Dalneva® (Dalneva®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAmlodipine + PerindoprilAmlodipine + Perindopril
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    • Dosage form: & nbsppills
    Composition:

    For 1 tablet 5 mg + 4 mg / 10 mg + 4 mg:

    Active substances:

    Amlodipine besylate (amlodipine besylate) 6.935 mg / 13.870 mg, equivalent to amlodipine 5 mg / 10 mg;

    Perindopril erbumin A substance - granules 21,000 mg / 21,000 mg, contains perindopril erbumine 4 mg / 4 mg

    Excipients: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium hydrogen carbonate, silicon dioxide colloid, magnesium stearate.

    For 1 tablet 5 mg + 8 mg / 10 mg + 8 mg:

    Active substances:

    Amlodipine besylate (amlodipine besylate) 6.935 mg / 13.870 mg, equivalent to amlodipine 5 mg / 10 mg;

    Perindopril erbumin A substance - granules 42,000 mg / 42,000 mg, contains perindopril erbumine 8 mg / 8 mg;

    Excipients: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium hydrogen carbonate, silicon dioxide colloid, magnesium stearate.

    Description:

    Tablets 5 mg + 4 mg: Round, slightly biconcave tablets with a bevel, white or almost white.

    Tablets 10 mg + 4 mg: Shaped, biconvex tablets with a risk on one side, white or almost white.

    Tablets 5 mg + 8 mg: Round, biconvex tablets with a bevel, white or almost white.

    Tablets 10 mg + 8 mg: Round, biconcave tablets with a facet and a risk on one side, white or almost white.

    Pharmacotherapeutic group:Antihypertensive agent combined (ACE inhibitor + BCCC)
    ATX: & nbsp

    C.09.A.A.04   Perindopril

    C.08.C.A.01   Amlodipine

    Pharmacodynamics:

    Perindopril

    Perindopril is an inhibitor of the enzyme converting angiotensin I to angiotensin II. An angiotensin-converting enzyme (ACE), or kininase II, is an exopeptidase that carries out both the conversion of angiotensin I into a vasoconstrictor substance angiotensin II and the disintegration of bradykinin having a vasodilating action to an inactive heptapeptide.

    Since ACE inactivates bradykinin, ACE inhibition is accompanied by an increase in the activity of both the circulating and tissue kallikrein-kinin system, and the system of prostaglandins is also activated.

    Perindopril has a therapeutic effect due to the active metabolite, perindoprilat. Other metabolites have no inhibitory effect on ACE under conditions in vitro.

    Arterial hypertension

    Perindopril is a drug for the treatment of arterial hypertension of any severity. Against the background of its use, there is a decrease in both systolic and diastolic arterial pressure (BP) in the "lying" and "standing" positions.

    Perindopril reduces the overall peripheral vascular resistance (OPSS), which leads to a decrease in blood pressure and an improvement in peripheral blood flow without changing the heart rate (heart rate).

    As a rule, the use of perindopril increases the renal blood flow, the glomerular filtration rate (GFR) does not change.

    Antihypertensive effect of the drug reaches a maximum in 4-6 hours after a single oral intake and is maintained for 24 hours.

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

    Decrease in blood pressure is achieved quickly enough. The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Termination of treatment does not cause a "ricochet" effect.

    Perindopril has vasodilating effect, contributes to the restoration of elasticity and large arteries of the vascular wall structure of small arteries and reduces left ventricular hypertrophy.

    Stable ischemic heart disease (CHD)

    The efficacy of perindopril in patients (12218 patients older than 18 years) with stable coronary artery disease without clinical symptoms of chronic heart failure (CHF) was studied in a 4-year study. 90% of study participants had previously suffered acute myocardial infarction and / or revascularization procedure.

    Most patients received standard therapy in addition to the test drug, including antiaggregants, lipid-lowering agents and beta-blockers. The combined end point, including cardiovascular mortality, non-fatal myocardial infarction, and / or cardiac arrest with successful resuscitation was chosen as the main efficacy criterion.

    Therapy with perindopril tert-butylamine at a dose of 8 mg / day, once a day (equivalent to 10 mg perindopril arginine), resulted in a significant reduction in absolute risk for the combined endpoint by 1.9% in patients who had previous myocardial infarction and / or revascularization procedure ,The absolute risk reduction was 2.2% compared with the placebo group.

    Double blockade of the renin-angiotensin-aldosterone system (RAAS)

    There are data from clinical trials of combined therapy with ACE inhibitor and angiotensin II receptor antagonist (ARA II).

    A clinical study was conducted involving patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus, accompanied by confirmed lesion of the target organ, as well as studies involving patients with type 2 diabetes and diabetic nephropathy.

    According to the studies, no significant positive effect of combination therapy on the occurrence of renal and / or cardiovascular events and mortality was found, while the risk of developing hyperkalemia, acute renal failure and / or arterial hypotension increased compared to monotherapy.

    Taking into account the similar intra-group pharmacodynamic properties of ACE inhibitors and APA II, these results can be expected for the interaction of any other drugs, representatives of ACE inhibitors and APA II classes.

    Therefore, ACE inhibitors and ARA II should not be used simultaneously in patients with diabetic nephropathy. There is evidence from a clinical trial to study the beneficial effects of the addition of aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease or a combination of these diseases. The study was terminated early due to the increased risk of adverse outcomes.

    Cardiovascular death and stroke were more common in the group of patients receiving aliskiren, compared with the placebo group, also undesirable events and serious adverse events of special interest (hyperkalemia, arterial hypotension and renal dysfunction) were recorded more often in the aliskiren group than in the placebo group.

    Amlodipine

    Amlodipine is a blocker of "slow" calcium channels (BCCC), a dihydropyridine derivative. 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 directa relaxing effect on the smooth muscle cells of the vascular wall.

    A detailed mechanism by which amlodipine has an antianginal effect, is not fully established, but it is known that amlodipine reduces the total ischemic load by two actions:

    - causes expansion of peripheral arterioles, decreasing OPSS (afterload). Since the heart rate does not change, myocardial oxygen demand decreases;

    - causes the expansion of the coronary arteries and arterioles both in the ischemic and intact zones. Their dilatation increases the flow of oxygen into the myocardium in patients with vasospastic angina (Prinzmetal angina, or variant angina).

    In patients with arterial hypertension (AH), amlodipine once a day provides a clinically significant reduction in blood pressure in the "standing" and "lying" 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 the total time of exercise, increases the time until the onset of angina attacks and before the onset of segment depression ST on 1 mm, and also reduces frequency of attacks of a stenocardia and consumption of nitroglycerin under tongue.

    Amlodipine does not have adverse metabolic effects and does not affect the concentration of plasma lipids.

    The drug can be used in patients with concomitant bronchial asthma, diabetes and gout.

    Ischemic heart disease (CHD)

    The results of the efficacy evaluation suggest that amlodipine intake is characterized by fewer hospitalizations for angina and revascularization procedures in patients with ischemic heart disease.

    Heart failure

    The results of hemodynamic studies, as well as the results of clinical trials involving patients with CHF II-IV functional class by classification NYHA demonstrated that amlodipine does not lead to clinical deterioration, based on data on exercise tolerance, left ventricular ejection fraction and clinical symptoms.

    In patients with CHF III-IV functional class by classification NYHA, against the background of taking digoxin, diuretics and ACE inhibitors, it was shown that the use of amlodipine does not increase the risk of mortality or mortality and morbidity associated with heart failure.

    Results of long-term studies in patients with CHF III and IV functional class by classification NYHA without clinical symptoms of IHD or objective data indicating the presence of IHD, when taking stable doses of ACE inhibitors, cardiac glycosides and diuretics, showed that taking amlodipine does not affect the mortality from cardiovascular disease. In this patient population, the use of amlodipine was accompanied by an increase in the number of reports on the development of pulmonary edema.

    Prevention of myocardial infarction

    The efficacy and safety of the use of amlodipine in a dose of 2.5-10 mg / day, an inhibitor of ACE lisinopril at a dose of 10-40 mg / day and a thiazide diuretic chlorthalidone at a dose of 12.5-25 mg / day as a "first-line" drug was studied in patients with mild or moderate hypertension and at least one of the additional risk factors for coronary events such as myocardial infarction or stroke, which was suffered more than 6 months before enrollment, or other confirmed cardiovascular disease of atherosclerotic origin, sugardiabetes,serum cholesterol concentration of high-density lipoprotein (HDL-C) less than 35 mg / dL, left ventricular hypertrophy according to electrocardiography or echocardiography, smoking.

    The main criterion for assessing efficacy is a combined index of the frequency of deaths from ischemic heart disease and the incidence of non-fatal myocardial infarction. There were no significant differences between the groups of amlodipine and chlorthalidone according to the main evaluation criterion. The incidence of heart failure in the amlodipine group was significantly higher than in the chlorthalidone group - 10.2% and 7.7%, respectively, the overall mortality rate in the amlodipine and chlorthalidone group did not differ significantly.

    Perindopril / amlodipine

    Efficacy with long-term use of amlodipine in combination with perindopril and atenolol in combination with bendroflumethiazide in patients aged 40 to 79 years with AH and at least 3 of additional risk factors: left ventricular hypertrophy according to ECG or echocardiography, type 2 diabetes, atherosclerosis of peripheral arteries, a previous stroke or transient ischemic attack, male sex,age 55 years and older, microalbuminuria or proteinuria, smoking, total cholesterol / HDL cholesterol ≥ 6, early development of IHD in immediate relatives was studied in the study ASCOT-BPLA.

    The main criterion for evaluating efficacy is a combined indicator of the incidence of non-fatal myocardial infarction (including painless) and lethal outcomes of IHD.

    The incidence of complications provided by the main evaluation criterion in the amlodipine / perindopril group was 10% lower than in the atenolol / bendroflumethiazide group, but this difference was not statistically significant.

    In the amlodipine / perindopril group, there was a significant reduction in the incidence of complications provided for by additional efficacy criteria (except for fatal and nonfatal heart failure).

    Pharmacokinetics:

    The amount of absorption of amlodipine and perindopril in the application of the Dal'nev® preparation does not differ significantly from that of monopreparations.

    Perindopril

    After ingestion perindopril quickly absorbed and reaches the maximum concentration in the blood plasma for 1 hour. The half-life (T1/2) of perindopril from the blood plasma is approximately 1 hour.

    Perindopril does not have pharmacological activity, it is a prodrug.

    Approximately 27% of the total amount of perindopril ingested enters the bloodstream as an active metabolite, perindoprilate. In addition to perindoprilata, another 5 metabolites are formed that do not have pharmacological activity. The maximum concentration of perindoprilate (Cmax) in the blood plasma is achieved 3-4 hours after ingestion.

    Eating food reduces the bioavailability of perindopril, so the drug should be taken 1 time per day, in the morning, before eating.

    There is a linear dependence of the concentration of perindopril in blood plasma on the value of the dose taken internally.

    The volume of distribution of free perindoprilata is approximately 0.2 l / kg. The association of perindoprilata with plasma proteins (mainly with ACE) is 20% and depends on its concentration. Perindoprilat is excreted by the kidneys, T1/2 unbound fraction is approximately 17 hours, so the equilibrium concentration is reached within 4 days after ingestion.

    The excretion of perindoprilat is slowed in elderly patients and in patients with cardiac and renal insufficiency,so monitoring such patients should include regular monitoring of creatinine concentrations and potassium levels in the blood plasma.

    The dialysed clearance of perindoprilat is 70 ml / min.

    The pharmacokinetics of perindopril has been changed in patients with liver cirrhosis: the hepatic clearance decreases by half, but the amount of perindoprilat formed does not decrease, so dose adjustment is not required.

    Amlodipine

    Amlodipine is well absorbed when ingested at therapeutic doses and reaches Cmax in blood plasma after 6-12 hours. Absolute bioavailability is 64-80%. The volume of distribution is approximately 21 l / kg. Eating food does not affect the bioavailability of amlodipine. Research in conditions in vitro showed that approximately 97.5% of circulating amlodipine is associated with plasma proteins.

    The final T1/2 from blood plasma - 35-50 hours, which allows taking the drug 1 time per day.

    Amlodipine is metabolized in the liver with the formation of inactive metabolites. Approximately 60% of the accepted dose is excreted by the kidneys, 10% - unchanged.

    Older patients: time to reach Cmax (TCmax) in blood plasma is the same in elderly patients and young adults.There is a tendency to decrease the clearance of amlodipine in elderly patients, which is accompanied by an increase in the area under the concentration-time curve (AUC). The recommended dosing regimen for elderly patients is the same as for younger patients, although dose increases should be carried out with caution.

    Liver failure: T1/2 Amlodipine is prolonged in patients with impaired liver function.

    Indications:

    Arterial hypertension and / or ischemic heart disease: stable angina pectoris in patients who require perindopril and amlodipine therapy.

    Contraindications:

    Perindopril

    - Hypersensitivity to perindopril or other ACE inhibitors.

    - Angioedema (angioedema) in the anamnesis (including those taking other ACE inhibitors).

    - Hereditary / idiopathic angioedema.

    - Pregnancy (see the section "Application during pregnancy and during breastfeeding"),

    - Simultaneous use with aliskiren-containing drugs in patients with diabetes mellitus or impaired renal function (GFR <60 mL / min / 1.73 m2 surface area of ​​the body) (see the sections "Interaction with other drugs" and "Pharmacodynamics").

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

    Amlodipine

    - Hypersensitivity to amlodipine and other dihydropyridine derivatives.

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

    - Shock (including cardiogenic).

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

    - Hemodynamically unstable heart failure after acute myocardial infarction.

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

    Dalnev®

    - All contraindications associated with perindopril and amlodipine, the above refer also to the combined preparation of Dalnev®.

    - Hypersensitivity to the excipients included in the preparation.

    - Renal failure (creatinine clearance [CC] less than 60 ml / min).

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

    Carefully:

    Hepatic failure, chronic heart failure (CHF), aortic and / or mitral stenosis,hypertrophic obstructive cardiomyopathy (GOKMP), angina pectoris, acute myocardial infarction (and within 1 month after myocardial infarction), simultaneous use of inducers and / or inhibitors of the isoenzyme CYP3A4, arterial hypotension, sinus node weakness syndrome, elderly age, bilateral stenosis of the renal arteries, arterial stenosis of the only functioning kidney, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), immunosuppressant therapy, allopurinol, procainamide (risk of developing neutropenia, agranulocytosis), reduced circulating blood volume (bcc) (diuretic intake, diet with restriction of table salt, vomiting, diarrhea), atherosclerosis, cerebrovascular diseases, renovascus yarnaya hypertension, diabetes mellitus, use dangrolena, estramustine, potassium-sparing diuretics, potassium preparations, potassium-based salt substitutes food and drugs lithium, hyperkalemia, surgery / anesthesia general, treatment of patients blacks, hemodialysis using vysokoprotochnyh polyacrylonitrile membranes - the risk ofanaphylactoid reactions, before the procedure of 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 (lack of clinical data).

    Pregnancy and lactation:

    The drug Dalneva® is contraindicated in pregnancy.

    The drug Dalnev® is not recommended for use during breastfeeding. It is necessary to evaluate the significance of long-term therapy to decide whether to stop breastfeeding or to cancel the drug.

    Pregnancy

    Perindopril

    The use of ACE inhibitors is not recommended for use in the first trimester of pregnancy (see section "Special instructions"). The use of ACE inhibitors is contraindicated in the II and III trimester of pregnancy (see the sections "Contraindications" and "Special instructions").

    At the moment, there is no conclusive epidemiological evidence of teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy. However, a slight increase in the risk of fetal development disorders can not be ruled out.When planning pregnancy, you should cancel the drug Dalneva® and prescribe other antihypertensive drugs that are approved for use in pregnancy. When establishing pregnancy, immediately stop therapy with ACE inhibitors and, if necessary, prescribe another therapy.

    It is known that the effect of ACE inhibitors on the fetus in the II and III trimesters of pregnancy can lead to disruption of its development (decreased kidney function, oligohydramnios, slowing ossification of the skull bones) and development of complications in the newborn (kidney failure, arterial hypotension, hyperkalemia).

    If the patient received ACE inhibitors during the second or third trimester of pregnancy, an ultrasound is recommended to assess the condition of the skull and the function of the fetus / baby kidney.

    Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision because of the risk of developing arterial hypotension (see the sections "Contraindications" and "Special instructions").

    Amlodipine

    The safety of the use of amlodipine in pregnancy is not established.

    In experimental animal studies, the fetotoxic and embryotoxic effects of the drug have been established when applied in high doses. Use during pregnancy is possible only in the absence of a safer alternative and when the disease carries a greater risk to the mother and fetus.

    Breastfeeding period

    Perindopril

    Due to the lack of information regarding the use of nerindopril during lactation, the use of perindopril is not recommended, it is preferable to adhere to alternative treatment with a more studied safety profile during breastfeeding, especially when feeding newborns or premature babies. There is no data on the excretion of perindopril with breast milk.

    Amlodipine

    There is no data on the excretion of amlodipine in breast milk. The decision to continue / discontinue therapy or breastfeeding should be taken in consideration of the benefits of breastfeeding for the baby and the benefits of taking amlodipine for the mother.

    Impact on fertility

    Perindopril

    No effect of perindopril on reproductive function or fertility was detected.

    Amlodipine

    In some patients who received BCCC, biochemical changes in the head of spermatozoa were detected. However, at present there is insufficient clinical data on the potential impact of amlodipine on fertility. In a study in rats, undesirable effects on fertility in males were identified.

    Dosing and Administration:

    Inside, one tablet once a day, preferably in the morning before eating.

    The dose of the drug Dalnev® is selected after previous selection of doses of individual components of the drug: perindopril and amlodipine in patients with arterial hypertension and stable angina.

    If necessary, the dose of the drug Dalnev® can be changed on the basis of individual selection of doses of individual components: (amlodipine 5 mg + perindopril 4 mg) or (amlodipine 10 mg + perindopril 4 mg) or (amlodipine 5 mg + perindopril 8 mg) or (amlodipine 10 mg + perindopril 8 mg).

    The maximum daily dose: amlodipine 10 mg + perindopril 8 mg.

    Impaired renal function

    The drug Dalnev® can be used in patients with SC more than 60 ml / min.

    The drug Dalneva® is contraindicated for use in patients with SC less than 60 ml / min.Such patients are recommended individual selection of doses of perindopril and amlodipine. The change in the concentration of amlodipine in the blood plasma does not correlate with the degree of renal insufficiency.

    Liver failure

    Care should be taken when using the drug Dalnev® in patients with hepatic insufficiency, since there are no recommendations on the dosage of the drug in such patients.

    Elderly patients

    When using the drug Dalnev ® in elderly patients, dose adjustment is not required.

    Children and teens

    The drug Dalnev® should not be administered to children and adolescents under 18 years of age, because there is no data on the efficacy and safety of perindopril and amlodipine in these patient groups, both in monotherapy and in combination therapy.

    Side effects:

    Classification of the frequency of development of side effects of the World Health Organization (WHO):

    Often

    ≥ 1/10

    often

    from ≥ 1/100 to <1/10

    infrequently

    from ≥ 1/1000 to <1/100

    rarely

    from ≥ 1/10000 to <1/1000

    rarely

    from <1/10000

    frequency unknown

    can not be estimated from the available data.

    In each group, undesirable effects are presented in order of decreasing severity.

    From the side of the blood and lymphatic system:

    very rare: leukopenia / neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, hemolytic anemia in patients with congenital deficiency of glucose-6-phosphate dehydrogenase, a decrease in hemoglobin and hematocrit.

    From the immune system:

    infrequently: hives.

    Metabolic disorders:

    infrequently: weight gain, weight loss;

    very rarely: hyperglycemia; frequency unknown: hypoglycemia.

    From the nervous system:

    often: drowsiness, dizziness, headache, paresthesia, vertigo;

    infrequently: insomnia, mood lability, sleep disturbance, tremor, hypoesthesia;

    very rarely: peripheral neuropathy, confusion;

    frequency unknown: extrapyramidal disorders.

    From the sense organs:

    often: visual impairment (including diplopia), tinnitus.

    From the side of the cardiovascular system:

    often: a feeling of palpitation, "hot flashes" of blood to the skin of the face, a pronounced decrease in blood pressure;

    infrequently: fainting, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation);

    rarely: pain behind the sternum;

    very rarely: angina pectoris, myocardial infarction, possibly due to excess BP reduction in patients at high risk, stroke, possibly due to excess BP reduction in patients at high risk, vasculitis.

    From the respiratory system:

    often: dyspnea, cough;

    infrequently: rhinitis, bronchospasm;

    very rarely: eosinophilic pneumonia.

    From the digestive system:

    often: abdominal pain, nausea, vomiting, indigestion, diarrhea, constipation;

    infrequent: dryness of the oral mucosa, a violation of taste perception, a change in the rhythm of defecation (including diarrhea and constipation);

    very rarely: pancreatitis, gingival hyperplasia, gastritis, hepatitis, cholestatic jaundice, cytolytic or cholestatic hepatitis.

    From the skin:

    often: itching, skin rash;

    infrequently: angioedema of the face, limbs, lips, mucous membranes of the mouth, tongue, vocal folds and / or larynx, alopecia, hemorrhagic rash, photosensitivity, increased sweating;

    very rarely: Quincke's edema, erythema multiforme, Stevens-Johnson syndrome.

    From the side of the musculoskeletal system:

    often: muscle spasms, muscle cramps;

    infrequently: arthralgia, myalgia, back pain.

    From the urinary system:

    infrequently: a violation of urination, nocturia, frequent urination, renal failure;

    very rarely: acute renal failure.

    From the side of the reproductive system:

    infrequently: impotence, gynecomastia.

    Other:

    very often: swelling;

    often: asthenia, increased fatigue;

    infrequently: chest pain, malaise.

    Laboratory indicators:

    rarely: an increase in the concentration of bilirubin in the blood plasma;

    very rarely: increased activity of "liver" transaminases in the blood plasma: aspartate aminotransferase (ACT), alanine aminotransferase (ALT) (most often - in combination with cholestasis);

    the frequency is unknown: an increase in the concentration of urea and creatinine in the blood serum.

    Additional information on amlodipine: individual cases are registered extrapyramidal syndrome with BCCI.

    Overdose:

    Information about an overdose of the drug Dalnev® is absent.

    Perindopril

    Data on perindopril overdose are limited.

    Symptoms: marked reduction in blood pressure, shock, disorders of water and electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

    Treatment: emergency measures are reduced to excretion of the drug from the body: gastric lavage and / or the appointment of activated charcoal, followed by the restoration of BCC.

    In marked decrease in blood pressure should be transferred to the patient in the position of "lying" to the back legs with raised, to carry out measures for the restoration bcc if necessary (e.g., intravenous infusion of 0.9% sodium chloride solution). Intravenous administration of catecholamines is also possible. With the help of hemodialysis can be removed perindopril from the systemic blood flow. With a bradycardia that is resistant to therapy, it may be necessary to implant an artificial pacemaker. A dynamic control of the general condition, the concentration of creatinine and the content of electrolytes in the blood plasma is necessary.

    Amlodipine

    Information about an overdose of amlodipine is limited.

    Symptoms: a marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheralvasodilation (the risk of development of severe and persistent arterial hypotension, including the development of shock and death).

    Treatment: gastric lavage, the appointment of activated charcoal (especially in the first 2 hours after an overdose), maintaining the function of the cardiovascular system, elevated position of the lower extremities, control of bcc and diuresis, symptomatic and supportive therapy. To restore the vascular tone - the use of vasoconstrictors (in the absence of contraindications to their use), to eliminate the effects of calcium channel blockade - intravenous calcium gluconate solution. Hemodialysis is ineffective.

    Interaction:

    Perindopril

    Simultaneous use is not recommended

    Double blockade of the renin-angiotensin-aldosterone system (RAAS)

    Clinical studies have shown that the dual blockade of RAAS by simultaneous use of ACE inhibitors, angiotensin II receptor antagonists (ARA II) or aliskiren is associated with a higher incidence of side effects such as hypotension, hyperkalemia and decreased renal function (including acute renal function insufficiency) in comparison with application of one preparation from the listed groups.

    Potassium-sparing diuretics, potassium preparations or potassium-containing substitutes for edible salt: Despite the fact that the potassium content in the blood serum remains within the normal range, in some patients, peripodopril may exhibit hyperkalemia. Potassium-sparing diuretics (for example, spironolactone. triamterene or amiloride), potassium preparations or potassium-containing substitutes for edible salt can lead to a significant increase in potassium levels in the blood plasma, so their use simultaneously with ACE inhibitors is not recommended. If simultaneous therapy is necessary (in case of confirmed hypokalemia), care should be taken and regular monitoring of potassium content in plasma and ECG parameters should be carried out.

    Lithium preparations: while simultaneous use of lithium drugs and ACE inhibitors, cases of reversible increase of lithium in blood plasma and related toxic effects were recorded. Simultaneous therapy with perindopril and lithium preparations is not recommended. If this combination therapy is necessary, it should be carried out under regular control of lithium content in plasmablood.

    Estramustine: simultaneous use is accompanied by an increased risk of angioedema.

    Simultaneous application, cautious

    Non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 inhibitors (COX-2), acetylsalicylic acid in high doses (more than 3 g / day) and nonselective NSAIDs): The use of NSAIDs may lead to a reduction in diuretic, natriuretic and antihypertensive effects of ACE inhibitors. The simultaneous use of ACE inhibitors and NSAIDs may lead to a deterioration of renal function, including the development of acute renal failure and increase in the potassium content in blood serum, especially in patients with reduced kidney function. Care should be taken when using this combination, especially in elderly patients. Patients in this case need to compensate for the loss of fluid, carefully monitor the kidney function both at the beginning and during the treatment.

    Hypoglycemic drugs (hypoglycemic agents for ingestion and / or insulin): the use of ACE inhibitors can enhance the hypoglycemic effect of insulin or sulfonylurea derivatives in patients with diabetes mellitus.The development of episodes of hypoglycemia was noted very rarely (possibly there is an increase in glucose tolerance, leading to a decrease in the need for insulin).

    Tacrolimus: there is a risk of increasing serum tacrolimus concentration with simultaneous use with amlodipine, but the pharmacokinetic mechanism of this interaction has not been fully studied. In order to avoid toxicity tacrolimus. when using amlodipine in patients receiving tacrolimus, monitoring of serum tacrolimus concentration and correction of its dose are necessary if necessary.

    Clarithromycin: clarithromycin is an inhibitor of the isoenzyme CYP3A4. There is an increased risk of developing arterial hypotension in patients who simultaneously use clarithromycin with amlodipine. Careful observation of patients is recommended with the simultaneous use of amlodipine with clarithromycin.

    Cyclosporine: studies on the interaction of cyclosporine with amlodipine in healthy volunteers or other population groups were not performed, except for patients after kidney transplantation, where the residual concentration of cyclosporine increased (on average 0% -40%).Consideration should be given to the need to monitor serum concentrations of cyclosporine in patients after kidney transplantation that simultaneously take amlodipine, if necessary, reduce the dose of cyclosporine.

    Simultaneous application, requiring attention

    Diuretics (thiazide and "loop"): in patients taking diuretics, especially with excessive excretion of fluid and / or electrolytes, a significant reduction in blood pressure can occur at the beginning of the use of ACE inhibitors. The risk of developing arterial hypotension can be reduced by eliminating the diuretic, increasing the intake of liquid and / or table salt before starting therapy, starting therapy with low doses of perindopril with a further gradual increase.

    Sympathomimetics: sympathomimetics can weaken the antihypertensive effect of ACE inhibitors.

    Preparations of gold: in patients receiving concomitant injection therapy with gold preparations (sodium aurotomy malate) and ACE inhibitors, including perindopril, rarely nitrate-like reactions ("hot flushes" of the blood to the skin of the face, nausea, vomiting, lowering blood pressure).

    Allopurinol, cytostatic and immunosuppressive agents, glucocorticosteroids (for systemic use), and procainamide: simultaneous use with ACE inhibitors may be accompanied by an increased risk of developing leukopenia.

    Means for general anesthesia: simultaneous use of ACE inhibitors and agents for general anesthesia can lead to an increase in antihypertensive effect. Amlodipine

    Simultaneous use is not recommended

    Dantrolene (intravenous administration): in the experiments on animals after the administration of verapamil and dantrolene (intravenously), cases of ventricular fibrillation with a lethal outcome and cardiovascular insufficiency associated with hyperkalemia were observed. Given the risk of developing hyperkalemia, simultaneous use of BCCM, including amlodipine and dantrolene, should be avoided.

    A simultaneous application requiring special care

    Inductors CYP3A4 (rifampicin, preparations of St. John's wort, an anticonvulsant, such as carbamazepine, phenobarbital, phenytoin, phosphenytoin, primidon): it is possible to reduce the plasma concentration of amlodipine due to increased metabolism in the liver.Caution should be exercised with the simultaneous use of amlodipine and inducers of microsomal oxidation and, if necessary, adjust the dose of amlodipine.

    Powerful and moderate inhibitors of isoenzyme CYP3A4 (protease inhibitors, azole antifungals [itraconazole and ketoconazole], macrolides such as erythromycin and clarithromycin, verapamil and diltiazem): may increase plasma concentrations of amlodipine and an increased risk of side effects, especially in elderly patients. Caution should be exercised with simultaneous use and, if necessary, adjust the dose of amlodipine.

    Simultaneous application requiring attention

    Simultaneous application of beta-blockers (bisoprolol, metoprolol) and alpha and beta-adrenoblocker carvedilol, used for CHF: increases the risk of developing arterial hypotension and worsening of the course of CHF in patients with uncontrolled or latent CHF (increased inotropic effect). In addition, beta-adrenoblockers can reduce excessive reflex cardiac sympathetic activation against the background of concomitant CHF.

    Other combinations

    In monotherapy amlodipine safely apply simultaneously from thiazide diuretics, ACE inhibitors, prolonged-action nitrates, nitroglycerin (for sublingual use), digoxin, warfarin, atorvastatin, sildenafil, antacids (aluminum colloidal hydroxide, magnesium hydroxide), simethicone, cimetidine, NSAIDs, antibiotics and hypoglycemic agents for oral administration.

    There is no interaction of the following drugs with amlodipine

    - with the simultaneous use of amlodipine and cimetidine pharmacokinetic parameters of amlodipine did not change;

    - with the simultaneous use of amlodipine and sildenafil there was no increase in the antihypertensive effect of each drug;

    - grapefruit juice: taking 240 ml of grapefruit juice together with a single dose of amlodipine (10 mg orally) had no significant effect on the pharmacokinetics of amlodipine.

    Amlodipine does not affect the pharmacokinetics of the following drugs

    - atorvastatin: taking repeated doses of amlodipine 10 mg in combination with atorvastatin at a dose of 80 mg does not lead to a significant change in the equilibrium pharmacokinetic parameters of atorvastatin;

    - digoxin: simultaneous use of amlodipine and digoxin is not accompanied by a change in serum digoxin concentration and renal clearance of digoxin in healthy volunteers;

    - warfarin: in healthy male volunteers taking warfarip, the addition of amlodipine does not significantly affect the change in the prothrombin time indicator due to warfarin.

    Dalneva®

    A simultaneous application requiring special attention

    Baclofen: Potentiation of antihypertensive action is possible. It is necessary to monitor blood pressure and function of the nights, as well as dose adjustment of amlodipine.

    Simultaneous application requiring attention

    Hypotensive drugs (eg, beta-blockers) and vasodilators: it is possible to increase the antihypertensive effect of perindopril and amlodipine.

    Care should be taken when using nitroglycerin, other nitrates or other vasodilators, because it is possible to further reduce blood pressure.

    Corticosteroids (mineral and glucocorticosteroids), tetracosactide: decrease in antihypertensive action (fluid retention and sodium ions as a result of actioncorticosteroids).

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

    Amifostine: can potentiate the antihypertensive effect of amlodipine.

    Tricyclic antidepressants / antipsychotics / general anesthetics: increased antihypertensive effect and increased risk of orthostatic hypotension.

    Special instructions:

    Special instructions relating to amlodipine and perindopril are also applicable to the preparation of Dalnev®.

    Perindopril

    Double blockade of RAAS

    It has been proven that simultaneous use of ACE inhibitors, ARA II or aliskiren increases the risk of arterial hypotension, hyperkalemia and decreased renal function (including acute renal failure). Therefore, double blockade of RAAS by simultaneous use of ACE inhibitors, APA II or aliskiren is not recommended.

    In case of simultaneous use of these drugs, therapy should be performed only under the supervision of a doctor and subject to constant monitoring of kidney function, electrolyte content and blood pressure.

    Do not simultaneously use ACE inhibitors and APA II in patients with diabetic nephropathy.

    Hypersensitivity / angioedema (angioedema)

    With the use of ACE inhibitors, including perindopril, in rare cases, angioedema may develop in the face, lips, tongue, vocal cords, and / or larynx. When these symptoms appear, the use of the Dalneva® preparation should be stopped immediately, the patient should be observed until the signs of edema disappear completely.

    If angioedema affects only the face and lips, then its manifestations usually go away alone or antihistamines may be used to treat its symptoms. Angioedema, accompanied by swelling of the tongue or larynx, can lead to airway obstruction and death.

    When such symptoms occur, immediately enter subcutaneously epinephrine (epinephrine) in a dilution of 1: 1000 (0.3 or 0.5 ml) and / or provide airway patency. The patient should be under medical supervision until the symptoms disappear completely and persistently.

    Patients with a history of Quincke edema not associated with the use of ACE inhibitors may be at increased risk of developing it with the use of drugs of this group.

    In rare cases, on the background of therapy with ACE inhibitors, intestinal angioedema develops (angioedema of the intestine). In this case, patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without a prior angioedema and at a normal serum concentration of C1-esterase. The diagnosis is established by means of computed tomography of the abdominal cavity, ultrasound examination or at the time of surgical intervention. Symptoms disappear after the cessation of the use of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the differential diagnosis should take into account the possibility of developing an intestinal angioedema.

    Anaphylactoid reactions during desensitization procedures

    There are separate reports on the development of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with Hymenoptera insects.ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. The appointment of an ACE inhibitor should be avoided for patients receiving immunotherapy with venom of Hymenoptera. Nevertheless, the development of anaphylactoid reactions can be avoided by the temporary withdrawal of the ACE inhibitor at least 24 hours before the desensitization procedure begins.

    Anaphylactoid reactions during apheresis of LDL with dextran sulfate

    In rare cases, in patients receiving ACE inhibitors, when performing low-density lipoprotein (LDL) apheresis using dextran sulfate may develop life threatening anaphylactoid reactions. To prevent anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each procedure for LDL apheresis using dextran sulfate.

    Hemodialysis

    In patients receiving ACE inhibitors, hemodialysis using high-flow membranes (for example, AN69®), anaphylactoid reactions were noted. Therefore, it is desirable to use a different type of membrane or to applyantihypertensive drug of another pharmacotherapeutic group.

    Neutropenia / agranulocytosis, thrombocytopenia and anemia

    In patients taking ACE inhibitors, there may be cases of development of neutropenia / agranulocytosis, thrombocytopenia and anemia. In patients with normal renal function in the absence of other complications, neutropenia develops rarely and passes on its own after the withdrawal of ACE inhibitors.

    Perindopril should be used with great care in patients with connective tissue diseases and, simultaneously receiving immunosuppressive therapy, allopurinol or procainamide, especially with existing impairments of kidney function. Some patients may develop severe infections that are not amenable to intensive antibiotic therapy. In the case of prescribing perindopril, it is recommended to control the amount of blood leukocytes. The patient should be warned that in case of any signs of an infectious disease (sore throat, fever), you should immediately consult a doctor.

    The risk of developing arterial hypotension and / or renal failure (in patients with CHF,violation of water-electrolyte balance, etc.)

    With cirrhosis of the liver, accompanied by edema and ascites, arterial hypotension. CHF may show a significant activation of RAAS, especially in severe hypovolemia and a decrease in the content of electrolytes in blood plasma (against a diet with restriction of table salt or long-term use of diuretics).

    The use of an ACE inhibitor causes blockade of the RAAS; in this connection, a sharp decrease in blood pressure and / or an increase in the plasma creatinine concentration, which indicates the development of acute renal failure, is more likely to occur with the first dose or during the first two weeks of therapy with Dalnev®.

    ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic arterial hypotension rarely occurs in patients without concomitant diseases. The risk of a marked decrease in blood pressure was elevated in patients with reduced BCC. which can be observed against diuretic therapy, with strict diet with restriction of table salt, hemodialysis, with diarrhea or vomiting, or in patients with high-grade arterial hypertension with high renin activity.Patients with a high risk of developing symptomatic arterial hypotension should carefully monitor blood pressure, kidney function and potassium levels in the blood serum during therapy with Dalnev®.

    The same precautions apply to patients with angina or cerebrovascular disease, in whom a marked decrease in blood pressure may lead to the development of myocardial infarction or impaired cerebral circulation.

    In the case of development of arterial hypotension the patient should be transferred to the "lying" position on the back with raised legs. If necessary, replenish bcc by intravenous injection of 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for the further administration of Dalnev®. After the recovery of bcc and AD, treatment with Dalnev® can be continued.

    Aortic stenosis / mitral stenosis / Hypertrophic obstructive cardiomyopathy

    ACE inhibitors should be used with caution in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as in patients with mitral stenosis.

    Potassium-sparing diuretics and potassium preparations

    Simultaneous use of perindopril and potassium-sparing diuretics, as well as potassium and potassium-containing substitutes for table salt is not recommended.

    Cough

    Against the background of therapy with an ACE inhibitor, a dry, unproductive cough may occur that disappears after the withdrawal of this group. When dry cough occurs, remember the possible association of this symptom with the use of an ACE inhibitor.

    Children and teenagers under the age of 18

    The drug Dalneva® is contraindicated in children and adolescents under the age of 18 due to the lack of data on the efficacy and safety of the drug in this age group.

    Impaired renal function

    In some patients with bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, taking ACE inhibitors, there was an increase in urea and creatinine levels in the blood plasma, reversible after the withdrawal of therapy. These changes are more likely in patients with renal insufficiency. In patients with renovascular hypertension, there is an increased risk of severe arterial hypotension and renal failure.

    In some patients with hypertension without obvious signs of existing kidney diseases that have been taking perindopril simultaneously with the diuretic, there was a small and temporary increase in the concentrations of urea and creatinine in the blood serum. These changes often develop in patients with a previous impairment of kidney function.

    Impaired liver function

    Rarely, the use of ACE inhibitors is accompanied by a syndrome, the development of which begins with cholestatic jaundice and which then progresses to fulminant liver necrosis, sometimes fatal. The mechanism of development of this syndrome is unclear. If during the application of the ACE inhibitor jaundice appears or the activity of "liver" transaminases in blood plasma increases, the ACE inhibitor should be immediately canceled, and the patient must remain under appropriate medical supervision.

    Ethnic Features

    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, may have 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 Negroid races with arterial hypertension are more likely to have low renin plasma activity.

    Surgical procedures / General anesthesia

    The use of ACE inhibitors in patients undergoing extensive surgery and / or general anesthesia can lead to a marked decrease in blood pressure if general anesthetics with an antihypertensive effect are used. This is due to the blocking of the formation of angiotensin II against a background of compensatory enhancement of renin activity. If the development of arterial hypotension is associated with the mechanism described, the BCC should be increased. It is recommended to stop using the drug 24 hours before surgery.

    Hyperkalemia

    Against the background of therapy with ACE inhibitors, including perindopril, in some patients, the potassium content in the blood plasma may increase. Risk factors for hyperkalemia include renal failure, decreased renal function, elderly age (over 70 years), diabetes mellitus, intercurrent conditions, in particular, dehydration, acute cardiac decompensation, metabolic acidosis, simultaneous use of potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene or amiloride), potassium preparations or potassium-containing substitutes for edible salt or the simultaneous use of other drugs that increase the potassium content in the blood plasma (eg, heparin).

    Hyperkalemia can cause serious, sometimes life-threatening arrhythmias. If you need to simultaneously use perindopril and one of the above substances, you should be careful and regularly monitor the potassium content in the blood plasma.

    Patients with diabetes mellitus

    In patients with diabetes who take hypoglycemic agents for ingestion and / or insulin, in the first few months of therapy with ACE inhibitors, careful monitoring of blood glucose concentration is necessary.

    Amlodipine

    Impaired liver function

    In patients with impaired liver function T1/2 Amlodipine is lengthened. When prescribing the drug, such patients should be careful and regularly monitor the activity of "liver" enzymes in the blood plasma.

    Patients with heart failure

    In patients with CHF (III and IV functional class by classification NYHA) treatment is conducted with caution, in connection with the possibility of developing pulmonary edema.

    Effect on the ability to drive transp. cf. and fur:AT communication with the possibility of dizziness and other side effects on the background of the use of the Dal'nev® preparation, care must be taken when driving vehicles and working with other technical devices that require an increased concentration of attention and speed of psychomotor reactions.
    Form release / dosage:

    Tablets, 5 mg + 4 mg, 10 mg + 4 mg, 5 mg + 8 mg, 10 mg + 8 mg.

    Packaging:

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

    3 or 9 contour cell packs, 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:

    3 years.

    Do not use the drug after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001992
    Date of registration:01.02.2013 / 18.09.2013
    Expiration Date:01.02.2018
    The owner of the registration certificate:KRKA-RUS, LLC KRKA-RUS, LLC Russia
    Manufacturer: & nbsp
    Representation: & nbspKRKA KRKA Slovenia
    Information update date: & nbsp21.04.2017
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