Nortivan - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline 35,600 mg, crospovidone 19,750 mg, silicon dioxide colloid 5,300 mg, magnesium stearate 1,875 mg; external phase (microcrystalline cellulose 35,600 mg, magnesium stearate 1,875 mg);

shell: fall off TAN (E171) 1.430 mg, macrogol 400 0.312 mg, talc 0.050 mg, ferric iron oxide yellow (E172) 0.073 mg, ferric oxide red oxide (E172) 0.008 mg, iron oxide dye black (E172) 0.002 mg).

Dosage of 80 mg

active substance: valsartan 80,000 mg;

Excipients: cellulose microcrystalline 71,200 mg, crospovidone 39,500 mg, silicon dioxide colloid 10,600 mg, magnesium stearate 3,750 mg; external phase (microcrystalline cellulose 71,200 mg, magnesium stearate 3,750 mg);

sheath: opedraj PINK 030034410 10,000 mg (hypromellose 6 cc 6,250 mg, titanium dioxide (E171) 2,691 mg, macrogol 400 0.625 mg, talc 0.100 mg, iron oxide yellow oxide (E172) 0.146 mg, ferric iron oxide red (E172) 0.188 mg).

Dosage of 160 mg

active substance: valsartan 160,000 mg;

Excipients: cellulose microcrystalline 142,400 mg, crospovidone 79,000 mg, silicon dioxide colloid 21,200 mg, magnesium stearate 7,500 mg; external phase (microcrystalline cellulose 142,400 mg, magnesium stearate 7,500 mg);

sheath: opedraj PINK 03300344 20,000 mg (hypromellose 6 cc 12,500 mg, titanium dioxide (E171) 5,383 mg, macrogol 400 1.250 mg, talc 0,200 mg, ferric oxide yellow oxide (E172) 0.292 mg, ferric oxide red oxide (E172) 0.375 mg).

Description:

Tablets of 40 mg. Round biconvex tablets covered with a film coat, light brown in color, on one side engraving C73, on the other - risk.

Tablets 80 mg. Oblong biconvex tablets covered with a film membrane, pink in color, C74 engraving on one side, risk on the other side.

Tablets 160 mg. Oblong biconvex tablets covered with a film membrane, pink in color, C75 engraving on one side, risk on the other side.

Pharmacotherapeutic group:angiotensin II receptor antagonist

ATX: & nbsp

C.09.C.A.03 Valsartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:

Valsartan is an antihypertensive drug, a specific angiotensin II receptor antagonist. It acts selectively on the AT₁ a subtype of receptors that are responsible for the known effects of angiotensin II. The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, which is formed from angiotensin I with the participation of an angiotensin-converting enzyme (ACE).Angiotensin II binds to specific receptors located on cell membranes in various tissues.

Has a wide range of physiological effects, including, in particular, both direct and indirect participation in the regulation of blood pressure (BP). Being a potent vasoconstrictor, angiotensin II causes a direct pressor response. In addition, it promotes the retention of sodium ions in the body and stimulates the secretion of aldosterone.

The affinity of valsartan for the receptors of the subtype AT₁ much (about 20 000 times) higher than to the receptors of the AT subtype₂.

Valsartan does not inhibit ACE, also known as kininase II, which converts angiotensin I into angiotensin II and breaks down bradykinin. Since there is no effect on ACE and there is no accumulation of bradykinin or substance P, it is unlikely that the use of angiotensin II antagonists can be associated with a cough. According to the results of clinical studies, where valsartan compared with an ACE inhibitor, the incidence of dry cough was significantly lower (p <0.05) in patients who received valsartan, than in patients receiving an ACE inhibitor (2.6% vs. 7.9%, respectively).In a clinical study in patients who had a dry cough during therapy with ACE inhibitors in history, the incidence of cough was 19.5% in patients who received valsartan and 19.0% receiving thiazide diuretics, compared with 68.5% of patients who received ACE inhibitor therapy (p <0.05). Valsartan does not bind or block receptors of other hormones or ion channels, which play an important role in regulating the activity of the cardiovascular system.

Arterial hypertension

The use of valsartan in patients with arterial hypertension leads to a decrease in blood pressure without changing the heart rate (heart rate).

In most patients after taking a single dose of the drug, the onset of antihypertensive action is observed for 2 hours, and the maximum decrease in blood pressure is achieved within 4-6 hours and persists for 24 hours after ingestion.

With the repeated administration of valsartan, its antihypertensive effect is stabilized, regardless of the dose, achieved after 2-4 weeks and maintained at the achieved level during prolonged therapy. The discontinuation of valsartan is not accompanied by a sharp rise in blood pressure or other undesirable clinical consequences.

Valsartan does not affect the concentration of total cholesterol, triglycerides, fasting glucose and uric acid in the serum.

After a recent myocardial infarction

In patients with acute myocardial infarction and confirmed heart failure and / or a violation of systolic function of the left ventricle, the use of valsartan in combination therapy, including acetylsalicylic acid, beta adrenoblockers, ACE inhibitors, thrombolytics and HMG-CoA reductase inhibitors, leads to a reduction in mortality from cardiovascular causes after acute myocardial infarction and an increase in the time to development of the cardiovascular event. The frequency of hospitalizations for heart failure and the rate of recurrence of myocardial infarction decrease.

Pharmacokinetics:

Valsartan is rapidly absorbed after ingestion, but the degree of absorption varies widely. The average absolute bioavailability is 23%. The pharmacokinetic curve of valsartan has a downward bi-exponential character (half-life (T_1/2) αphase less than 1 hour and (T_1/2) of the β-phase is about 9 hours).

The pharmacokinetics of valsartan in the range of doses studied is linear.

With repeated admission valsartan inside the changes in the pharmacokinetics of the drug is not observed, and when taking the drug once a day - its accumulation is negligible.

The time required to reach the maximum concentration (C_mOh) - 2 hours.

Plasma concentrations of valsartan are similar in men and women. Valsartan is largely associated with serum proteins (94-97%), mainly with albumin. The volume of distribution in the equilibrium state is low (about 17 liters). In comparison with the hepatic blood flow (about 30 l / h), the plasma clearance of the drug is relatively low (about 2 l / h).

After taking the medication, 83% of the dose taken internally is withdrawn through the intestine and 13% by the kidneys, mostly unchanged. About 20% of the accepted dose is excreted in the form of metabolites. The main metabolite is valeryl-4-hydroxyvalsartan. The enzymes involved in the metabolism of valsartan are not defined and do not belong to the isoenzymes of the cytochrome P450 system.

When taking valsartan with food, the area under the concentration-time curve decreases (AUC) by 48%. Nevertheless, 8 hours after taking the drug, plasma concentrations of valsartan taken on an empty stomach and with food are the same. Decrease AUC is not accompanied by a clinically significant decrease in the therapeutic effect, so the drug can be used both before and after meals.

Pharmacokinetics in specific patient groups

Elderly patients

In some elderly patients, the systemic effect of valsartan is more pronounced compared with younger patients.

In elderly patients, a lower initial dose of 40 mg of valsartan is recommended.

Patients with impaired renal function

Given that the renal clearance is only 30% of the total clearance, in patients with impaired renal function (creatinine clearance 20-50 ml / min), dose adjustment is not required, in patients with impaired renal function (CC less than 20 ml / min) it is recommended to start treatment with a dose of 40 mg. Because the degree of binding of valsartan to plasma proteins is high, its excretion in hemodialysis is unlikely.

Patients with impaired hepatic function

About 70% of the absorbed dose of valsartan is excreted through the intestines with bile, mostly unchanged. Valsartan does not undergo significant biotransformation, therefore its systemic effect does not correlate with the degree of impaired hepatic function.Therefore, patients with hepatic insufficiency of non-biliary origin and in the absence of cholestasis do not require a change in the dose of valsartan. In patients with biliary cirrhosis or obstruction of the biliary tract AUC Valsartan increases approximately 2-fold compared with healthy volunteers.

Indications:

- Arterial hypertension;

- with acute myocardial infarction as part of combination therapy in patients with stable hemodynamic parameters with asymptomatic left ventricular systolic dysfunction and / or heart failure in order to reduce mortality in myocardial infarction.

Contraindications:

- Hypersensitivity to valsartan or other components of the drug;

- pregnancy;

- lactation period;

- severe hepatic insufficiency (on the Child-Pugh scale more than 9 points), cirrhosis, obstruction of the biliary tract (cholestasis);

- age to 18 years (efficacy and safety not established).

Carefully:- Arterial hypotension;

- hepatic insufficiency (on the Child-Pugh scale less than 9 points);

- renal failure (CC less than 20 ml / min), including patients on hemodialysis;

- after a recent myocardial infarction;

- hyponatremia; a diet with a restriction of sodium intake;

- bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney;

- conditions accompanied by a decrease in the volume of circulating blood (BCC) (including diarrhea, vomiting);

- patients older than 75 years.

Pregnancy and lactation:

The use of Nortivan® during pregnancy is contraindicated. Renal perfusion of the fetus, which depends on the development of RAAS, begins to function in the third trimester of pregnancy. The risk to the fetus increases with the use of valsartan in the second and third trimesters. Preparations acting on RAAS, if used in the second and third trimester of pregnancy, can cause damage and death of the fetus. There are reports of spontaneous miscarriages, lack of water, and a violation of the kidney function of the newborn in cases where pregnant women were taking valsartan.

Data on the isolation of valsartan with breast milk are absent. If Nortivan® is needed during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake, the multiplicity of intake - 1-2 times a day.

Arterial hypertension

For most patients, the recommended dose of Nortivan® is 80 mg once daily, regardless of the age, sex or race of the patient. The hypotensive effect is manifested during 2 weeks of therapy, and the maximum effect is observed after 4 weeks of therapy.

In some patients who can not achieve the target BP, the dose can be increased to 160 mg per day. Further increase in antihypertensive effects can be achieved either by increasing the dose of Nortivan® to a maximum of 320 mg per day, or by adding Nortivan® thiazide diuretics to therapy.

Nortivan® can also be used concomitantly with other antihypertensive agents.

Use in patients older than 75 years

It is recommended to start treatment with a lower dose, 40 mg once a day.

Use in patients with impaired renal function

In patients with impaired renal function (CC less than 20 ml / min) or in patients on hemodialysis, it is recommended to begin treatment with a lower dose of 40 mg once a day.

In patients with impaired renal function (KK 20-50 ml / min), correction of the initial dose of the drug is not required.

Use in patients with reduced BCC

For patients with BCC (for example, in patients receiving treatment with high doses of diuretics in which the dose of diuretic can not be reduced), the initial dose of Nortivan® is 40 mg once a day.

Use in patients with impaired liver function Patients with mild to moderate hepatic insufficiency (less than 9 on the Child-Pugh scale) are recommended to use the recommended initial dose of 40 mg once daily. The maximum daily dose is 80 mg.

Do not exceed the daily dose of 80 mg.

Application in children and adolescents

The safety and efficacy of Nortivan® in children and adolescents under the age of 18 years have not been established.

Use in patients after a previous myocardial infarction

Therapy can be started already in the first 12 hours after an acute myocardial infarction in an initial dose of 20 mg (1/2 tablet 40 mg) twice a day, possibly a gradual increase in the dose of Nortivan® (40 mg, 80 mg) for several weeks , until the maximum dose of 160 mg twice a day, taking into account the tolerability of the drug.

When detecting hypotension or renal dysfunction, the question of reducing the dose of the drug should be considered.

Nortivan® can be used in patients receiving standard therapy after a myocardial infarction, including acetylsalicylic acid, beta-adrenoblockers, inhibitors of HMG-CoA reductase.

When using the drug Nortivan® after a previous myocardial infarction in patients with impaired renal function (KK 20-50 ml / min) does not require correction of the dose of the drug.

Currently, there are no data on the use of the drug after a previous myocardial infarction in patients with severe renal insufficiency (creatinine concentration> 221 μmol / L). For this reason, Nortivan® should be used with caution in these patients, with an appropriate assessment of renal function (see section Special instructions).

Side effects:

In clinical trials in patients with hypertension, adverse events were mild and transient. The incidence of adverse events was not related to gender, age, or race.

The frequency is defined as: very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥ 1/1000, <1/100); rarely (≥ 1 / 10,000, <1/1000); very rarely, including individual messages (<1/10 000).

Infections:
Often	Viral infections
Infrequently	Infections of the upper respiratory tract, pharyngitis, sinusitis
Rarely	Rhinitis
On the part of the hematopoiesis system:
Often	Neutropenia
Rarely	Thrombocytopenia
Allergic reactions:
Rarely	Reactions of hypersensitivity, (angioedema, skin rash, itching, hypersensitivity reactions, including serum sickness and vasculitis).
Laboratory indicators:
Infrequently	Hyperkalemia *
Rarely	Reduction of hemoglobin and hematocrit, neutropenia, thrombocytopenia, hypercreatininaemia, hyperbilirubinemia, increased activity of "liver" transaminases, increased urea nitrogen in serum.
From the central nervous system:
Infrequently	Fainting*, insomnia, fatigue, asthenia, decreased libido
Rarely	Dizziness
Rarely	Headache, mild and transient disorders of taste sensitivity
From the organ of hearing:
Infrequently	Vertigo
From the cardiovascular system:
Infrequently	Heart failure, marked decrease in blood pressure, orthostatic hypotension , peripheral edema
From the respiratory system:
Infrequently	Cough, epistaxis
From the digestive system:
Infrequently	Diarrhea, abdominal pain
Rarely	Nausea
From the hepatobiliary system:
Rarely	Dysfunction of the liver
From the musculoskeletal system:
Infrequently	Backache
Rarely	Arthralgia, myalgia
From the urinary system:
Rarely	Decreased kidney function , renal failure

When using the drug Nortivan® after a myocardial infarction:

* Hyperkalemia, syncope, orthostatic hypotension, heart failure - are infrequent;

** decreased renal function, renal failure - are very rare.

Overdose:

Symptoms: despite the lack of sufficient data, the main expected manifestation of an overdose of the drug will be tachycardia and a marked decrease in blood pressure, which can lead to collapse and / or shock.

Treatment: there is no specific antidote. If the drug is taken recently, you should induce vomiting, rinse the stomach, take Activated carbon. With a pronounced decrease in blood pressure by the usual method treatment is an intravenous injection of 0.9% sodium chloride solution. Hemodialysis is ineffective.

Interaction:

Because the valsartan does not undergo significant metabolism, significant drug interactions associated with the induction or inhibition of the cytochrome P450 system should not be expected.

Clinically significant pharmacokinetic interactions with other drugs have not been observed. Drugs tested in clinical trials included cimetidine, warfarin, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine and glibenclamide.

With the simultaneous use of lithium preparations with ACE inhibitors, there have been reports of a reversible increase in lithium content in the blood plasma and an increase in its toxicity. In very rare cases, such changes were observed when taking lithium preparations with angiotensin II receptor antagonists. Caution is advisable to use lithium preparations with Nortivan®. If this combination is necessary, then it is recommended to control the lithium content in the blood plasma.

Simultaneous reception of potassium-sparing diuretics (spironolactone, triamterene, amiloride), potassium-containing food additives and potassium preparations, can lead to an increase in the potassium content in the blood plasma.

At simultaneous reception of angiotensin II receptor antagonists with non-steroidal anti-inflammatory drugs (NSAIDs) (including selective inhibitors of cyclooxygenase-2 (COX-2), acetylsalicylic acid (more than 3 g / day) and other nonselective NSAIDs, a decrease in the antihypertensive effect of valsartan is possible.

Simultaneous use of angiotensin II receptor antagonists and NSAIDs increases the risk of renal dysfunction, including acute renal failure and an increase in potassium levels in the blood plasma, especially in patients with impaired renal function. Care should be taken with simultaneous application, especially in elderly patients. After the beginning of the combination therapy, and also in the course of treatment, it is necessary to control the BCC and kidney function.

By the results of the study in vitro Valsartan is a substrate for the hepatic transporters of OATP1B1 and MRP2.

Special instructions:

Hyponatremia and decreased BCC

In patients with severe sodium deficiency and / or reduced bcc, such as those receiving high doses of diuretics, severe arterial hypotension may occur rarely after starting therapy with Nortivan®.Patients in whom a dose of diuretics can not be reduced for the purpose of correcting the sodium and / or BCC content, the recommended initial dose of Nortivan® is 40 mg.

Stenosis of the renal artery

Short-term use of valsartan in patients with renovascular hypertension, secondary to unilateral renal artery stenosis, did not cause any significant changes in renal hemodynamics, serum creatinine, or blood urea nitrogen (AMC). However, since the use of other drugs that act on RAAS can increase the concentration of urea and creatinine in the blood serum, it is recommended to monitor these parameters and monitor this group of patients as a precautionary measure.

Liver failure

Based on pharmacokinetic data that demonstrate a significant increase in valsartan plasma concentration in patients with hypertension with concomitant mild to moderate hepatic insufficiency (less than 9 on the Child-Pugh scale), use of lower doses of Nortivan® is recommended (see " Method of administration and dose ").In such patients, the daily dose of 80 mg should not be exceeded. The question of the use of a dose higher than 80 mg twice a day should be considered only if the clinical benefits are more likely to exceed the potential risk associated with an increase in the antihypertensive effect of Nortivan® (see the "Application and dosage" section). . Patients with severe hepatic insufficiency (on the Child-Pugh scale more than 9 points), cirrhosis of the liver, obstruction of the biliary tract, use of the drug Nortivan® is contraindicated (see section "Contraindications").

Impaired renal function

Due to the suppression of RAAS activity, there was reported increased urea concentration, creatinine in the blood serum and a violation of the function of tits, including acute renal failure (very rare), which was observed especially in patients with an existing renal dysfunction or in patients with severe chronic heart failure.

Against the background of simultaneous intake of potassium preparations, it is necessary to control the potassium content in the blood serum, especially in patients with impaired renal function or in elderly patients (see Fig.sections "Side effect" and "Interaction with other drugs").

Condition after a myocardial infarctionYes

The use of Nortivan® in patients after myocardial infarction usually results in a slight decrease in blood pressure, but it is not usually necessary to follow the recommendations for the dosing regimen for the withdrawal of Nortivan® due to hypotension.

Caution should be exercised when prescribing Nortivan® in patients who have had myocardial infarction (see the section on "Dosage and Administration").

Due to the suppression of RAAS activity in predisposed patients, one can expect impaired renal function. Assessment of the condition of patients after a previous myocardial infarction should always include an assessment of renal function.

Combination with hydrochlorothiazide allows to achieve a significant additional reduction in blood pressure.

Effect on the ability to drive transp. cf. and fur:

Studies to study the effect of the drug Nortivan® on the ability to drive vehicles and use of technical means were not conducted. However, care should be taken, as dizziness or fatigue may occur during treatment.

Form release / dosage:

Tablets, film-coated, 40 mg, 80 mg, 160 mg.

Packaging:

10 tablets per blister Al / Al.

For 3 blisters with instructions for use in a cardboard box.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-005569/10

Date of registration:17.06.2010

The owner of the registration certificate:GEDEON RICHTER, OJSC GEDEON RICHTER, OJSC Hungary

Manufacturer: & nbsp

GEDEON RICHTER, Ltd. Hungary

GEDEON RICHTER POLAND, Co. Ltd. Poland

Representation: & nbspGEDEON RICHTER OJSC GEDEON RICHTER OJSC Hungary

Information update date: & nbsp07.12.2015

Illustrated instructions

Instructions

Nortivan® (Nortivan®)