Ko-Dalnev® (Co-Dalneva®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbsppills
Composition:

1 tablet 5 mg + 0.625 mg + 2 mg contains:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.935 mg, equivalent to amlodipine 5 mg, indapamide 0.625 mg,

Perindopril erbumine In the substance-granules 10,206 mg

The active substance of the substance-granules: perindopril erbumine 2,000 mg Auxiliary substances of granule substance: microcrystalline cellulose 7,900 mg, calcium chloride hexahydrate 0.600 mg]

Excipients: cellulose microcrystalline 90,244 mg, pregelatinized starch 21,000 mg, sodium carboxymethyl starch 8,400 mg, sodium hydrogen carbonate 0.760 mg, silicon dioxide colloid 0.430 mg, magnesium stearate 1,400 mg

1 tablet 5 mg + 1,25 mg + 4 mg contains:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.935 mg, equivalent to amlodipine 5 mg, indapamide 1,250 mg,

Perindopril erbumine In the substance-granules 20,412mg

The active substance of the substance-granules: perindopril erbumine 4.000 mg Auxiliary substances of granule substance: microcrystalline cellulose 15,800 mg, calcium chloride hexahydrate 1,200 mg

Excipients: cellulose microcrystalline 79.413 mg pregelatinized starch 21,000 mg, sodium carboxymethylstarch 8,400 mg, sodium hydrogen carbonate 0.760 mg, silicon dioxide colloid 0.430 mg, magnesium stearate 1.400 mg

1 tablet 10 mg + 1.25 mg + 4 mg contains:

Active substances:

Amlodipine besylate (amlodipine besylate) 13.870 mg, which is equivalent to amlodipine 10 mg, Indapamide 1.250 mg,

Perindopril erbumine In the substance-granules 20,412mg

The active substance of the substance-granules: Perindopril erbumine 4,000 mg Auxiliary substances of granule substance: microcrystalline cellulose 15,800 mg, calcium chloride hexahydrate 1,200 mg]

Excipients: cellulose microcrystalline 180.488 mg, pregelatinized starch 42,000 mg, sodium carboxymethylstarch 16,800 mg, sodium hydrogen carbonate 1,520 mg, silicon dioxide colloid 0,860 mg, magnesium stearate 2,800 mg

1 tablet 5 mg + 2.5 mg + 8 mg contains:

Active substances:

Amlodipine besylate (amlodipine besylate) 6.935 mg, equivalent to amlodipine 5 mg, indapamide 2,500 mg,

Perindopril erbumine In substance-granules 40,824mg

The active substance of the substance-granules: psrndopril erbumine 8,000 mg Auxiliary substances of granule substance: microcrystalline cellulose 31,600 mg, calcium chloride hexahydrate 2,400 mg

Excipients: cellulose microcrystalline 165.761 mg, pregelatinized starch 42,000 mg, sodium carboxymethylstarch 16,800 mg, sodium hydrogen carbonate 1,520 mg, silicon dioxide colloid 0,860 mg, magnesium stearate 2,800 mg

1 tablet 10 mg + 2.5 mg + 8 mg contains:

Active substances:

Amlodipine besylate (amlodipine besylate) 13.870 mg, which is equivalent to amlodipine 10 mg, Indapamide 2.500 mg,

Perindopril erbumine In the substance-granules 40.824 mg

[The active substance of the substance-granules: perindopril erbumine 8,000 mg Auxiliary substances of granule substance: cellulose microcrystalline 31,600 mg, calcium chloride hexahydrate 2,400 mg]

Excipients: cellulose microcrystalline 158.826 mg, pregelatinized starch 42,000 mg, sodium carboxymethyl starch 16,800 mg, sodium hydrogen carbonate 1,520 mg, silicon dioxide colloid 0,860 mg, magnesium stearate 2,800 mg.

Description:

Tablets 5 mg + 0.625 mg + 2 mg:

Oval, biconvex tablets with a risk on one side, white or almost white.

Tablets 5 mg + 1.25 mg + 4 mg:

Round, slightly biconcave tablets with a facet on both sides, white or almost white.

Tablets 5 mg + 2.5 mg + 8 mg:

Round, biconvex tablets with a facet on both sides, white or almost white.

Tablets 10 mg + 1.25 mg + 4 mg:

Oval, biconvex tablets with a risk on one side, white or almost white.

Tablets 10 mg + 2.5 mg + 8 mg:

Round, biconvex tablets with a facet on both sides and a risk on one side, white or almost white.

Pharmacotherapeutic group:hypotensive combined agent (blocker of "slow" calcium channels + diuretic + angiotensin-converting enzyme inhibitor)
Pharmacodynamics:

Ko-Dalnev® - combined preparation containing perindopril erbumine (angiotensin-converting enzyme inhibitor (A11F)), indapamide (thiazide-like diuretic) and amlodipine (blocker of "slow" calcium channels (IUMC)).

Ko-Dalnev® combines the properties of each of the active substances, which at the same time have a potentiating effect.

Pharmacodynamics

Amlodipine

Amlodipine - BCCC, a derivative of dihydropyridine. Amlodipine inhibits the transmembrane transition of calcium ions to cardiomyocytes and smooth muscle cells of the vascular wall. The antihypertensive effect of amlodipine is due to a direct relaxing effect on the smooth muscle cells of the vascular wall. The mechanism of antianginal action of amlodipine is not fully understood, it is supposedly associated with the following effects:

- causes expansion of peripheral arterioles, reducing the overall peripheral vascular resistance (OPSS) - postnagruzku, which leads to a decrease in the need for myocardium in oxygen;

- causes the expansion of coronary arteries and arterioles both in intact and in ischemic areas of the myocardium, which increases the flow of oxygen into the myocardium, including in patients with Prinzmetal angina.

In patients with arterial hypertension (AH), amlodipine once a day provides a clinically significant reduction in blood pressure (BP) (in the "lying" and "standing") for 24 hours. Antihypertensive action develops slowly, in connection with which, the development of acute arterial hypotension is uncharacteristic. In patients with angina, receiving amlodipine once a day increases exercise tolerance, time to the development of angina attack and to the "ischemic" depression of the segment ST, reduces the incidence of angina attacks and the need for taking nitroglycerin (short-acting forms). Amlodipine does not affect the lipid profile and does not cause changes in lipid-lowering plasma parameters. The drug can be used in patients with bronchial asthma (BA), diabetes mellitus (DM) and gout.

Indapamide

Indapamide is a sulfonamide derivative.By pharmacological properties is close to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the Henle loop, which leads to an increase in renal excretion of sodium and chlorine ions, and to a lesser extent potassium and magnesium ions, thereby increasing diuresis and lowering blood pressure.

In the regime of monotherapy, the antihypertensive effect persists for 24 hours and appears when the drug is used in doses that have a minimal diuretic effect. Antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in OPSS. On the background of taking indapamide, left ventricular hypertrophy (LVH) decreases. Indapamide does not affect the concentration of lipids in the blood plasma (triglycerides, total cholesterol,

lipoproteins of low and high density), on the parameters of carbohydrate metabolism (including in patients with diabetes).

Perindopril

Perindopril is an inhibitor of the angiotensin-converting enzyme. ACE, or kininase II, is an exopeptidase that converts angiotensin I into a vasoconstrictor substance, angiotensin II, and also destroys bradykinin, which has vasodilating properties, to an inactive heptapeptide.

As a result, perindopril provides the following effects:

- reduces the secretion of aldosterone;

- increases the activity of plasma renin by the principle of "negative" feedback;

- with prolonged use lowers the OPSS - afterload of the heart, which is due, mainly, to the action on the muscular and renal vessels. Decrease in OPSS is not accompanied by a delay of sodium and water and does not cause a reflex tachycardia.

The study of hemodynamic parameters in patients with chronic heart failure (CHF) revealed:

- decrease of filling pressure in the left and right ventricles of the heart;

- reduction in OPSS;

- increased cardiac output and cardiac index;

- increased peripheral blood flow in the muscles.

In addition, there was an improvement in the results of the sample with exercise. The action of perindopril is carried out through an active metabolite - perindoprilata. Other metabolites of nc exert an inhibitory effect on ACE in conditions in vitro.

Perindopril is effective in treating hypertension of any severity, reduces both systolic and diastolic blood pressure in the "lying" and "standing" positions. Antihypertensive effect reaches a maximum in 4-6 hours after a single oral intake and persists for 24 hours.

Antihypertensive action 24 hours after a single oral intake is about 87-100% of the maximum antihypertensive effect.

Perindopril has an antihypertensive effect in patients with both low and normal renin activity in blood plasma.

The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Termination of therapy does not cause the withdrawal syndrome.

Perindopril has vasodilating properties and contributes to the restoration of the elasticity of large arteries, the structure of the vascular wall of small arteries, and also reduces LVH.

Simultaneous use with thiazide diuretic enhances the severity of antihypertensive action and reduces the risk of hypokalemia in patients receiving diuretics.

Perindopril / Indapamide

The combination of perindopril / indapamide has a dose-dependent antihypertensive effect on both systolic and diastolic blood pressure (in the "standing" and "lying" positions) regardless of the age of the patient. The antihypertensive effect persists for 24 hours. The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Termination of therapy does not cause the withdrawal syndrome.

In clinical studies, the simultaneous use of perindopril and indapamide increased the severity of antihypertensive action compared with monotherapy with each drug. The combination of perindopril terbutylamine (perindopril erbumine) / indapamide led to a significantly more marked decrease in LVH than monotherapy with enalapril. The most significant effect on LVH is achieved with the use of perindopril terbutylamine (perindopril erbumine) 8 mg / indapamide 2.5 mg.

Pharmacokinetics:

Amlodipine

Suction, distribution

After oral administration amlodipine slowly absorbed from the gastrointestinal tract (GIT). Eating food does not affect the bioavailability of amlodipine. The maximum concentration (CmOh) amlodipine in the blood plasma is achieved 6-12 hours after ingestion. Absolute bioavailability is about 64-80%. Volume of distribution (Vd) is approximately 21 l / kg. In studies in vitro the degree of binding of amlodipine with plasma proteins was about 97.5%.

Metabolism, excretion

The final half-life (T1 / 2) from the blood plasma is about 35-50 hours, which allows amlodipine 1 time per day. Amlodipine metabolized in the liver with the formation of inactive metabolites, with 10% of the dose of amlodipine taken internally withdrawn unchanged, about 60% - kidneys in the form of metabolites. Amlodipine is not excreted from the body by hemodialysis.

Time to reach CmAmlodipine does not differ in elderly and younger patients. In elderly patients, amlodipine clearance decreases, which leads to an increase in the area under the concentration-time curve (AUC) and T1 / 2. Dose adjustments in elderly patients are required, but caution should be used to increase the dose of amlodipine. Increase AUC and T1 / 2 in patients with CHF corresponds to the expected value for this age group. In patients with impaired renal function, changes in amlodipine concentration in the blood plasma do not correlate with the degree of renal failure. A slight elongation of T1 / 2 is possible.

In patients with impaired hepatic function, the use of amlodipine is limited, there is a decrease in clearance of amlodipine, which leads to an increase in T1 / 2 and AUC by about 40-60%.

Indapamide

Suction, distribution

Indapamide is rapidly and completely absorbed from the digestive tract. FROMmax in blood plasma is achieved approximately 1 hour after ingestion. The degree of binding to plasma proteins is 79%.

Metabolism, excretion

T1/2 is 14-24 hours (an average of 18 hours). Repeated reception of indapamide does not lead to its cumulation. Eliminated mainly by the kidneys (70% of the ingested dose) and through the intestine (22%) in the form of inactive metabolites.

The pharmacokinetics of indapamide does not change in patients with renal insufficiency.

Perindopril

Absorption, metabolism

Ingestion perindopril quickly absorbed. FROMmOh in blood plasma is achieved 1 hour after ingestion.

Perindopril is a prodrug, i.e. does not have pharmacological activity. About 27% of the dose of perindopril taken internally enters the bloodstream in the form of an active metabolite - perindoprilata. In addition to the active metabolite - perindoprilata, another 5 metabolites are formed that do not have pharmacological activity. FROMmOh Perindoprilata in blood plasma is achieved 3-4 hours after ingestion. Eating slows the conversion of perindopril to perindoprilat, thus affecting bioavailability. therefore perindopril should be taken 1 time a day, in the morning, before receiving beggars.

There is a linear dependence of the concentration of perindopril in the blood plasma from the ingested dose.

Distribution

Vd free perindoprilata is approximately 0.2 l / kg. The degree of binding perindoprilata with blood plasma proteins (mainly with A11F) is about 20% and is dose-dependent.

Excretion

T1 / 2 perindopril from plasma is 1 hour. Perindoprilat is eliminated from the body by the kidneys. The final T1 / 2 free fraction is about 17 hours, the equilibrium state is reached within 4 days. The excretion of perindoprilat is slowed in elderly patients, as well as in patients with cardiac and renal insufficiency. Correction of dose in patients with renal insufficiency is performed taking into account the degree of impaired renal function (creatinine clearance (CC)). The dialytic clearance of perindoprilat is 70 ml / min.

The pharmacokinetics of perindopril changes in patients with cirrhosis of the liver: liver clearance decreases by a factor of 2. However, the amount of perindoprilata formed does not decrease, so dose adjustment is not required (see Fig.sections "Method of administration and dose" and "Special instructions").

Indications:

- Arterial hypertension (if necessary simultaneous therapy with amlodipine, indapamide and perindopril in doses used in monotherapy of individual components).

Contraindications:

- Hypersensitivity to amlodipine and other derivatives of dihydropyridine, indapamide and other derivatives of sulfonamide, perindopril and other ACE inhibitors, as well as to the excipients included in the preparation.

- Angioedema (angioedema) in an anamnesis associated with the administration of ACE inhibitors.

- Hereditary / idiopathic angioedema.

- Two-sided stenosis of the renal arteries, stenosis of the artery of a single kidney.

- Severe arterial hypotension (systolic blood pressure less than 90 mm Hg).

- Shock, including cardiogenic shock.

- Unstable angina (with the exception of Prinzmetal angina).

- Obstruction of the left ventricular outflow tract (eg, clinically significant aortic stenosis).

- Hemodynamically unstable heart failure after acute myocardial infarction.

- Renal failure (CC less than 60 ml / min).

- Severe hepatic insufficiency, including hepatic encephalopathy.

- Refractory hypokalemia.

- Simultaneous use with drugs that can cause polymorphic ventricular arrhythmia of the "pirouette" type (see section "Interaction with other drugs"),

- Simultaneous use with potassium-sparing diuretics, potassium and lithium preparations, in patients with elevated potassium levels in blood plasma.

- Simultaneous use of drugs that extend the interval QT.

- Simultaneous use with aliskiren and aliskirenzodrugs in drugs in patients with diabetes mellitus.

- Pregnancy and the period of breastfeeding (see the section "Pregnancy and the period of breastfeeding"),

- Age to 18 years (effectiveness and safety not established).

Given the lack of sufficient clinical experience, should not be used in patients on hemodialysis, as well as in patients with untreated heart failure in the stage of decompensation.

Carefully:

With caution (see also the sections "Special instructions" and "Interaction with other medicinal products"):

hepatic insufficiency of mild and moderate severity, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), immunosuppressant therapy, allopurinol, procainamide (risk of neutropenia and agranulocytosis), oppression of bone marrow hematopoiesis, reduced circulating blood volume (diuretics, diet with restriction of table salt, vomiting, diarrhea, hemodialysis), ischemic heart disease, atherosclerosis, cerebrovascular diseases, renovascular hypertension, sugar diabetes, chronic heart failure (IV functional class classification NYHA), hyperuricemia (especially in combination with gout and urate nephrolithiasis), simultaneous use of dantrolene, estramustine, surgical intervention / general anesthesia, lability AD, hemodialysis using high-flow membranes (for example, AN69®), before the procedure for apheresis of low density lipoproteins (LDL) with the help of dextran sulfate, simultaneous desensitizing therapy with allergens (for example, Hymenoptera venom), condition after kidney transplantation,aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy (GOKMP), use in elderly patients and patients of the Negroid race.

Pregnancy and lactation:

Pregnancy

The preparation of Ko-Dalnev® contraindicated in pregnancy (see section "Contraindications").

When planning pregnancy or when it comes on the background of taking the drug Ko-Dalnev® should immediately stop taking and prescribe an alternative antihypertensive therapy with a proven safety profile.

The safety of the use of amlodipine in pregnancy is not established. The limited information available on the use of amlodipine and other BCCC in pregnancy indicates that there is no adverse effect on the fetus. In animal experiments, signs of reproductive toxicity were observed with high doses of amlodipine. In some patients receiving BCCI therapy, a reversible decrease in sperm motility was noted. Clinical data concerning the potential effect of amlodipine on reproductive function is not enough. Long-term use of thiazide diuretics in III trimester of pregnancy can cause hypovolemia in the mother and decrease utero-placental blood flow, which leads to fetoplacental ischemia and delayed development of the fetus. In rare cases, against the background of diuretics shortly before delivery, neonates develop hypoglycemia and thrombocytopenia.

The available data on the teratogenicity of ACE inhibitors in the first trimester of pregnancy are not convincing, but this risk can not be completely ruled out. In II and III the effects of ACE inhibitors on the fetus may lead to a disruption of its development (decreased kidney function, oligohydramnion, slowing ossification of the skull bones) and development of complications in newborns (kidney failure, arterial hypotension, hyperkalemia). If an ACE inhibitor is used in the second or third trimester of pregnancy, it is recommended to perform ultrasound examination of the kidneys and bones of the skull of the fetus. Newborns, whose mothers received ACE inhibitors during pregnancy, need careful medical supervision, since there is a risk of developing arterial hypotension.

Breastfeeding period

There is no data on the excretion of amlodipine with breast milk. However, it is known that other BCCC derivatives of dihydropyridine are dispensed with breast milk.

Indapamide is excreted in breast milk. Admission of thiazide diuretics causes a decrease or suppression of lactation in the mother, a newborn may develop increased sensitivity to sulfonamide derivatives, hypokalemia and "nuclear" jaundice.

It is not known whether perindopril with breast milk.

The preparation of Ko-Dalnev® contraindicated in breastfeeding. If you need to use the drug Ko-Dalnev® During lactation breastfeeding should be discontinued.

Dosing and Administration:

Inside, but 1 tablet I once a day, preferably in the morning, before taking the write.

The dose of the drug Ko-Dalnev® is selected after previous titration of the doses of the individual active components of the drug.

The maximum daily dose of the drug Ko-Dalnev® is 10 mg of amlodipine + 2.5 mg of indapamide + 8 mg of perindopril.

Older patients and patients with impaired renal function

The preparation of Ko-Dalnev® is contraindicated for use in patients with moderate to severe severe renal dysfunction (CC less than 60 ml / min) (see section "Contraindications"). The preparation of Ko-Dalnev® can be used in patients with QC equal to and exceeding 60 ml / min. Such patients are recommended individual selection of doses of amlodipine, indapamide, perindopril.

Amlodipine, used in equivalent doses, is equally well tolerated by patients of both the elderly and younger age. It is not necessary to change the dosage regimen in elderly patients, but the dose increase should be carried out with caution, which is associated with age-related changes and lengthening Tia The change in the concentration of amlodipine in the blood plasma does not correlate with the degree of renal insufficiency.

The excretion of perindoprilat in elderly patients and patients with renal insufficiency is slowed. Therefore, in such patients it is necessary to regularly monitor the concentration of creatinine and the content of potassium in the blood plasma.

Patients with impaired hepatic function

The preparation of Ko-Dalnev® is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Care should be taken when using the drug in patients with mild and moderate impairment of liver function.

Side effects:

Frequency classification development of side effects of the World Health Organization (WHO):

very often> 1/10

often from> 1/100 to <1/10

infrequently from> 1/1000 to <1/100

rarely from> 1/10000 to <1/1000

very rarely <1/10000

frequency is unknown: can not be estimated from the available data.

Classification

MedDRA

Undesirable effects

Frequency

Amlodipine

Perindopril / Indapamide

Violations of the blood and lymphatic system

Leukopenia / neutropenia

Rarely

Rarely

Agranulocytosis or pancytopenia


Rarely

Thrombocytopenia

Rarely

Rarely

Aplastic anemia

-

Rarely

Hemolytic anemia

-

Rarely

In the treatment of ACE inhibitors in certain situations (after kidney transplantation, during dialysis), the development of anemia

-

Rarely

Immune system disorders

Hypersensitivity reactions in patients,

predisposed to bronchoobstructive and allergic reactions

-

Infrequently


Allergic reactions

Rarely

-

Violations from

Hyperglycaemia

Rarely

-

sides of metabolism and nutrition

Increase or decrease in body weight

Infrequently

-

Disorders of the psyche

Insomnia

Infrequently

-


Lability of mood (including anxiety)

Infrequently

Infrequently


Depression

Infrequently

-


Sleep disturbance

-

Infrequently


Confusion of consciousness

Rarely

Rarely

Disturbances from the nervous system

Drowsiness (especially at the beginning of treatment)

Often



Dizziness (especially at the beginning of treatment)

Often

Often


Headache

Often

Often


Tremor

Infrequently

-


Hypesesia

Infrequently

-


Paresthesia

Infrequently

Often


Muscle hypertension

Rarely

-


Peripheral

neuropathy

Rarely



Vertigo

-

Often


Fainting

Infrequently

Frequency unknown

Disturbances on the part of the organ of sight

Visual impairment (including diplopia)

Infrequently

Often

Hearing and labyrinthine disorders

violations

Noise ("ringing") in the ears

Infrequently

Often

Heart Disease

Heart palpitations

Often

-


Angina pectoris

-

Rarely


Myocardial infarction, possibly due to excessive reduction in blood pressure in patients at high risk

Rarely

Rarely


Heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation)

Rarely

Rarely


Polymorphic ventricular tachycardia of the type "pirouette" (possibly fatal)

-

Frequency unknown

Vascular disorders

Feeling of "tides" of blood to the skin of the face

Often

-


A marked decrease in LD (including orthostatic hypotension)

Infrequently

Infrequently


Vasculitis (including, hemorrhagic vasculitis)

Rarely

Infrequently

Disturbances from the respiratory system, chest and mediastinal organs

Dyspnea

Infrequently

Often


Rhinitis

Infrequently

Rarely


Cough

Rarely

Often


Bronchospasm

-

Infrequently


Eosinophilic pneumonia

-

Rarely

Disorders from the gastrointestinal tract

Hyperplasia of gums

Rarely

-


Abdominal pain, nausea

Often

Often


Pain in epigastrium

-

Often


Vomiting

Infrequently

Often


Dyspepsia

Infrequently

Often


Changes in the bowel movement (including diarrhea, constipation)

Infrequently

Often


Dryness of the oral mucosa

Infrequently

Often


Disturbance of taste perception


Often


Pancreatitis

Rarely

Rarely


Gastritis

Rarely

-


Decreased appetite

-

Often


Angioedema of the intestine


Rarely

Disturbances from the liver and bile excretory

ways

Hepatitis*

Rarely

-


Jaundice*

Rarely

Rarely


Hepatic encephalopathy in patients with hepatic impairment

-

Frequency unknown

Disturbances from the skin and subcutaneous tissues

Hives

Infrequently

Infrequently


Angioedema, swelling of the face, extremities, lips, mucous membrane of the tongue, vocal folds and / or larynx (see section "Special instructions")

Rarely

Infrequently


Multiforme exudative erythema

Rarely

Rarely


Exanthema

Infrequently

-


Alopecia

Infrequently

-


Purpura

Infrequently

-


Skin discoloration

Infrequently

-


Increased sweating

Infrequently

Infrequently


Itchy skin

Infrequently

Often


Skin rash

Infrequently

Often


Exfoliative dermatitis

Rarely



Stevens-Johnson Syndrome

Rarely

Rarely


Photosensitivity

Rarely

Frequency unknown


Maculopapular rash

-

Often


Toxic epidermal necrolysis

-

Rarely


Possible worsening of the course of the acute form of systemic lupus erythematosus


Infrequently

Disturbances from the musculoskeletal system and connective tissue

Arthralgia, myalgia

Infrequently

-


Swelling of the ankles

Often

-


Muscle Cramps

Infrequently

Often


Backache

Infrequently

-

Disorders from the kidneys and urinary tract

Painful

urination, nocturia,

rapidity

urination

Infrequently

-


Renal insufficiency

-

Infrequently


Acute renal failure (OP11)


Rarely

Violations of the genitals and mammary gland

Impotence

Infrequently

Infrequently


Gynecomastia

Infrequently


Are common

disorders and disorders at the site of administration

Peripheral edema

Often

-


Increased fatigue

Often

-


Chest pain

Infrequently

-


Asthenia

Infrequently

Often


Pain of different localization

Infrequently



General malaise

Infrequently

-

Laboratory and

instrumental

data

Increase in concentration

whey

bilirubina, activity

"hepatic" enzymes

(alanine aminotransferase

(ALT) *,

aspartate aminotransferase

(ACT)*)

Rarely

Frequency unknown


Increase the interval QT on an electrocardiogram (ECG)

-

Frequency unknownMr.a


Increase in concentration and creatinine in urine and blood plasma, which occurs after the abolition of therapy

-

Frequency unknown


Hypokalemia

-

Frequency unknown


Hyponatremia and hypovolemia leading to dehydration and orthostatic hypotension

-

Frequency unknown


Increase in the concentration of uric acid and glucose in the blood plasma

-

Frequency unknown


Hyperkalemia

-

Frequency unknown


Hypercalcemia

-

Rarely

* In most cases, it is associated with cholestasis

Overdose:

Symptoms

The most likely symptoms in overdose are a marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (the risk of development of severe and persistent arterial hypotension, including the development of shock and death). Sometimes a marked decrease in blood pressure is accompanied by nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which can go to anuria (as a result of hypovolemia). Also, violations of the water-electrolyte balance (ginonatremia, hypokalemia) can be observed.

Treatment

Emergency measures are aimed at removing the drug from the gastrointestinal tract: gastric lavage and / or reception of activated carbon, followed by restoration of the water-electrolyte balance. With a marked decrease in blood pressure, the patient should be placed with an elevated position of the lower extremities, if necessary, correct hypovolemia (for example, intravenous infusion of 0.9% sodium chloride solution).

Perindoprilat, an active metabolite of perindopril, is removed by hemodialysis. Amlodipine is closely associated with blood plasma proteins, therefore hemodialysis is ineffective.

Indapamide is not removed by hemodialysis.

Interaction:

Amlodipine

Simultaneous use is not recommended

Dantrolene (intravenous administration)

In laboratory animals, cases of ventricular fibrillation with a lethal outcome and collapse on the background of verapamil and intravenous dantrolene were observed, accompanied by hyperkalemia. Due to the risk of development Hyperkalemia is recommended to avoid simultaneous use of BCCC (amlodipine) and dantrolene in patients prone to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

A simultaneous application requiring special attention

Inductors of isoenzyme CYP3A4

Data on the influence of isoenzyme inducers CYP3A4 on amlodipip, are absent. Simultaneous application of isoenzyme inducers CYP3A4 (rifampicin, preparations of St. John's wort Perforated) may lead to a decrease concentration of amlodipine in blood plasma.Caution should be exercised while taking amlodipine with isoenzyme inducers CYP3A4.

Inhibitor inhibitors CYP3A4

The simultaneous use of amlodipine with potent or moderate isoenzyme inhibitors CYP3A4 (protease inhibitors, antifungal agents of the azole group, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. In this connection, it may be necessary to monitor the clinical state and dose adjustment.

Simultaneous application requiring attention

Amlodipine increases the antihypertensive effect of drugs for antihypertensive therapy.

Other combinations of drugs

In clinical trials of drug interactions amlodipine had no effect on the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine. Simultaneous reception of amlodipine and the use of grapefruit or grapefruit juice is not recommended,in connection with the possible increase in the bioavailability of amlodipine in some patients, which may lead to an increase in the antihypertensive effect.

Indapamide

A simultaneous application requiring special attention

Preparations that can cause a polymorphic ventricular tachycardia such as "pirouette"

Given the risk of hypokalemia, caution should be exercised when using indapamide with drugs that can induce polymorphic ventricular tachycardia such as pirouettes, for example antiarrhythmics (quinidine, hydroquinidine, disopyramide, amiodarone, dofstilide, ibutilide, brethil tosylate, sotalol), some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoroperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide), other drugs such as bepridil, cisapride, dipemanyl methyl sulfate, erythromycin intravenously (iv), halofantrine, misolastine, moxifloxacin, pentamidine, sparfloxacin, wincamine in / in, methadone, astemizole, terpepadine.It is necessary to avoid simultaneous application with the above drugs with the development of hypokalemia, carry out its correction, monitor the ECG (interval QT).

Drugs that can cause hypokalemia

Simultaneous reception with amphotericin B in IV, systemic glucocorticosteroids and mineralocorticosteroids, tetracosactide, laxatives, stimulating gastrointestinal motility, increases the risk of hypokalemia (additive effect). It is necessary to control the content of potassium in the blood plasma, if necessary - correction of hypokalemia. Particular care should be taken when using with cardiac glycosides. You should use laxatives that do not stimulate the motility of the gastrointestinal tract.

Cardiac glycosides

Hypokalemia increases the toxic effect of cardiac glycosides. In case of simultaneous use, it is necessary to monitor the potassium content in the blood plasma and the ECG parameters and, if necessary, to decide whether to continue the therapy.

Simultaneous application requiring attention

Metformin

Functional renal failure, which can occur with the use of diuretics, especially "loop"while simultaneous use of metformin increases the risk of lactic acidosis. Do not use metformin, if the SC in the blood plasma exceeds 15 mg / L (135 μmol / L) in men and 12 mg / L (110 μmol / L) in women.

Iodine-containing contrast agents

Dehydration of the body against the background of taking diuretics increases the risk of acute renal failure, especially when high doses of iodine-containing contrast agents are administered. Before using iodine-containing contrast agents, hypovolemia should be compensated.

Salt calcium

With simultaneous application, it is possible to develop hypercalcemia due to a reduction in the excretion of calcium by the kidneys.

Cyclosporin

It is possible to increase QC in blood plasma without changing the concentration of cyclosporine, even with normal water and sodium content.

Perindopril

Simultaneous use is not recommended

Aliskiren

The simultaneous use of perindopril with aliskiren is contraindicated in patients with diabetes or moderate or severe renal dysfunction (CC less than 60 mL / min). Potassium-sparing diuretics, potassium preparations and potassium-containing substitutes for edible salt

At the foyer of therapy with ACE inhibitors, the potassium content in the blood plasma, as a rule, remains within normal limits, but hyperkalaemia may develop. Simultaneous reception of potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), preparations of potassium and potassium-containing substitutes for edible salt can lead to a significant increase in the potassium content in the blood plasma. If necessary, the simultaneous reception of the above ACE inhibitor therapy (in the case of hypokalemia) should be careful to carry out regular monitoring the potassium content in the blood plasma and ECG parameters.

Estramustine

Simultaneous use of ACE inhibitors with estramustine is accompanied by a risk of angioedema development.

A simultaneous application requiring special attention

Double blockade of the renin-angiotensin-aldosterone system (RAAS) in patients with atherosclerosis, heart failure or diabetes, target organ accompanied lesion is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and renal function (including the development of ARF) in comparison with a preparation of one of these groups.Double blockade of RAAS is possible only in certain cases under the careful control of the function of the nights.

Non-steroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (ASA) (more than 3 g / day)

The simultaneous use of ACE inhibitors with NSAIDs (including ASA dose of exerting anti-inflammatory action, inhibitors of cyclooxygenase-2 (COX-2) and non-selective NSAIDs) may reduce the antihypertensive effect and also a deterioration nochek functions including development of the arrester and improving the content of potassium in the blood plasma, especially in patients with reduced renal function. Care should be taken when using this combination, especially in elderly patients. Patients need to compensate for fluid loss and have regular monitoring of kidney function, both at the beginning of treatment and during treatment.

Hypoglycemic agents (derivatives of sulfonylureas and insulin)

ACE inhibitors can enhance the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. Hypoglycaemia occurs very rarely (likely due to the increase in glucose tolerance and reduce insulin requirements).

Simultaneous application requiring attention

Diuretics (thiazide and "loop")

In patients receiving diuretics, especially with excessive excretion of fluid and / or electrolytes, at the beginning of therapy with an ACE inhibitor, a significant reduction in blood pressure can be observed. The risk of developing arterial hypotension can be reduced by eliminating the diuretic, correcting hypovolemia and electrolyte balance, and also appointing perindopril in a low dose (2 mg / day), gradually increasing it.

Allopurinol, cytostatic and immunosuppressive drugs, glucocorticosteroids (for systemic use) and procainamide

Simultaneous use with ACE inhibitors may increase the risk of developing leukopenia.

Preparations for general anesthesia

Simultaneous use of ACE inhibitors and agents for general anesthesia can lead to an increased antihypertensive effect.

Preparations of gold

When using inhibitors of AG1F, including perindopril, in patients receiving an intravenous preparation of gold (sodium aurotomy malate), a symptom complex including facial flushing, nausea, vomiting, and arterial hypotension was described.

Glyptins (linaglyptin, saxagliptin, sitagliptin, vitagliptin)

Simultaneous use with ACE inhibitors may increase the risk of angioedema development due to inhibition of dipeptidyl peptidase IV (DAP-IV) glyptin.

Sympathomimetics

Sympathomimetics can reduce the antihypertensive effect of ACE inhibitors.

Ko-Dalnev®

Simultaneous use is not recommended

Lithium preparations

With the simultaneous use of ACE inhibitors with lithium preparations, a reversible increase in the concentration of lithium in blood plasma can occur with the development of intoxication.

Simultaneous use with thiazide diuretics can contribute to

an additional increase in the concentration of lithium and an increased risk of intoxication. The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. In the case of this therapy, regular monitoring of the concentration of lithium in the blood plasma is necessary.

A simultaneous application requiring special attention

Baclofen

Perhaps increased antihypertensive effect. It is necessary to monitor blood pressure and kidney function, if necessary, adjust the dose of antihypertensive drugs.

Simultaneous application requiring attention

Hypotensive drugs (eg, beta-blockers) and vasodilators

With simultaneous use with antihypertensive drugs may increase the antihypertensive effect. Caution should be exercised when using nitroglycerin, other nitrates or other vasodilators at the same time, as there may be an additional reduction in blood pressure. Corticosteroids (mineral- and glucocorticosteroids), tetracosactide

Reduction of antihypertensive action (fluid retention and sodium as a result of corticosteroids).

Alpha-blockers (prazozin, alfuzosin, doxazosin, tamsulosin, terazosin) Increased antihypertensive action and increased risk of orthostatic hypotension.

Amifostine

It is possible to increase the antihypertensive effect of amlodipine.

Tricyclic antidepressants / antipsychotics / general anesthetic agents Increased antihypertensive action and increased risk of orthostatic hypotension (additive effect).

Special instructions:


Ko-Dalnev®

Impaired renal function

The preparation of Co-Dalnev is contraindicated in patients with SC less than 60 ml / min.

In some patients with AH without previous obvious impairment of renal function against the background of therapy, laboratory signs of functional renal failure may appear. In this case, the drug should be discontinued. AT further it is possible to renew the combined therapy, using low doses of the combination of perindopril and indapamide, or apply these drugs separately. Such patients need regular monitoring of potassium content and serum creatinine concentration 2 weeks after the start of therapy and then every 2 months.

The development of renal insufficiency often occurs in patients with severe CHF or an initial impairment of kidney function, including with stenosis of the renal artery. The drug ns is recommended for patients with bilateral stenosis of the renal artery or stenosis of the artery of a single functioning kidney.

Arterial hypotension and disturbance of water-electrolyte balance

In patients with hyponatremia (especially with renal artery stenosis, including bilateral), there is a risk of sudden development of arterial hypotension.Therefore, attention should be paid to the possible symptoms of dehydration and a decrease in the electrolyte content in the blood plasma, for example, after diarrhea or vomiting. The use of ACE inhibitors causes blockade of RAAS and therefore may be accompanied by a sharp decrease in blood pressure and / or an increase in the concentration of creatinine in the blood plasma, which indicates the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy and sometimes develop acutely. Such patients need regular monitoring of the content of plasma electrolytes. In severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required. Transient arterial hypotension is not a contraindication for the continuation of therapy. After recovery of circulating blood volume (BCC) and blood pressure, treatment can be resumed using low doses of perindopril and indapamide, or applied separately.

Elderly patients

Before starting the preparation of Ko-Dalnev® it is necessary to evaluate the functional activity of the kidneys and the content of potassium in the blood plasma.At the beginning of therapy, the dose of the drug is selected, taking into account the degree of BP reduction, especially in case of a decrease in BCC and loss of electrolytes, which allows to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of developing arterial hypotension exists in all patients, but special care should be taken in patients with ischemic heart disease (INS) and cerebrovascular disease. In such patients, treatment starts with low doses preparation.

Amlodipine

CHF

In patients with CHF (III and IV functional class classification NYHA) treatment is carried out with caution, in connection with the possibility of developing pulmonary edema. BCCI, including amlodipine, should be used with caution in patients with CHF, due to the possible increase in the risk of development of adverse events from the cardiovascular system and mortality.

Impaired liver function

In patients with a violation of liver function T1 / 2 and AUC Amlodipine increases. Admission of amlodipine should be started with the lowest doses and caution both at the beginning of therapy and with increasing doses of amlodipine. Patients with severe dysfunction of the liver should be gradually increased the dose, careful monitoring of the clinical condition is necessary.

Indapamide

In the presence of a violation of liver function, the use of thiazide and thiazide-like diuretics can lead to the development of hepatic encephalopathy. In this case, stop taking the medication immediately.

Photosensitivity

Against the background of taking thiazide and thiazide-like diuretics, cases of the development of the photosensitivity reaction were reported. If the photosensitivity reaction develops, discontinue treatment. If it is necessary to continue therapy with diuretics, it is recommended to protect the skin from exposure to sunlight or artificial ultraviolet rays.

Water-electrolyte balance

The content of sodium in the blood plasma

Before the start of treatment it is necessary to determine the sodium content in the blood plasma. Against the background of taking the drug should regularly monitor this indicator. All diuretics are capable of causing hyponatraemia, which sometimes leads to serious complications. At the initial stage of therapy, a decrease in the sodium level in the blood plasma can be asymptomatic, so regular laboratory monitoring is necessary. Older patients are shown more frequent control of sodium in the blood plasma.

The content of potassium in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. It is necessary to avoid hypokalemia (less than 3.4 mmol / L) in the following categories of patients from high-risk groups: elderly patients, patients, patients with cirrhosis of the liver, including with edema and ascites, patients with IHD, CHF. In such patients, hypokalemia increases the toxic effect of cardiac glycosides and increases the risk of arrhythmia.

The high-risk group also includes patients with an elongated interval QT, as hereditary, hack and caused by medicinal action. Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially polymorphic ventricular pirouette tachycardia, which can lead to death. In all the cases described above, regular monitoring of the potassium content in the blood plasma is necessary. It is necessary to determine the content of potassium in the blood plasma during the first week after the initiation of therapy. If hypokalemia is detected, appropriate therapy should be performed.

Calcium in the blood plasma

Thiazide and thiazide-like diuretics reduce the excretion of calcium by the kidneys, which can cause a slight temporary increase in calcium in the blood plasma. Expressed hypercalcemia may be associated with previously undiagnosed hyperparathyroidism. In such cases, it is necessary to conduct a study of the function of the parathyroid glands, having previously canceled the administration of diuretics.

Uric acid

In patients with elevated uric acid concentrations in blood plasma, the frequency of gout attacks may increase with therapy.

Impaired renal function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired function of the nights (plasma creatinine concentration in adult patients is below 25 mg / L or 220 μmol / L). In elderly patients, CC is calculated taking into account age, body weight and sex.

In patients with hypovolemia and hyponatremia, early treatment with diuretics may result in a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma.This transient functional renal failure is not dangerous for patients with unchanged renal function, however, in patients with renal insufficiency, its severity can be increased.

These patients should regularly monitor the potassium content and creatinine concentration in the blood plasma.

Athletes

Indapamide can give a positive reaction during doping control.

Perindopril

Neutropenia / agranulocytosis

Against the background of the administration of ACE inhibitors, neutropenia / agranulocytosis, thrombocytopenia and anemia can occur. In patients with normal renal function, in the absence of other risk factors, neutropenia develops rarely. After the abolition of the ACE inhibitor, neutropenia and agranulocytosis pass independently. With extreme caution should be applied perindopril in patients with systemic connective tissue diseases on the background of therapy with immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy.When using perindopril in these patients it is recommended to periodically monitor the number of leukocytes in the blood plasma. If any symptoms of infectious diseases (eg, sore throat, fever) appear, patients should consult a doctor.

Hypersensitivity / angioedema

Against the background of taking ACE inhibitors, including perindopril, in rare cases development of angioedema of the face, limbs, lips, tongue, vocal cords and / or larynx can be observed. If symptoms appear, stop taking the medication immediately and continue monitoring the patient until the symptom is completely relieved. Typically, the edema of the face and lips treatment ns requires, although for relief of symptoms can be used antihistamines. Angioedema, accompanied by swelling of the larynx, can lead to death. Swelling of the tongue, vocal cords, or larynx can lead to airway obstruction. If such symptoms occur, immediately inject epinephrine (adrenaline) solution in a 1: 1000 dilution (0.3-0.5 ml) subcutaneously and / or provide airway patency.In patients with angioedema, a history that is not associated with the administration of ACE inhibitors. the risk of developing it may be increased when taking medications of this group.

In rare cases, against the background of therapy with ACE inhibitors, angioedema develops in the intestine. In this case, patients have complaints of abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without a previous angioedema and at a normal level of C-1 esterase. The diagnosis was established using computed tomography, ultrasound examination of the abdominal cavity organs, or during surgical intervention. Symptoms disappear after stopping the intake of ACE inhibitors. Therefore, patients with complaints of pain in the abdominal area, taking inhibitors ACE, in the conduct of differential diagnosis should take into account the possibility of angioedema edema of the intestine.

Anaphylactoid reactions during desensitization

There are some reports of the development of anaphylactoid reactions in patients taking AIF inhibitors during desensitizing therapy (for example, the venom of Hymenoptera insects: bees, wasps).The development of such reactions was avoided by the temporary withdrawal of ACE inhibitors (no less than 24 hours before desensitization), with the occasional administration of an ACE inhibitor anaphylactoid reaction appeared again.

Anaphylactoid reactions during apheresis LDL

In rare cases in patients receiving ACE inhibitors, in the conduct of LDL-apheresis using dextran sulfate may develop life threatening anaphylactoid reactions. To prevent such reactions, you should temporarily stop taking ACE inhibitors before each apheresis procedure.

Hemodialysis

In rare cases in patients receiving ACE inhibitors, hemodialysis using high-permeability membranes (for example, AN69®) anaphylactoid reactions developed. Therefore, it is recommended to use a different type of membrane or use an antihypertensive drug of another pharmacotherapeutic group.

Cough

Against the background of therapy with ACE inhibitors, dry cough may occur. Cough persists for a long time against the background of taking this group's drugs and disappears after their withdrawal. When a patient has a dry cough, remember the possibility of his appearance in connection with the receptionan ACE inhibitor. If it is necessary to use drugs of this group, the ACE inhibitor may be continued.

Aortic and mitral stenosis, GOKMP

ACE inhibitors should be used with caution in patients with obstruction of the left ventricular outflow tract and in mitral stenosis.

Diabetes

In patients with diabetes mellitus receiving hypoglycemic agents for ingestion or insulin, during the first month of treatment with an ACE inhibitor, regular monitoring of the glucose concentration in the blood plasma is necessary.

Surgery / general anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia can lead to a marked decrease in blood pressure, especially with the use of general anesthetics with an antihypertensive effect. It is recommended to stop the use of long-acting inhibitors, including perindopril, 24 hours before surgery.

Ethnic differences

In patients of the Negroid race more often than in the representatives of other races, against the background of the use of ACE inhibitors, angioedema develops. Perindopril, as well as other ACE inhibitors, obviously has a less pronounced antihypertensive effect in patients of the Negroid race compared with representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race are more likely to have low renin plasma activity.

Liver failure

In rare cases, when taking ACE inhibitors, cholestatic jaundice occurs. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. With a significant increase in the activity of "hepatic" enzymes or the appearance of jaundice when taking ACE inhibitors should stop taking the drug and continue to monitor the patient.

Hyperkalemia

Against the background of taking ACE inhibitors, hyperkalemia may develop. Risk factors for hyperkalemia is renal failure, advanced age (over 70 years), diabetes mellitus, some comorbid conditions (dehydration, acute decompensation of chronic heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium preparations, potassium-containing substitutes for edible salt, and other agents that promote potassium levels in the blood plasma (eg, heparin) (especially in patients with reduced function of the nights). Hyperkalemia can lead to serious, sometimes fatal heart rhythm disturbances. If it is necessary to use the drug simultaneously with the above-mentioned drugs, you should be careful and regularly monitor the potassium content in the blood plasma.

Renovascular hypertension

The method of treating reninvascular hypertension is revascularization. Nevertheless, the use of ACE inhibitors can be effective in patients with renovascular hypertension, both waiting for surgery and when it is not possible.

In patients with diagnosed or suspected renal artery stenosis treatment should begin with lower doses of the drug Ko-Dalnev®. Some patients may develop functional kidney failure, which occurs after the drug is discontinued.

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

In connection with the possibility of the appearance of weakness, dizziness against the background of application preparation of Ko-Dalnev® care must be taken when driving vehicles and working with other technical devices that require a high concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, 5 mg + 0.625 mg + 2 mg, 5 mg + 1.25 mg + 4 mg, 5 mg + 2.5 mg + 8 mg, 10 mg + 1.25 mg + 4 mg, 10 mg + 2.5 mg + 8 mg.

Packaging:

For 10 or 14 tablets in a contour acheikova packing of the combined material OPA / Al / PVC and aluminum foil.

By 1,2, 3, 6 or 9 contour cell packs (10 tablets each) or 1, 2, 4 or 6 out-of-round cell packs (14 tablets each), together with instructions for use, are placed in a pack of cardboard.
Storage conditions:

At a temperature of no higher than 25 ° C in the original packaging.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription
Registration number:LP-002958
Date of registration:16.04.2015
The owner of the registration certificate:KRKA-RUS, LLC KRKA-RUS, LLC Russia
Manufacturer: & nbsp
Representation: & nbspKRKA KRKA Slovenia
Information update date: & nbsp16.04.2015
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