Теветен® plus

General characteristics. Structure:

Active agents: an eprosartana мезилат — 735,8 mg that corresponds to 600 mg of an eprosartan, a hydrochlorothiazide −12,5 mg.

Excipients: cellulose microcrystallic — 43,3 mg, lactoses monohydrate — 43,3 mg, starch corn prezhelatinizirovanny — 43,3 mg, кросповидон — 38,5 mg, magnesium stearate of 7,2 mg, the water purified — 50,9 mg.

Cover: Opadry II Butterscotch 85F27320 — 39 of mg (polyvinyl alcohol — 15,60 mg, a macrogoal of 3350 — 7,88 mg, talc — 5,77 mg, titanium dioxide (E171) — 9,41 mg, ferrous oxide yellow (E172) — 0,33 mg, ferrous oxide black (E172) — 0,004 mg).

Description:

Tablets film coated yellowy-brown color of an oval form biconvex with an engraving "5147" on one party. On a break of a tablet of white color.

Pharmacological properties:

Pharmacodynamics. Eprosartan

Angiotensin II of receptors the antagonist, selectively acts on AT1 the receptors located in vessels, heart, kidneys and bark of adrenal glands forms with them strong communication with the subsequent slow dissociation. Prevents development or weakens effects of angiotensin II, activity the system renin-angiotensin-aldosteronovoy (SRAA) oppresses. Renders the vazodilatiruyushchy, hypotensive and mediated diuretic action.

Reduces arterial vasoconstriction, the general peripheric vascular resistance (GPVR), pressure in a small circle of blood circulation, a reabsorption of water and sodium in a proximal segment of renal tubules, secretion of Aldosteronum. At prolonged use suppresses proliferative influence of angiotensin II on cells of unstriated muscles of vessels and a myocardium. Hypotensive action after reception of a single dose inside develops within 24 hours, and the stable therapeutic effect develops at regular intake — in 2-3 weeks without influence on the heart rate (HR).

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

Increases a renal blood stream and a glomerular filtration rate, reduces removal of albumine (nefroprotektorny action), at preservation of renal self-control regardless of degree of manifestation of a renal failure.

Does not exert impact on lipidic, carbohydrate and purine metabolism.

At the termination of treatment does not cause a syndrome of "cancellation".

Less than inhibitors of an angiotensin-converting enzyme (APF), emergence of the effects connected with activity of bradikinin causes (including dry persistent cough).

Hydrochlorothiazide

The hydrochlorothiazide is thiazide diuretic. Tiazida influence mechanisms of a reabsorption of electrolytes in a renal tubule, increasing the volume of release of liquid, sodium and chlorine.

Thanks to diuretic action of a hydrochlorothiazide, blood plasma volume decreases, activity of a renin in a blood plasma increases, secretion of Aldosteronum amplifies that causes the increased removal of potassium and hydrocarbonates kidneys and decrease in content of potassium in blood serum. The mechanism of hypotensive action of a hydrochlorothiazide — the combined diuretic and vazodilatiruyushchy effect.

Теветен® plus

At patients with the increased systolic arterial pressure (AP) эпросартан provides statistically significant decrease in the ABP. Addition to a single daily dose (600 or 1200 mg) of an eprosartan of 12,5 mg of a hydrochlorothiazide provides additional statistically significant decrease in the systolic ABP in comparison with daily reception only of an eprosartan.

The combined reception of an eprosartan with a hydrochlorothiazide reduces the potassium loss connected with diuretic effect of a hydrochlorothiazide. Diuretic effect of the drug Teveten® plus develops within the first 2 hours, and reaches a maximum — in 4 hours after intake.

The stable hypotensive effect develops, as a rule, in 2-3 weeks of treatment.

Pharmacokinetics. Eprosartan

At intake absolute bioavailability makes about 13%. The maximum concentration (Cmax) in a blood plasma is defined in 1-2 hours. The elimination half-life (T1/2) makes usually 5 — 9 hours. Communication with proteins of a blood plasma — high (98%) also remains therapeutic concentration, constant after achievement, in a blood plasma. Extent of linkng with proteins of a blood plasma does not depend on a sex, age, function of a liver of patients and does not change at the moderated or slightly expressed renal failure, but can decrease at a heavy renal failure.

Practically does not kumulirut.

The volume of distribution makes 13 l, the general clearance — 130 ml/min. At intake it is removed generally in not changed look through intestines (90%), kidneys (7%). An insignificant part (less than 2%) is removed by kidneys in the form of glucuronides.

At elderly patients of Cmax value and the area under a curve "concentration time" (AUC) increase, on average, twice that, however, does not demand dose adjustment.

At a liver failure of AUC value increase, on average, a primernona of 40% that does not demand dose adjustment.

At patients with the moderate chronic renal failure (CRF) (the clearance of creatinine (CC) from 30 to 59 ml/min.) of AUC and Cmax for 30%, and from heavy HPN (KK from 5 to 29 ml/min.) — is 50% higher in comparison with healthy volunteers.

The pharmacokinetics of an eprosartan does not differ at male and female patients.

Hydrochlorothiazide

The hydrochlorothiazide is not metabolized, quickly removed by kidneys. Not less than 61% of the dose accepted inside are removed in not changed look within 24 hours. Does not get through a blood-brain barrier, but gets through a placental barrier and it is allocated with breast milk.

Теветен® plus

The concomitant use of an eprosartan and hydrochlorothiazide does not exert clinically significant impact on pharmacokinetics of both components.

Meal does not influence bioavailability of an eprosartan and hydrochlorothiazide, but detains them absorption. The maximum concentration in a blood plasma are reached in 4 hours after reception of an eprosartan and in 3 hours after reception of a hydrochlorothiazide inside.

Indications to use:

Arterial hypertension (in monotherapy or in a combination with other antihypertensives).

Route of administration and doses:

Inside, on 1 tablet a day in the morning, irrespective of meal.

Drug Teveten® dose adjustments plus at elderly patients, patients with easy and moderate abnormal liver functions, and also patients with a renal failure (KK more than 30 ml/min.) are not required.

Features of use:

Patients with renal failures

At patients whose renal function depends on activity of RAAS (for example, patients with heavy chronic heart failure of the IV functional class on NYHA classification) during treatment by APF inhibitors the oliguria and/or the progressing azotemia, and, in rare instances, an acute renal failure can develop. These phenomena are most probable at the patients who are at the same time accepting diuretics. Due to the insufficient experience of use of angiotensin II of receptors of antagonists for patients with heavy chronic heart failure of the IV functional class on NYHA classification, it is impossible to exclude disturbances of renal function against the background of drug Teveten® use plus, owing to suppression of activity of RAAS. Before purpose of the drug Teveten® plus to patients with a renal failure and, periodically, in the course of treatment it is necessary to control function of kidneys. If during this period deterioration in renal function, treatment by the drug Teveten® plus is observed

it is necessary to stop.

Patients with abnormal liver functions

The hydrochlorothiazide has to be applied with care to treatment of patients with moderate or heavy degree of an abnormal liver function. Clinical experience of use of the drug Teveten® plus in treatment of patients with heavy degree of an abnormal liver function is absent (see the section "Contraindications").

Metabolic and endocrine effects

The hydrochlorothiazide can reduce tolerance to glucose that can demand dose adjustment of hypoglycemic means for intake and insulin. Latentno the proceeding diabetes mellitus can demonstrate in the course of treatment by the drug Teveten® plus. At the dose of 12,5 mg of a hydrochlorothiazide which is contained in the drug Teveten® plus only insignificant metabolic or endocrine effects were observed so far.

Disturbances of water and electrolytic balance

Use of a hydrochlorothiazide can lead to disturbance of water and electrolytic balance of blood (a hypopotassemia, a hyponatremia, a hypercalcemia, a hypomagnesiemia and a gipokhloremichesky alkalosis).

To all patients who are receiving medical treatment for diuretics including a hydrochlorothiazide, it is necessary to control periodically the content of electrolytes in blood serum. Kaliysberegayushchy diuretics and drugs of potassium it is necessary to use together with the drug Teveten® plus with care.

Symptomatic arterial hypotension

At decrease in OTsK or decrease in content of electrolytes (for example, during treatment by high doses of diuretics, repeated vomiting, long diarrhea, an electrolyte-deficient and low-salt diet), administration of drug of Teveten® plus can cause sharp decrease in the ABP. Correction of OTsK and if it is possible, cancellation of diuretics prior to treatment by the drug Teveten® plus is necessary.

Influence on ability to manage vehicles or to be engaged in other types of activity requiring special attention and speed of psychomotor reactions.

During treatment by the drug Teveten® plus it is necessary to be careful at control of vehicles and occupation potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions in connection with possibility of dizziness and weakness.

Side effects:

At the patients who were taking part in clinical trials of the drug Teveten® plus the following undesirable reactions are noted (* - frequency is comparable to placebo):

Very often (> 1/10): head боль*.

Often (> 1/100, <1/10): dizziness *, skin rash, itch, nonspecific gastrointestinal frustration (nausea, diarrhea, vomiting), adynamy.

Infrequently (> 1/1000, <1/100): hypersensitivity reactions *, the expressed decrease in the ABP, Kvinke* swelled.

Any of the listed reactions, except arterial hypotension, did not meet in researches of the combined drug (эпросартан + a hydrochlorothiazide) higher frequency, than at use only of an eprosartan.

Most often at the patients receiving treatment eprosartany such undesirable reactions as a headache and nonspecific disturbances from the digestive tract (DT) were observed, respectively, shown approximately at 11% and 8% of patients.

Proceeding from spontaneous messages at post-marketing use of an eprosartan, it became known of the following side effects (their frequency was not estimated):

From kidneys and urinary tract: renal failure, including poche-

chny insufficiency at patients with the increased risk its development (renal artery stenosis).

During use of a hydrochlorothiazide in clinical practice the following side effects were recorded (their frequency was not estimated):

From a GIT: nausea, vomiting, diarrhea, lock, intra hepatic cholestatic jaundice, pancreatitis, abdominal pain.

From immune system: anaphylactic reactions.

From a nervous system: dizziness, paresthesias, headache.

From cardiovascular system: the expressed decrease in the ABP, orthostatic hypotension, a vasculitis.

From blood and lymphatic system:

leukopenia, agranulocytosis, thrombocytopenia,

aplastic and hemolitic anemias.

From kidneys and urinary tract: intersticial nephrite, renal failure, damage of kidneys.

From respiratory system, bodies of a thorax and a mediastinum: pneumonitis, fluid lungs.

From skin and hypodermic fabrics: skin rash, toxic and epidermal necrolysis, photosensitivity reactions.

From a metabolism and food:

hyperglycemia, hyperuricemia, gout, hyponatremia, hypopotassemia, hypochloraemia, hypercalcemia, hypomagnesiemia, hyper - a cholesterinemia, a gipertriglitseridemiya, anorexia.

From generative organs: erectile dysfunction.

Disturbances of mentality: disturbances of a libido.

From an acoustic organ and labyrinth disturbances: вертиго.

From skeletal and muscular and connecting fabric: muscular spasms,

system lupus erythematosus.

The general frustration and disturbances in an injection site: pyrexia, adynamy.

Proceeding from spontaneous messages at post-marketing use of the drug Teveten® plus, it became known of the following side effects (their frequency was not estimated):

Disturbances of mentality: uneasiness, depression, sleeplessness, nervousness, concern.

Interaction with other medicines:

Теветен® plus

The hypotensive effect of the drug Teveten® plus can amplify at simultaneous use with other antihypertensives. Non-steroidal anti-inflammatory drugs can weaken diuretic and hypotensive effect of the drug Teveten® plus. Hypotensive effect of the drug Teveten® plus can decrease at simultaneous use with kaliysberegayushchy diuretics and drugs of potassium.

Eprosartan

Eprosartan does not influence pharmacokinetics of digoxin and a pharmacodynamics of warfarin or Glibenclamidum. Also influence of an eprosartan on pharmacokinetics of ranitidine, a ketokonazol or a flukonazol is noted.

There is an experience of safe use of an eprosartan together with blockers of "slow" calcium channels (for example, nifedipine of the prolonged action) without considerable strengthening of risk of development of side effects.

Reversible increase in concentration of lithium in blood serum and increase in toxicity was noted at combined use of drugs of lithium with APF inhibitors. It is impossible to exclude a possibility of development of similar effect after use of an eprosartan. Regular control of concentration of lithium in blood serum at simultaneous use of the drug Teveten® is necessary plus and the drugs containing lithium.

Eprosartan does not inhibit isoenzymes of CYP1A, 2A6, 2S9/8, 2S19, 2D6, 2E and ZA of system of in vitro P450 cytochrome.

Gidrokhporotiazid

Reducing the content of potassium in blood serum, the hydrochlorothiazide can strengthen effect and side effect of cardiac glycosides and antiarrhytmic means.

Increases risk of a hypopotassemia if it is applied along with diuretics, laxatives, mineralokortikoida and adrenocorticotropic hormone (AKTG).

Can reduce tolerance to glucose that can demand dose adjustment of hypoglycemic means for intake and insulin.

Absorption of a hydrochlorothiazide decreases at simultaneous use of the anion-exchange pitches, for example, of Colestyraminum or a kolestipol. The hydrochlorothiazide can strengthen effect of not depolarizing muscle relaxants.

Contraindications:

 
Hypersensitivity to an eprosartan, a hydrochlorothiazide and other derivatives of streptocide and other components of drug.
Pregnancy and period of a lactation.
Heavy renal failure (KK less than 30 ml/min.).
Age up to 18 years (efficiency and safety are not established).
Hemodynamically significant bilateral stenosis of renal arteries and stenosis of an artery of the only kidney.
Rare hereditary intolerance of a galactose, deficit of lactase or syndrome of insufficiency of absorption of glucose galactose (drug contains lactose).

With care

Heavy chronic heart failure (the IV functional class on NYHA classification), a bilateral stenosis of renal arteries, a stenosis of an artery of the only kidney, decrease in the volume of the circulating blood (VCB), disturbance of water and electrolytic balance of blood (owing to reception of high doses of diuretics, repeated vomiting, long diarrhea, an electrolyte-deficient diet), a moderate or heavy abnormal liver function, a diabetes mellitus. Clinical experience of use of the drug Teveten® plus in treatment of patients with heavy abnormal liver functions is absent.

Use at pregnancy and in the period of a lactation

Pregnancy

The drug Teveten® plus is contraindicated to use during pregnancy.

Eprosartan

Results of the epidemiological researches concerning risk of development of teratogenic effects at use of APF inhibitors during the first trimester of pregnancy do not allow to draw unambiguous conclusions, however

small increase in risk cannot be excluded. While data of controlled epidemiological researches concerning risk of use of angiotensin II of receptors of antagonists are absent, the similar risk can exist for this class of drugs.

Except for cases when continuation of therapy of angiotensin II of receptors by antagonists is considered as necessary, the patients planning pregnancy have to pass to reception of the resolved antihypertensives possessing the established characteristics of safety for use during pregnancy. Therapy eprosartany has to be stopped immediately after pregnancy diagnosing, and alternative therapy has to be in case of need begun.

It is known that therapy of angiotensin II of receptors by antagonists in II and III trimesters of pregnancy is toxic for a fruit (deterioration in function of kidneys, an oligoamnios, a delay of ossification of bones of a skull) and the newborn (a renal failure, arterial hypotension, a hyperpotassemia).

If treatment eprosartany is necessary in the II trimester of pregnancy, it is recommended to carry out ultrasonic control of function of kidneys and control of a condition of a skull at a fruit.

Newborns whose mothers accepted эпросартан have to be observed carefully regarding detection of arterial hypotension.

Hydrochlorothiazide

Experience of use of a hydrochlorothiazide during pregnancy, in particular, in the I trimester, is limited.

The hydrochlorothiazide gets through a placental barrier. In view of the mechanism of action of a hydrochlorothiazide, use of this drug in II and III trimesters of pregnancy can lead to disturbance of fetoplacental perfusion and development of pathological effects in the newborn and a fruit, such as jaundice, electrolytic disturbances and thrombocytopenia. It is not necessary to apply a hydrochlorothiazide at gestational hypostases, arterial hypertension at pregnant women or a preeclampsia, in connection with risk of decrease in volume of a blood plasma and development of hypoperfusion of a placenta and lack of any positive effects to the course of a disease.

The hydrochlorothiazide should not be applied at essential hypertensia at pregnant women, except for rare situations when there are no therapeutic alternatives.

Lactation period

Теветен® plus

Due to the lack of information concerning use during breastfeeding use of Tevetena® plus is not recommended, purpose of antihypertensives, with well established safety profile is preferable especially when feeding newborns or prematurely been born children.

Overdose:

It was not reported about drug Teveten® overdose cases plus. The overdose, most likely, will cause the expressed decrease in the ABP. Other symptoms can be connected with decrease in OTsK and loss of electrolytes (a hypopotassemia, a gipokhporemiya, a hyponatremia), and, most possibly, will be shown as nausea and drowsiness.

Treatment has to be symptomatic and supporting. Depending on time of administration of drug inside, provocation of vomiting, a gastric lavage, and/or use of absorbent carbon is necessary. At the expressed decrease in the ABP, the patient needs to be laid on a back, to raise legs and to hold events for recovery of OTsK. Eprosartan does not leave by means of a hemodialysis.

Storage conditions:

In the place, dry, unavailable to children, at a temperature not above 25 °C. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets are film coated, 12,5 mg + 600 mg.

On 14 tablets in PVC / Aklar / Is scarlet blisters.

On 1, 2 or 4 PVH/Aklar/Ap of the blister together with the application instruction in a cardboard pack.