombocytopenia, aplastic anemia.

From the immune system:

uncommon - hypersensitivity reactions; frequency unknown - anaphylactic reactions.

Metabolism and nutrition:

often - hyperglycemia; uncommon - hyperuricemia, exacerbation of gout, hyponatremia, hypokalemia, hypochloremia, hypercholesterolemia; frequency unknown - hypercalcemia, hypomagnesemia, hypertriglyceridemia, anorexia.

From the mental side:

infrequently - depression, anxiety, insomnia, nervousness, libido disorders; frequency unknown - anxiety.

From the nervous system:

very often - headache (11%), often - dizziness, paresthesia.

From the side of 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:

often - marked decrease in blood pressure, orthostatic hypotension; frequency unknown - necrotizing angiitis.

From the respiratory system:

often - rhinitis; rarely - respiratory distress syndrome (including pneumonitis and non-cardiogenic pulmonary edema).

From the digestive system:

often - nonspecific gastrointestinal disorders (nausea, vomiting, diarrhea); infrequently - constipation; rarely - pancreatitis.

From the liver and biliary tract:

frequency unknown - jaundice, incl. intrahepatic cholestatic jaundice.

For the skin and subcutaneous tissues:

often - allergic skin reactions (skin rash, itching); uncommon - 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), glycosuria.
From the genital organs:
infrequently - sexual dysfunction.

Common disorders:

often - asthenia; infrequently - hyperthermia.

special instructions

In patients whose renal function depends on the activity of the RAAS (for example, with severe chronic heart failure of functional class IV according to the NYHA classification), oliguria and/or progressive azotemia and, in rare cases, acute renal failure may develop during treatment with ACE inhibitors. These events are most likely to occur in patients taking diuretics concomitantly. Due to insufficient experience with the use of angiotensin II receptor antagonists in patients with severe chronic heart failure class IV according to the NYHA classification, renal dysfunction cannot be excluded during the use of the combination of eprosartan + hydrochlorothiazide due to suppression of RAAS activity. Due to the increased risk of severe hypotension and renal failure in these patients, renal function should be carefully monitored.

Before starting treatment with the combination of eprosartan + hydrochlorothiazide in patients with renal failure and periodically during treatment, renal function, potassium and uric acid levels in the blood serum should be monitored. If renal function deteriorates during this period, treatment with the combination should be discontinued.

Hydrochlorothiazide-associated azotemia may occur in patients with impaired renal function.

Eprosartan should be used with caution in the treatment of patients with mild to 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 to moderate liver failure.

Changes in water and electrolyte balance can cause hepatic coma.

Hydrochlorothiazide can reduce glucose tolerance, which may require dose adjustment of hypoglycemic agents and insulin. Latent diabetes mellitus may manifest itself during treatment with this combination.

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

All patients receiving diuretics, including hydrochlorothiazide, should periodically monitor serum electrolytes.

With severe hyponatremia or a decrease in 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. It is necessary to correct hyponatremia and/or volumetric volume and, if possible, discontinue diuretics before starting treatment with this combination.

Hydrochlorothiazide, being a sulfonamide, can cause idiosyncrasy, expressed in 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 to use the drug. Untreated acute angle-closure glaucoma can lead to irreversible vision loss. Primary treatment is to discontinue hydrochlorothiazide as quickly as possible. Urgent medical or surgical treatment may be required if intraocular pressure remains uncontrolled. Risk factors for developing an attack of acute angle-closure glaucoma may include a history of allergic reactions to sulfonamide or penicillin.

In patients with primary hyperaldosteronism, the use of antihypertensive drugs 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 in patients with a history of allergies, incl. with hypersensitivity to sulfonamide derivatives.

Hydrochlorothiazide may give a positive result in a drug 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 with the individual use of drugs acting on the RAAS. In this regard, double blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended. If a double blockade is necessary, it should be carried out strictly under the supervision of a specialist and with constant monitoring of kidney function, electrolyte levels and blood pressure.

The combined 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 machinery
During treatment with this combination, the patient should be careful 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.

Use during pregnancy and breastfeeding

Restrictions during pregnancy - Contraindicated. Restrictions when breastfeeding - No restrictions.

Contraindicated for use during pregnancy and lactation (breastfeeding).

Drug interactions Teveten plus

The reduction in blood pressure by Teveten Plus may be enhanced by concomitant use of another antihypertensive drug. A decrease in the level of potassium in the blood of hydrochlorothiazide may increase the effect or side effects of digitalis and antiarrhythmic drugs. Hydrochlorothiazide increases the risk of hypokalemia when used concomitantly with drugs that cause potassium loss, such as diuretics that remove potassium, laxatives, corticosteroids and ACTH. There may be a need to change the dose of glucose-lowering medications in patients with diabetes. Teveten Plus may cause a reversible increase in serum lithium concentrations and therefore an increased risk of lithium toxicity. Careful monitoring of serum lithium levels is recommended when lithium and Teveten plus are co-administered. The absorption of hydrochlorothiazide is reduced by the use of anion exchange resins such as cholestyramine (INN - colestipolum) or cholestipol (INN - colestipolum). NSAIDs may weaken the antihypertensive effect of Teveten Plus. Hydrochlorothiazide may increase the effects of non-depolarizing muscle relaxants (such as tubocurarine) and the risk of side effects of amantadine. Eprosartan did not have an inhibitory effect on the enzymes of the human cytochrome P450 system - CYP 1A, 2A6, 2C9/8, 2C19, 2D6, 2E and 3A in vitro .

Teveten®

Angiotensin II receptor antagonist (ARA II) selectively acts on angiotensin receptors located in the blood vessels, heart, kidneys and adrenal cortex, forms a strong bond with them followed by slow dissociation.

Angiotensin II binds to AT1 receptors in many tissues (for example, vascular smooth muscle, adrenal glands, kidneys, heart) and causes vasoconstriction, sodium ion retention and aldosterone release, target organ damage - myocardial and vascular hypertrophy.

Eprosartan prevents the development or weakens the effects of angiotensin II, inhibits the activity of the renin-angiotensin-aldosterone system (RAAS). It has a vasodilating, antihypertensive and indirect diuretic effect. Reduces arterial vasoconstriction, total peripheral vascular resistance (TPVR), pressure in the pulmonary circulation, reabsorption of fluid and sodium ions in the proximal segment of the renal tubules, and aldosterone secretion. With long-term use, it suppresses the proliferative effect of angiotensin II on vascular and myocardial smooth muscle cells.

The antihypertensive effect after taking a single dose lasts for 24 hours, a persistent therapeutic effect appears with regular use - after 2-3 weeks without changing heart rate (HR).

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

In patients with arterial hypertension, eprosartan does not affect fasting blood concentrations of triglycerides, total cholesterol or low-density lipoprotein (LDL) cholesterol. In addition, eprosartan does not affect fasting blood glucose concentrations.

Increases renal blood flow and glomerular filtration rate (GFR), reduces the excretion of albumin (nephroprotective effect) while maintaining renal self-regulation, regardless of the severity of renal failure.

Does not affect purine metabolism, does not have a significant effect on the excretion of uric acid by the kidneys.

Less common than angiotensin-converting enzyme (ACE) inhibitors, it causes bradykinin-related effects (including dry persistent cough). The incidence of dry, persistent cough in patients receiving eprosartan is 1.5%. When replacing the ACE inhibitor with eprosartan in patients with cough, the incidence of dry persistent cough corresponds to placebo.

Discontinuation of treatment with eprosartan is not accompanied by withdrawal syndrome.

During clinical studies, the use of the drug in a daily dose of up to 1200 mg for 8 weeks was effective, with no apparent relationship between the dose and the frequency of reported side effects.

Eprosartan does not inhibit the isoenzymes CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E and 3A of the cytochrome P450 system in vitro.

The ONTARGET and VA NEPHRON-D studies, which examined the combined use of an ACE inhibitor with an ARB II, did not reveal significant beneficial effects on renal and/or cardiovascular function and mortality, while at the same time there was an increased risk of hyperkalemia, acute kidney injury and/or arterial hypotension compared with monotherapy. Given the similar pharmacodynamic characteristics, these results are also relevant for other ACE inhibitors and ARB II.

ACE inhibitors and ARB II should not be used simultaneously in patients with diabetic nephropathy.

The ALTITUDE trial (adding aliskiren to standard ACE inhibitor or AR II therapy) was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular death and stroke were significantly more common in the aliskiren-added group than in the placebo group, and adverse events and serious adverse events (hyperkalemia, hypotension, and renal dysfunction) were more common in the aliskiren group than in the placebo group. placebo group.

In the MOSES (Morbidity and Mortality after Stroke Comparison of Eprosartan and Nitrendipine for Secondary Prevention) study of 1,405 patients with hypertension and a history of cerebrovascular disease, 78% of patients in the eprosartan group received 600 mg once daily; 12% - up to 800 mg per day; in the nitrendipine group, 47% received 10 mg and 42% received 20 mg per day (in 11% of patients, doses reached 40 mg per day). Target blood pressure values ​​were achieved in both groups and were maintained throughout the study. The eprosartan group had significantly better results (21% risk reduction) for the primary endpoint of all-cause mortality, cerebrovascular events (transient cerebrovascular accident, long-term reversible ischemic neurological deficit, stroke) and cardiovascular events ( unstable angina, myocardial infarction, heart failure, pulmonary embolism and fatal arrhythmia), including recurrent diseases. In the primary data analysis, the numerical risk index decreased by 12% for cerebrovascular and 30% for cardiovascular disorders. The overall mortality rate was better in the nitrendipine group; 8.4% in the eprosartan group (57 of 681 patients) versus 7.7% in the nitrendipine group (52 of 671 patients) (hazard ratio 1.07, 95% CI 0.73 to 1.56, p=0.725 ). Fatal and non-fatal myocardial infarction developed in 18 of 20, and stroke in 36 of 42 patients, which numerically supported eprosartan. According to the primary endpoint, the effect of eprosartan was more pronounced in patients who did not receive beta-blockers.

Teveten plus overdose, symptoms and treatment

The most likely manifestation is arterial hypotension. Other symptoms may be associated with dehydration or decreased electrolyte levels (hypokalemia, hypochloremia, hyponatremia) and most likely include nausea and drowsiness. Treatment should be supportive and symptomatic. Depending on the time that has passed since the overdose, you can induce vomiting, lavage the stomach and/or apply activated charcoal. If arterial hypotension occurs, the patient must be placed in a horizontal position and the blood volume must be restored and the electrolyte balance corrected. Eprosartan is not removed by hemodialysis.