Dalneva

Special instructions related to amlodipine and perindopril also apply to Dalneva.

Perindopril

Hypersensitivity/angioedema (Quincke's edema)

When using ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, lips, tongue, vocal folds, and/or larynx may occur. If these symptoms appear, use of the drug should be stopped immediately, and the patient should be observed until signs of edema disappear completely.

If angioedema affects only the face and lips, its symptoms usually resolve on their own, or antihistamines can be used to treat the symptoms. Angioedema, accompanied by swelling of the tongue or larynx, can lead to airway obstruction and death.

If such symptoms appear, you should immediately administer epinephrine (adrenaline) subcutaneously at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency. The patient should be under medical supervision until symptoms disappear completely and permanently.

Patients with a history of angioedema not associated with the use of ACE inhibitors may have an increased risk of developing it when using drugs in this group.

In rare cases, intestinal angioedema (angioedema of the intestine) develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal C-1-esterase levels. The diagnosis is made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping the use of ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of developing intestinal angioedema must be taken into account when making a differential diagnosis.

Anaphylactoid reactions during desensitization procedures

There are isolated reports of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy with Hymenoptera venom. ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, the development of anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

Anaphylactoid reactions during LDL apheresis using dextran sulfate

In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using high-flux membranes.

Hemodialysis

Anaphylactic reactions have been observed in patients receiving ACE inhibitors during hemodialysis using high-flow membranes. Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.

Neutropenia/agranulocytosis, thrombocytopenia and anemia

In patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia and anemia may develop. In patients with normal renal function in the absence of other complications, neutropenia rarely develops and resolves spontaneously after discontinuation of ACE inhibitors.

Perindopril should be used with great caution in patients with connective tissue diseases and simultaneously receiving immunosuppressive therapy, allopurinol or procainamide, especially with existing renal impairment. Some patients may develop severe infections that do not respond to intensive antibiotic therapy. If perindopril is prescribed, monitoring the number of leukocytes in the blood plasma is recommended. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), consult a doctor immediately.

Risk of arterial hypotension and/or renal failure (in patients with chronic heart failure, fluid and electrolyte imbalance, etc.)

In liver cirrhosis, accompanied by edema and ascites, arterial hypotension, and CHF, significant activation of the renin-angiotensin-aldosterone system (RAAS) may be observed, especially with severe hypovolemia and a decrease in the content of electrolytes in the blood plasma (against the background of a diet with limited salt or long-term use of diuretics ).

The use of an ACE inhibitor causes blockade of the RAAS, and therefore a sharp decrease in blood pressure and/or an increase in the concentration of creatinine in the blood plasma is possible, indicating the development of acute renal failure, which is more often observed when taking the first dose or during the first two weeks of therapy.

ACE inhibitors can cause a sharp decrease in blood pressure. Symptomatic hypotension rarely occurs in patients without underlying medical conditions. The risk of an excessive decrease in blood pressure is increased in patients with reduced blood volume, which can be observed during diuretic therapy, while following a strict diet with limited salt, hemodialysis, with diarrhea or vomiting, or in patients with severe arterial hypertension with high renin activity. In patients at high risk of developing symptomatic hypotension, blood pressure, renal function, and serum potassium levels should be carefully monitored during drug therapy.

The same precautions apply to patients with angina pectoris or cerebrovascular diseases, in whom a pronounced decrease in blood pressure can lead to the development of myocardial infarction or cerebrovascular accident.

If arterial hypotension develops, the patient should be transferred to the supine position with legs elevated. If necessary, replenish the blood volume with intravenous administration of 0.9% sodium chloride solution. Transient arterial hypotension is not a contraindication for further use of the drug. After restoration of blood volume and blood pressure, therapy can be continued.

Aortic stenosis/Mitral stenosis/Hypertrophic obstructive cardiomyopathy

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

Potassium-sparing diuretics and potassium supplements

The simultaneous use of perindopril and potassium-sparing diuretics, as well as potassium preparations and potassium-containing salt substitutes is not recommended.

Cough

During therapy with an ACE inhibitor, a dry, nonproductive cough may occur, which disappears after discontinuation of drugs in this group. If a dry cough appears, you should be aware of the possible connection of this symptom with the use of an ACE inhibitor.

Children and adolescents under 18 years of age

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

Renal dysfunction

If renal function is impaired (creatinine clearance less than 60 ml/min), individual selection of doses of perindopril and amlodipine is recommended. Regular monitoring of potassium and creatinine levels in the blood plasma is a necessary condition in the treatment of such patients.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, taking ACE inhibitors, there was an increase in plasma urea and creatinine concentrations, reversible after discontinuation of therapy. These changes are more likely in patients with renal failure. Patients with renovascular hypertension are at increased risk of severe hypotension and renal failure. In some hypertensive patients without obvious evidence of existing renal disease who took perindopril concomitantly with a diuretic, small and transient increases in serum urea and creatinine concentrations were observed. These changes more often develop in patients with pre-existing renal impairment.

Liver dysfunction

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 with death. The mechanism of development of this syndrome is unclear. If jaundice occurs or liver transaminases increase during use of an ACE inhibitor, the ACE inhibitor should be discontinued immediately and the patient should remain under appropriate medical supervision.

Ethnic characteristics

In patients of the Negroid race, angioedema develops more often than in representatives of other races while using ACE inhibitors. Perindopril, like other ACE inhibitors, may have a less pronounced hypotensive effect in patients of the Black race compared to representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race more often have low plasma renin activity.

Surgery/general anesthesia

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

Hyperkalemia

During therapy with ACE inhibitors, including perindopril, plasma potassium levels may increase in some patients. Risk factors for the development of hyperkalemia are renal failure, decreased renal function, old age (over 70 years), diabetes mellitus, intercurrent conditions, in particular dehydration, acute cardiac decompensation, metabolic acidosis, simultaneous use of potassium-sparing diuretics (for example, spironolactone, eplerenone, triamterene or amiloride), potassium-containing drugs or supplements, potassium-containing salt substitutes, or concomitant use of other drugs that increase plasma potassium levels (eg, heparin). Hyperkalemia can cause serious, sometimes life-threatening arrhythmias. If it is necessary to use perindopril and one of the above substances simultaneously, caution should be exercised and the potassium level in the blood plasma should be regularly monitored.

Patients with diabetes mellitus

In patients with diabetes mellitus taking oral hypoglycemic agents and/or insulin, increased monitoring of blood glucose concentrations is necessary during the first few months of therapy with ACE inhibitors.

Amlodipine

Liver dysfunction

In patients with impaired liver function, T1/2 of amlodipine is prolonged. When prescribing the drug to such patients, caution should be exercised and the activity of liver enzymes should be regularly monitored.

Patients with heart failure

In patients with CHF (functional class III and IV according to the NYHA classification), treatment is carried out with caution, due to the possibility of developing pulmonary edema.

Release form and composition

Dalneva is available in the form of almost white or white tablets: 5 mg + 4 mg – slightly biconvex round, with a chamfer; 10 mg + 4 mg – biconvex capsule-shaped, on one side there is a dividing line; 5 mg + 8 mg – round biconvex shape, with a chamfer; 10 mg + 8 mg – round, biconvex shape, with a chamfer and a dividing line on one side (10 pcs. in a blister pack, 3 or 9 packs in a cardboard box).

1 tablet contains:

active ingredients: amlodipine besylate + perindopril erbumine A (in the form of granules) – 6.935 mg + 21 mg, 13.87 mg + 21 mg, 6.935 mg + 42 mg or 13.87 mg + 42 mg, which is equivalent to the content of 5 mg + 4 mg, 10 mg + 4 mg, 5 mg + 8 mg or 10 mg amlodipine + 8 mg perindopril erbumine;
auxiliary components: microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate.

Directions for use and dosage

Tablets are taken orally, preferably before breakfast, 1 piece. in a day.

The daily dose is established based on the results of preliminary titration of doses of each of the components of the drug using the method of individual selection, taking into account clinical indications.

The maximum dose is 10 mg + 8 mg per day.

In case of kidney disease (creatinine clearance more than 60 ml/min), the dose is set depending on the degree of impairment of its function. Changing the level of amlodipine in the blood plasma does not affect the severity of renal failure.

Elderly patients do not require dose adjustment.

Drug interactions

When concomitant therapy with other drugs is necessary, it is necessary to take into account the interaction with them of each of the active components of the drug.

With simultaneous use of Dalneva:

spironolactone, triamterene, amiloride and other potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes can cause a significant increase in plasma potassium levels;
Lithium preparations contribute to an increase in the concentration of lithium in the blood serum and the development of toxic effects;
Estramustine increases the risk of developing angioedema;
non-steroidal and non-selective anti-inflammatory drugs, high doses (more than 3 g per day) of acetylsalicylic acid can lead to a decrease in the hypotensive, diuretic, natriuretic effect of perindopril, a deterioration in renal function up to the development of acute renal failure, an increase in the potassium content in the blood serum;
oral hypoglycemic agents, insulin enhance their effect;
thiazide and loop diuretics can significantly reduce blood pressure;
sympathomimetics can reduce the hypotensive effect of the drug;
gold preparations for injection sometimes cause nausea, vomiting, flushing of the face, and a decrease in blood pressure;
glucocorticosteroids (GCS) for systemic use, cytostatic and immunosuppressive agents, allopurinol, procainamide increase the risk of leukopenia;
agents for general anesthesia, tricyclic antidepressants, antipsychotics enhance the hypotensive effect of the drug, increasing the risk of developing orthostatic hypotension;
dantrolene for intravenous administration increases the risk of hyperkalemia;
rifampicin, St. John's wort, anticonvulsants (carbamazepine, phenobarbital, fosphenytoin, primidone, phenytoin) can cause increased metabolism of amlodipine and a decrease in its plasma concentration;
protease inhibitors, azole antifungals (itraconazole, ketoconazole), macrolides (including erythromycin, clarithromycin, diltiazem, verapamil) may increase the plasma concentration of amlodipine and increase the risk of adverse effects;
beta-blockers (bisoprolol, metoprolol), carvedilol increase the risk of arterial hypotension and enhance the negative inotropic effect of the drug;
baclofen, vasodilators can potentiate the hypotensive effect of the drug;
mineralocorticosteroids and corticosteroids, tetracosactide reduce the hypotensive effect of the drug;
prazosin, alfuzosin, tamsulosin, doxazosin, terazosin (alpha-blockers) enhance the hypotensive effect and increase the risk of orthostatic hypotension;
amifostine may increase the hypotensive effect of amlodipine;
cimetidine, sildenafil, grapefruit juice (240 ml) do not affect the pharmacokinetics of amlodipine;
cyclosporine, atorvastatin, digoxin, warfarin do not change their pharmacokinetic parameters.

Side effects

from the circulatory and lymphatic systems: very rarely - agranulocytosis, leukopenia or neutropenia, thrombocytopenia, pancytopenia, with congenital deficiency of glucose-6-phosphate dehydrogenase - hemolytic anemia, decreased hematocrit and hemoglobin concentrations;
from the cardiovascular system: often – a pronounced decrease in blood pressure, a rush of blood to the skin of the face, a feeling of palpitations; infrequently – fainting; rarely – chest pain; very rarely - angina pectoris, myocardial infarction, arrhythmias (including bradycardia, atrial fibrillation, ventricular tachycardia), stroke, vasculitis;
from the immune system: infrequently – urticaria;
from the nervous system: often – headache, dizziness, drowsiness, vertigo, paresthesia; uncommon – sleep disturbance, insomnia, tremor, mood lability, hypoesthesia; very rarely - confusion, peripheral neuropathy;
metabolic disorders: infrequently - increase or decrease in body weight; very rarely - hyperglycemia; frequency unknown - hypoglycemia;
from the senses: often – tinnitus, visual impairment;
from the digestive system: often – dyspepsia, nausea, vomiting, abdominal pain, constipation, diarrhea; infrequently - dryness of the oral mucosa, disturbance of the sense of taste, disturbance of the rhythm of bowel movements; very rarely - gastritis, gingival hyperplasia, pancreatitis, cholestatic jaundice, hepatitis, cholestatic or cytolytic hepatitis;
from the respiratory system: often – cough, shortness of breath; uncommon – bronchospasm, rhinitis; very rarely - eosinophilic pneumonia;
from the musculoskeletal system: often – muscle spasms; uncommon – back pain, arthralgia, myalgia;
on the part of the skin: often – itching, rash; uncommon – angioedema of the vocal folds and/or larynx, tongue, lips, mucous membranes, face or extremities, photosensitivity, hemorrhagic rash, excessive sweating, alopecia; very rarely - erythema multiforme, angioedema, Stevens-Johnson syndrome;
from the reproductive system: infrequently – gynecomastia, impotence;
from the urinary system: infrequently - nocturia, urinary dysfunction, renal failure, frequent urination; very rarely - acute renal failure;
laboratory parameters: rarely - increased bilirubin levels; very rarely - increased activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), often in combination with cholestasis; frequency unknown - increased levels of creatinine and urea in the blood serum;
other: often – asthenia, peripheral edema, increased fatigue; infrequently – malaise, chest pain.