Dalneva, pills 5mg+4mg, 30pcs

Composition

for 1 tablet 5 mg + 4 mg/10 mg + 4 mg/5 mg + 8 mg/10 mg + 8 mg

Active ingredients:

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

Perindopril erbumin A substance-granules 21,000 mg / 21,000 mg/42,000 mg / 42,000 mg, contains perindopril erbumin 4 mg/4 mg/8 mg/8 mg

Auxiliary substances:

Microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate

Pharmacological action

antihypertensive combined agent (angiotensin converting enzyme inhibitor + slow calcium channel blocker)

Clinical Pharmacology

Pharmacodynamics

Amlodipine

Amlodipine – BMCC, a dihydropyridine derivative. Amlodipine inhibits the transmembrane transfer of calcium ions to cardiomyocytes and smooth muscle cells of the vascular wall.

The antihypertensive effect of amlodipine is due to the direct relaxing effect on the smooth muscle cells of the vascular wall. The detailed mechanism by which amlodipine exerts its antianginal action is not fully established, but it is known that amlodipine reduces the overall ischemic load by two actions: :

• causes dilation of peripheral arterioles, reducing total peripheral vascular resistance (OPSS) (afterload). Since the heart rate (HR) does not change, the myocardial oxygen demand decreases;
• it causes expansion of the coronary arteries and arterioles in both the ischemic and intact zones. Their dilation increases oxygen supply to the myocardium in patients with vasospastic angina (Prinzmetal angina or variant angina).

In patients with arterial hypertension (AH), taking amlodipine once a day provides a clinically significant reduction in blood pressure (BP) in the “standing” and “lying” positions for 24 hours. The antihypertensive effect develops slowly, and therefore the development of acute arterial hypotension is uncharacteristic.

In patients with angina pectoris, taking amlodipine once a day increases the total time of physical activity, increases the time to the development of an angina attack and to the appearance of ST-segment depression by 1 mm, and also reduces the frequency of angina attacks and the consumption of nitroglycerin under the tongue.

Amlodipine has no adverse metabolic effects and does not affect the concentration of plasma lipids.

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

Coronary heart disease (CHD)

The results of the efficacy assessment indicate that amlodipine treatment is characterized by a lower number of hospitalizations for angina pectoris and revascularization procedures in patients with CHD.

Perindopril

Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II. ACE, or kininase II, is an exopeptidase that converts angiotensin I to the vasoconstrictor angiotensin II, and breaks down bradykinin, which has a vasodilating effect, to an inactive heptapeptide.

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

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

Arterial hypertension

Perindopril is a drug for the treatment of hypertension of any severity. Against the background of its use, there is a decrease in both systolic and diastolic blood pressure in the “lying” and “standing” positions.

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

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

The antihypertensive effect of the drug reaches a maximum in 4-6 hours after a single oral use and persists for 24 hours.

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

Blood pressure reduction is achieved fairly quickly. The therapeutic effect occurs less than 1 month after the start of therapy and is not accompanied by tachyphylaxis. Discontinuation of treatment does not cause a “rebound”effect.

Perindopril has a vasodilating effect, helps restore the elasticity of large arteries and the structure of the vascular wall of small arteries, and also reduces left ventricular hypertrophy.

Stable coronary heart disease

Efficacy of perindopril in patients (12,218 patients over 18 years of age) Patients with stable CHD without clinical symptoms of chronic heart failure (CHF) were studied in a 4-year study. 90% of the study participants had previously had an acute myocardial infarction and / or revascularization procedure.

Most patients received standard therapy, including antiplatelet agents, lipid-lowering agents, and beta-blockers, in addition to the study drug. The main efficacy criterion was a combined endpoint that included cardiovascular mortality, non-fatal myocardial infarction, and / or cardiac arrest with successful resuscitation.

Treatment with perindopril tretbutylamine 8 mg / day once daily (equivalent to 10 mg of perindopril arginine) resulted in a significant 1.9% reduction in absolute risk for the combined endpoint in patients who had previously had a myocardial infarction and / or revascularization procedure, a 2.2% reduction in absolute risk compared to the placebo group.

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

There are data from clinical studies of combination therapy with an ACE inhibitor and an angiotensin II receptor antagonist (ARA II).

The use of ACE inhibitors in combination with ARA II is contraindicated in patients with diabetic nephropathy. There is evidence from a clinical trial investigating the beneficial effects of adding aliskiren to standard therapy with an ACE inhibitor or ARA II in patients with type 2 diabetes mellitus and / or chronic kidney disease, or cardiovascular disease, or having a combination of these diseases. The study was terminated prematurely due to an increased risk of adverse outcomes. Cardiovascular death and stroke were reported more frequently in the aliskiren-treated group compared to the placebo group, and adverse events and serious adverse events of special interest (hyperkalemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group.

Amlodipine + perindopril

The effectiveness of long-term use of amlodipine in combination with perindopril and atenolol in combination with bendroflumethiazide in patients aged 40 to 79 years with hypertension and at least three of the following additional risk factors: left ventricular hypertrophy on the EKG or echocardiogram, diabetes mellitus type 2, atherosclerosis of peripheral arteries, previously a history of stroke or transient ischemic attack, male, age 55 and older, microalbuminuria or proteinuria, Smoking, total cholesterol/cholesterol of lipoproteins of high density ≥ 6, the early development of coronary artery disease in close relatives the study explored ASCOT-BPLA.

The main criterion for evaluating efficacy is a combined indicator of the frequency of non-fatal myocardial infarction (including pain-free) and fatal outcomes of CHD.

The frequency of complications provided for by the main evaluation criterion in the amlodipine/perindopril group was 10% lower than in the atenolol/bendroflumetiazid 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 non-fatal heart failure).

Pharmacokinetics

The amount of absorption of amlodipine and perindopril when using the combined drug Dalneva® does not significantly differ from that when using them as monopreparations.

Amlodipine

After oral use, amlodipine is slowly absorbed from the gastrointestinal tract (GI). Food intake does not affect the bioavailability of amlodipine.

The maximum concentration (cmax) of amlodipine in blood plasma is reached 6-12 hours after oral use. Absolute bioavailability is 64-80%. The volume of distribution is approximately 21 l/kg. Invitro studieshave shown that about 97.5% of circulating amlodipine is bound to plasma proteins.

Final half-life (_Half-life) from the blood plasma is 35-50 hours, which allows you to take the drug 1 time a day.

Amlodipine is metabolized in the liver to form inactive metabolites, with 10% of the dose of amlodipine being excreted unchanged and 60% as metabolites by the kidneys. Amlodipine is not eliminated from the body by dialysis.

The time to reachcmax (TC_max) of amlodipine in blood plasma does not differin elderly and younger patients. In elderly patients, the clearance of amlodipine is slowed down, which leads to an increase in the area under the concentration-time curve (AUC). The increase in AUC and_half-life in patients with CHF corresponds to the expected value for this age group.

In patients with impaired renal function, changes in the concentration of amlodipine in blood plasma do not correlate with the degree of renal failure. A slight extension of_{the half}-life is possible.

Data on the use of amlodipine in patients with hepatic insufficiency are limited. In patients with hepatic insufficiency, there is a decrease in the clearance of amlodipine, which leads to an elongation of_{the half}-life and an increase in AUC by approximately 40-60%.

Perindopril

After oral use, perindopril is rapidly absorbed and reaches C_maxin blood plasma within 1 hour. The plasma half-life of perindopril is approximately 1 hour.

Perindopril has no pharmacological activity, it is a prodrug. Approximately 27% of the total amount of oral perindopril enters the bloodstream as the active metabolite, perindoprilat. In addition to perindoprilat,5 more metabolites are formed that do not have pharmacological activity. _Cmax in blood plasma is reached 3-4 hours after oral use.

Food intake reduces the bioavailability of perindopril, so the drug should be taken once a day, in the morning, before meals.

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

The volume of distribution of free perindoprilate is approximately 0.2 l / kg. The association of perindoprilat with plasma proteins (mainly with ACE) is 20% and depends on its concentration. Perindoprilat is excreted by the kidneys, the_half-life of the unbound fraction is approximately 17 hours, so the equilibrium state is reached within 4 days after oral use.

The elimination of perindoprilat is delayed in elderly patients, as well as in patients with cardiac and renal insufficiency (see the section “Dosage and use”), so monitoring of such patients should include regular monitoring of creatinine concentration and potassium content in blood plasma.

The dialysis clearance of perindoprilat is 70 ml / min

. The pharmacokinetics of perindopril are impaired in patients with cirrhosis of the liver: its hepatic clearance decreases by 2 times. However, the amount of perindoprilat produced does not decrease, so no dose adjustment is required (see sections” Dosage and use “and”Special Instructions”).

Indications

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

Use during pregnancy and lactation

The drug Dalneva® is contraindicated during pregnancy.

Dalneva® is not recommended for use during breastfeeding. It is necessary to assess the significance of therapy for the mother in order to decide whether to stop breastfeeding or to discontinue the drug.

Pregnancy

Amlodipine

The safety of using amlodipine during pregnancy has not been established.

In experimental animal studies, the fetotoxic and embryotoxic effects of the drug were established when used 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.

Perindopril

The use of ACE inhibitors is not recommended for use in the first trimester of pregnancy (see the section “Special instructions”). The use of ACE inhibitors is contraindicated in the second and third trimesters of pregnancy (see sections “Contraindications” and “Special instructions”).

Currently, there are no conclusive epidemiological data on the teratogenic risk of taking ACE inhibitors in the first trimester of pregnancy. However, a small increase in the risk of fetal developmental disorders cannot be ruled out. When planning pregnancy, the drug Dalneva® should be discontinued and other antihypertensive agents approved for use during pregnancy should be prescribed. If pregnancy is established, ACE inhibitor therapy should be stopped immediately and, if necessary, another therapy should be prescribed.

It is known that the effect of ACE inhibitors on the fetus in the second and third trimesters of pregnancy can lead to impaired development (decreased renal function, oligohydramnios, slowing of ossification of the skull bones) and the development of complications in the newborn (renal failure, hypotension, hyperkalemia).

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

Newborns whose mothers received ACE inhibitors during pregnancy should be closely monitored due to the risk of developing hypotension (see the sections “Contraindications” and “Special Instructions”).

Breast-feeding period

Amlodipine

Amlodipine is excreted in breast milk. The proportion of maternal dose received by the children was estimated with an interquartile range of 3-7%, but not more than 15%. The effect of amlodipine on newborns is unknown. The decision to continue / discontinue therapy or breast-feeding should be made taking into account the benefits of breast-feeding for the child and the benefits of taking amlodipine for the mother.

Perindopril

Due to the lack of information regarding the use of perindopril during breast-feeding, perindopril is not recommended, and it is preferable to follow an alternative treatment with a more studied safety profile during breast-feeding, especially when feeding newborns or premature babies.

Contraindications

• Hypersensitivity to perindopril or other ACE inhibitors, amlodipine and other dihydropyridine derivatives, as well as to excipients included in the drug.

• Angioedema (angioedema) in the anamnesis (including against the background of taking other ACE inhibitors).
• Hereditary / idiopathic angioedema.
• Concomitant use with aliskiren and medicinal products containing aliskiren in patients with diabetes mellitus and / or moderate to severe renal impairment (GFR Pharmacodynamics”).
• Concomitant use with ARA II in patients with diabetic nephropathy (see section “Special instructions”).

* Concomitant use with neutral endopeptidase inhibitors (for example, with drugs containing sacubitril) due to a high risk of angioedema.

Extracorporeal therapy that leads to blood contact with negatively charged surfaces (see the section “Interaction with other drugs”).

• Severe bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney (see section “Special instructions”).

• Severe arterial hypotension (systolic blood pressure less than 90 mm Hg).
• Shock (including cardiogenic shock).
• Obstruction of the left ventricular exit tract (for example, clinically significant aortic stenosis).
• Hemodynamically unstable heart failure after acute myocardial infarction.

• Renal insufficiency (creatinine clearance < 60 ml / min).
• Pregnancy and breast-feeding period.

• Age up to 18 years (efficacy and safety have not been established).

Interaction

Amlodipine

Not recommended drug combinations

Dantrolene (intravenous use)

In laboratory animals, cases of ventricular fibrillation with a fatal outcome and collapse were noted against the background of verapamil and intravenous dantrolene use, accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of BMCC, including amlodipine, should be excluded in patients subject to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

Drug combinationsthat require special attention

Inducers of the CYP3A4 isoenzyme: when used concomitantly with inducers of the CYP3A4 isoenzyme, the concentration of amlodipine in blood plasma may change.Therefore, it is necessary to monitor blood pressure and adjust the dose both during and after their simultaneous use, especially in the case of use with powerful inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John’s wort preparations).

CYP3A4 inhibitors: concomitant use of amlodipine and potent or moderate inhibitors of the CYP3A4 isoenzyme (protease inhibitors, azole antifungal drugs, macrolides, for example, erythromycin or clarithromycin, verapamil or diltiazem) can lead to a significant increase in the concentration of amlodipine in blood plasma. The clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. Therefore, it may be necessary to monitor the clinical condition and adjust the dose.

Patients taking amlodipine concomitantly with clarithromycinhave an increased risk of hypotension. Patients taking perindopril concomitantly with clarithromycin should be carefully monitored.

Drug combinationsthat require attention

Amlodipine enhances the antihypertensive effect of antihypertensive drugs.

Tacrolimus: There is a risk of increased serum concentrations of tacrolimus when co-administered with amlodipine. In order to avoid the development of toxic effects of tacrolimus with the simultaneous use of these drugs, it is necessary to monitor the serum concentration of tacrolimus and adjust its dose if necessary.

Cyclosporine: studies on the interaction of cyclosporine with amlodipine in healthy volunteers or other population groups have not been conducted, with the exception of patients who underwent kidney transplantation, who showed variability in the increase of the lowest concentrations of cyclosporine in blood plasma (on average from 0% to 40%). Consideration should be given to monitoring serum cyclosporine concentrations in post-kidney transplant patients with concomitant use of amlodipine. If necessary, the dose of cyclosporine should be reduced.

Simvastatin: concomitant use of multiple doses of 10 mg amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. In patients taking Dalneva® at a dosage of 10 mg + 4 mg or 10 mg + 8 mg, simvastatin should be limited to 20 mg per day.

Concomitant use of amlodipine and consumption of grapefruit or grapefruit juice is not recommended, due to the possible increase in the bioavailability of amlodipine in some patients, which in turn may lead to increased effects of lowering blood pressure.

T-TOR inhibitors(mammalian Targetof Rapamycin–mammalian target of rapamycin): mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of the CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Clarithromycin: clarithromycin is an inhibitor of the CYP3A4 isoenzyme. There is an increased risk of hypotension in patients taking clarithromycin concomitantly with amlodipine. Careful monitoring of patients is recommended when amlodipine is co-administered with clarithromycin.

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

When used concomitantly, amlodipine may increase the systemic exposure of tasonermine in blood plasma. In such cases, it is necessary to regularly monitor the concentration of tasonermin in the blood plasma and adjust the dose if necessary.

Other drug combinations

Calcium supplements can reduce the effect of BMCC.

Concomitant use of BMCC with lithium preparations (no data available for amlodipine) may increase the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

In clinical drug interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

A single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetics of amlodipine.

Perindopril

These clinical studies show that dual blockade of RAAS through simultaneous use of ACE inhibitors, ARA II or aliskiren leads to an increase in the incidence of adverse events such as hypotension, hyperkalemia, and renal dysfunction (including acute renal failure) compared to situations in which uses only one drug acting on the RAAS (see “Pharmacologic properties. Pharmacodynamics”, “Contraindications”, “Special instructions”).

Medications that cause hyperkalemia

Some medications may increase the risk of hyperkalemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, ARA II, nonsteroidal anti-inflammatory drugs (NSAIDs), heparin, immunosuppressantssuch as cyclosporine or tacrolimus, trimethoprim, including a fixed combination of trimethoprim and sulfamethoxazole (co-trimoxazole). The combination of these drugs increases the risk of hyperkalemia.

Cyclosporine: concomitant use of ACE inhibitors with cyclosporine may cause hyperkalemia. It is recommended to monitor the potassium content in the blood serum.

Heparin: possible increase in serum potassium. It is recommended to monitor the potassium content in the blood serum.

Simultaneous use is contraindicated

Aliskiren and medicinal products containing aliskiren

Concomitant use of ACE inhibitors with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal impairment (GFR less than 60 ml/min / 1.73 m2 of body surface area) and is not recommended in other patients. (see section “Contraindications”). The risk of hyperkalemia, deterioration of kidney function, cardiovascular morbidity and mortality increases.

Extracorporeal therapy

Extracorporeal treatments that lead to blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flow membranes (such as polyacrylonitrile), or LDL apheresis using dextran sulfate, are contraindicated due to the increased risk of severe anaphylactoid reactions (see section “Contraindications”). If the patient needs extracorporeal therapy, the possibility of using a different type of dialysis membrane or a different class of antihypertensive drugs should be considered.

Neutral endopeptidase inhibitors

Concomitant use of ACE inhibitors with drugs containing sacubitril (a neprilysin inhibitor) increases the risk of angioedema, and therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. It is contraindicated to prescribe drugs containing sacubitrilto patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Not recommended drug combinations

Aliskiren and medicinal products containing aliskiren

Patients who do not have diabetes mellitus or impaired renal function may have an increased risk of hyperkalemia, impaired renal function, and increased incidence of cardiovascular morbidity and mortality.

Concomitant use of ACE and ARA II inhibitors

According to the available literature, in patients with an established diagnosis of atherosclerosis, heart failure, or diabetes mellitus with target organ damage, concomitant use of ACE inhibitors and ARA II leads to an increased incidence of hypotension, syncope, hyperkalemia, and deterioration of renal function (including acute renal failure) compared to situations where only one drug is used that affects the RAAS. The use of double blockade of the RAAS (for example, simultaneous use of ACE inhibitors and ARA II) should be limited to isolated cases with strict monitoring of renal function, blood potassium content and blood pressure (see the section “Special instructions”).

Estramustin

Concomitant use of estramustine with ACE inhibitors is associated with an increased risk of angioedema.

Co-trimoxazole (trimethoprim + sulfamethoxazole)

Concomitant use with co-trimoxazole (trimethoprim + sulfamethoxazole) may increase the risk of hyperkalemia (see section “Special instructions”). Potassium-sparing diuretics (e. g. triamterene, amiloride) and potassium salts

Usually, the potassium content in the blood plasma remains within the normal range, and some patients receiving ACE inhibitors may develop hyperkalemia. The use of potassium-sparing diuretics (for example, spironolactone, triamterene, eplerenone or amiloride), potassium-containing substitutes for table salt, and other drugs that increase the potassium content in the blood plasma can lead to a significant increase in the potassium content in the blood serum. Caution should also be exercised when prescribing perindopril concomitantly with other drugs that may increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim + sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic, such as amiloride. Therefore, the simultaneous use of perindopril with the above drugs is not recommended. If, however, concomitant use is indicated, it should be used with caution and regular monitoring of serum potassium levels.

Lithium preparations

With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the content of lithium in blood plasma and associated toxic effects (severe neurotoxic effects) may occur. Concomitant use of perindopril and lithium preparations is not recommended. If such therapy is necessary, regular monitoring of the lithium content in the blood plasma is necessary (see the section “Special instructions”).

Drug combinations that require special attention

Hypoglycemic agents (insulin, sulfonylureas)

According to data obtained in epidemiological studies, ACE inhibitors can enhance the hypoglycemic effect of insulin and sulfonylurea derivatives with the risk of hypoglycemia. This effect is most likely to be observed in the first weeks of concomitant use and in patients with impaired renal function.

Potassium-sparing diuretics

In patients receiving diuretics, especially in patients with hypovolemia and / or reduced salt concentrations, a marked decrease in blood pressure may occur at the beginning of perindopril therapy, the risk of which can be reduced by discontinuing the diuretic, replenishing fluid or salt loss before starting perindopril therapy, and prescribing perindopril at a low dose with a further gradual increase.

In hypertension in patients with hypovolemia or reduced salt content during diuretic therapy, diuretics should either be discontinued before starting the use of an ACE inhibitor (in this case, a potassium-sparing diuretic may be re-prescribed later), or an ACE inhibitor should be prescribed at a low dose with a further gradual increase.

When using diuretics in the case of CHF, an ACE inhibitor should be prescribed at a very low dose, possibly after reducing the dose of a concomitantly used potassium-sparing diuretic.

In all cases, renal function (plasma creatinine concentration) should be monitored during the first weeks of ACE inhibitor use.

Potassium-sparing diuretics (use of eplerenone, spironolactone in doses from 12.5 mg to 50 mg per day and low doses of ACE inhibitors)

In the treatment of NYHA functional class II-IV CHF with left ventricular ejection fraction < 40% in patients with ras

How to take, course of use and dosage

Inside, one tablet 1 time a day, preferably in the morning before meals.

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

If necessary, the dosage of the drug Dalneva® can be changed based on the 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.

Maximum daily dose: amlodipine 10 mg + perindopril 8 mg.

Overdose

There is no information on overdose with Dalneva®.

Amlodipine

Information about amlodipine overdose is limited.

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

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

Perindopril

Data on overdose with perindopril are limited.

Symptoms: marked decrease in blood pressure, shock, impaired water-electrolyte balance, renal failure, hyperventilation, tachycardia, palpitation, bradycardia, dizziness, restlessness and cough.

Treatment: emergency measures are limited to removing the drug from the body: gastric lavage and / or prescribing activated charcoal, followed by BCC restoration.

With a marked decrease in blood pressure, the patient should be transferred to the “lying” position on his back with his legs raised, if necessary, measures should be taken to restore the BCC (for example, an intravenous infusion of 0.9% sodium chloride solution). Intravenous use of catecholamines is also possible. Hemodialysis can remove perindopril from the systemic circulation. Treatment-resistant bradycardia may require pacemaker implantation. Dynamic monitoring of the general condition, creatinine concentration and electrolyte content in the blood plasma is required.

Description

Tablets 5 mg + 4 mg:

Round, slightly biconvex tablets with a chamfer, from white to almost white in color.

Tablets 10 mg + 4 mg:

Capsule-shaped, biconvex tablets with a risk on one side, from white to almost white in color.

Tablets 5 mg + 8 mg:

Round, biconvex tablets with a chamfer, from white to almost white color.

Tablets 10 mg + 8 mg:

Round, biconvex tablets with a chamfer, with a risk on one side, from white to almost white in color.

Special instructions

Renal artery stenosis (bilateral), the only functioning kidney, liver failure, renal failure, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, with allopurinol, procainamide by the (risk of neutropenia, agranulocytosis), reduced volume of circulating blood (BCC) (diuretics, salt-free diet, vomiting, diarrhea), atherosclerosis, cerebrovascular disease, ischemic heart disease with severe obstructive coronary artery disease, acute myocardial infarction (and the period within 1 month after), unstable angina, the syndrome of weakness of the sinus node (marked tachycardia, bradycardia), renovascular hypertension, diabetes mellitus, primary aldosteronism, CHF, simultaneous use of inhibitors or inducers of CYP3A4 isoenzyme, dantrolene, estramustine, potassium-sparing diuretics, potassium supplements, potassium-containing substitutes salt, lithium drugs, clarithromycin, tacrolimus, cyclosporine, hyperkalemia, surgery/General anesthesia, the patients of elderly age, oppression of bone marrow hematopoiesis, allergic history, or a history of angioedema, the hemodialysis using a high-flow membranes (e. g., AN69®), desensitizing therapy apheresis of low-density lipoprotein (LDL), aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy (HACMP) application in patients of the Negroid race, nonischemic etiology of CHF III-IV functional class NYHA classification.

The drug Dalneva® should not be prescribed to children and adolescents under 18 years of age, as there are no data on the efficacy and safety of perindopril and amlodipine in these groups of patients, both in monotherapy and as part of combination therapy.

Patients with impaired renal function

The drug Dalneva® can be used in patients with creatinine clearance equal to or greater than 60 ml/min.

The drug Dalneva® is contraindicated for use in patients with creatinine clearance less than 60 ml / min. Individual selection of perindopril and amlodipine doses is recommended for such patients. Changes in the concentration of amlodipine in blood plasma do not correlate with the severity of renal failure.

Elderly patients and patients with impaired liver function

It is necessary to reduce the initial dose of Dalneva® to the lowest dose of amlodipine (i. e., to 1 tablet of amlodipine 5 mg + perindopril 4 mg or amlodipine 5 mg + perindopril 8 mg).

Special instructions related to perindopril and amlodipine are also applicable to the drug Dalneva®.

Amlodipine

The efficacy and safety of amlodipine in hypertensive crisis has not been established.

Heart failure

Patients with heart failure should be treated with caution.

When using amlodipine in patients with CHF of NYHA functional class III and IV, pulmonary edema may develop. BMCC, including amlodipine, should be used with caution in patients with CHF, due to the possible increase in the risk of adverse events from the cardiovascular system and mortality.

Liver failure

In patients with impaired liver function_{, the half}-life and AUC of amlodipine are increased. Recommendations for the dosage of the drug are not established. Amlodipine should be started at the lowest possible dose and precautions should be taken both at the beginning of treatment and when increasing the dose. Patients with severe hepatic insufficiency should increase the dose gradually, ensuring careful monitoring of the clinical condition.

Elderly patients

In elderly patients, increasing the dose should be carried out with caution (see sections “Dosage and use” and ” Pharmacological properties. Pharmacokinetics”).

Kidney failure

Patients with renal insufficiency can take amlodipine in standard doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal failure. Amlodipine is not eliminated from the body by dialysis.

Mitral stenosis/aortic stenosis/HOCMP

Amlodipine is contraindicated in patients with left ventricular exit tract obstruction.

Withdrawal syndrome

Despite the absence of “withdrawal” syndrome in BMCC, discontinuation of treatment with Dalneva® should be carried out gradually, reducing the dose of the drug. Amlodipine does not prevent the development of “withdrawal” syndrome when abruptly stopping taking beta-blockers.

Peripheral edema

Mild to moderate peripheral edema was the most common adverse event of amlodipine in clinical trials. The frequency of peripheral edema increases with increasing dose (when using amlodipine at a dose of 2.5 mg,5 mg and 10 mg per day, edema occurred, respectively, in 1.8%,3% and 10% of patients). Peripheral edema associated with the use of amlodipine should be carefully differentiated from symptoms of progressive left ventricular heart failure.

Other things

It is necessary to maintain dental hygiene and follow up with a dentist (to prevent soreness, bleeding and gum hyperplasia).

Perindopril

Hypersensitivity/Angioedema (angioedema)

When using ACE inhibitors, including perindopril, in rare cases, angioedema of the face, lips, tongue, vocal folds and/or larynx may develop. This can happen at any time. If these symptoms occur, the use of Dalneva® should be stopped immediately, and the patient should be monitored until the signs of edema disappear completely. If angioedema affects only the face and lips, then its manifestations usually go away on their own or antihistamines can be used to treat its symptoms. Angioedema, accompanied by swelling of the tongue or larynx, can lead to airway obstruction and death. If such symptoms occur, epinephrine (epinephrine) should be immediately administered subcutaneously at a dilution of 1: 1000 (0.3 or 0.5 ml) and / or airway patency should be ensured. The patient should be under medical supervision until complete and persistent disappearance of symptoms.

Patients who have a history of angioedema that is not associated with the use of ACE inhibitors may have an increased risk of developing it against the background of the use of drugs in this group (see the section “Contraindications”).

In rare cases, intestinal angioedema (intestinal angioedema) develops during therapy with ACE inhibitors. At the same time, patients have abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and at a normal serum concentration of C1-esterase. The diagnosis is established by computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the differential diagnosis should take into account the possibility of developing intestinal angioedema (see the section “Side effects”).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (for example, temsirolimus, everolimus, sirolimus) or DPP-IV (gliptins, including vildagliptin) increases the risk of angioedema (for example, edema of the upper respiratory tract or tongue, accompanied or not by impaired respiratory function) (see the section “Interaction with other drugs”).

Caution should be exercised when starting therapy with racecadotril, mTOR inhibitors (for example, temsirolimus, everolimus, sirolimus) or gliptins, including vildagliptin, when used concomitantly with ACE inhibitors.

Anaphylactoid reactions during desensitization procedures

There are isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenopteran venom. In these patients, the anaphylactoid reaction was avoided by temporarily stopping ACE inhibitors, and if the drug was accidentally taken, the anaphylactoid reaction occurred again.

Anaphylactoid reactions during LDL apheresis with dextran sulfate

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each LDL apheresis procedure using dextran sulfate.

Neutropenia/agranulocytosis, thrombocytopenia and anemia

Patients taking ACE inhibitors may develop neutropenia/agranulocytosis, thrombocytopenia, and anemia. Neutropenia is rare in patients with normal renal function in the absence of other aggravating factors.

With caution, perindopril should be used in patients with systemic connective tissue diseases, while taking 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 prescribing perindopril to such patients, it is recommended to periodically monitor the number of white blood cells in the blood. Patients should inform the doctor about any signs of infectious diseases (for example, sore throat, fever).

Renovascular hypertension

Patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney during ACE inhibitor therapy have an increased risk of hypotension and renal failure. Taking diuretics may be an additional risk factor. Deterioration of renal function can be observed even with a slight change in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

Double blockade of the RAAS

There is evidence that concomitant use of ACE inhibitors, ARA II, or aliskiren increases the risk of hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal insufficiency (GFR less than 60 ml/min / 1.73 m2 of body surface area) and is not recommended in other patients. If therapy with double blockade of the RAAS is considered absolutely necessary, it should only be carried out under strict medical supervision and with regular monitoring of renal function, blood plasma electrolytes and blood pressure. The use of ACE inhibitors concomitantly with ARA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism, as a rule, are not susceptible to antihypertensive drugs, the action of which is based on the inhibition of RAAS. Therefore, taking the drug is not recommended.

Arterial hypotension

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic hypotension rarely develops in patients without concomitant diseases. The risk of a marked decrease in blood pressure is increased in patients with reduced BCC, which can be observed against the background of diuretic therapy, with a strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe hypertension with high renin activity (see the sections “Interaction with other drugs” and “Side effects”). In patients with an increased risk of developing symptomatic hypotension, blood pressure, renal function, and serum potassium should be carefully monitored during therapy with Dalneva®.

This approach is also used in patients with angina pectoris and cerebrovascular diseases, in which severe hypotension can lead to myocardial infarction or impaired cerebral circulation.

In case of hypotension, the patient should be placed in a supine position with the legs raised. If necessary, the BCC should be replenished by intravenous use of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle to further use of the drug. After recovery of BCC and blood pressure, treatment can be continued.

Mitral stenosis/aortic stenosis/HOCMP

Perindopril, like other ACE inhibitors, should be used with caution in patients with left ventricular exit tract obstruction (aortic stenosis, HOCMP), as well as in patients with mitral stenosis. Amlodipine is contraindicated in patients with left ventricular exit tract obstruction.

Impaired renal function

In patients with renal insufficiency (creatinine clearance less than 60 ml/min), individual selection of doses of perindopril and amlodipine is recommended (see the section “Dosage and use”). Such patients should be regularly monitored for potassium and serum creatinine (see section “Side effects”).

In patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney during therapy with ACE inhibitors, an increase in serum urea and creatinine concentrations may occur, which usually passes when therapy is discontinued. More often, this effect is observed in patients with renal insufficiency. The additional presence of renovascular hypertension leads to an increased risk of severe hypotension and renal failure in these patients. In some patients with hypertension without signs of renal vascular damage, an increase in serum urea and creatinine concentrations is possible, especially when perindopril is co-administered with a diuretic, usually insignificant and transient. More often, this effect is observed in patients with previous renal impairment.

Impaired liver function

In redk

Form of production

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

10 tablets each in a contour cell pack made of combined OPA/Al/PVC material and aluminum foil.

3 or 9 contour cell packages together with the instructions for use are placed in a pack of cardboard.

Storage conditions

At a temperature not exceeding 25°C, in the original packaging.

Keep out of reach of children.

Shelf

life is 3 years.

Do not use the drug after the expiration date.

Active ingredient

Amlodipine, Perindopril

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Hypertension, Angina