Special Instructions
Special Instructions
Renal artery stenosis (including bilateral), a single functioning kidney, hepatic insufficiency, renal failure, systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), therapy with immunosuppressants, allopurinol, procainamide (risk of neutropenia, agranulocytosis), reduced circulating blood volume (CBC) (taking diuretics, salt-free diet, vomiting, diarrhea), atherosclerosis, cerebrovascular diseases, CHD with severe obstructive coronary artery disease, acute myocardial infarction (and the period within 1 month after it), unstable angina, sinus node weakness syndrome (marked tachycardia, bradycardia), renovascular hypertension, diabetes mellitus, primary hyperaldosteronism, CHF, concomitant use of CYP3A4 isoenzyme inhibitors or inducers, dantrolene, estramustine, potassium-saving diuretics, potassium-containing salt substitutes, lithium drugs, clarithromycin, tacrolimus, cyclosporine, hyperkalemia, surgery/general anesthesia, elderly patient, suppression of medullary hematopoiesis, history of allergic reactions or angioedema, prior hemodialysis with high-flow membranes (e.g., AN69sup>®), desensitizing therapy, low-density lipoprotein (LDL) apheresis, aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy (HCMP), use in non-Hispanic patients, nonischemic CHF of NYHA class III-IV.

The drug Dalneva^® should not be administered to children and adolescents under 18 years of age because there are no data on the efficacy and safety of perindopril and amlodipine in these patient groups both in monotherapy and as part of combination therapy.
Patients with impaired renal function

The drug Dalneva^® may be used in patients with a CK equal to or greater than 60 ml/min.

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

Elderly patients and patients with impaired liver function

The initial dose of Dalneva^® should be reduced to contain the lowest dose of amlodipine (i.e. i.e., to 1 tablet of amlodipine 5 mg + perindopril 4 mg or amlodipine 5 mg + perindopril 8 mg).
The special indications related to perindopril and amlodipine also apply to the drug Dalneva^®.

Amlodipine

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

Heart failure

Treatment of patients with heart failure should be given with caution.

when using amlodipine in patients with chronic heart failure class III and IV according to NYHA classification, pulmonary edema may develop. PBMCs including amlodipine should be used with caution in patients with CHF due to the possible increase of risk of cardiovascular adverse events and mortality.

hepatic failure

In patients with impaired liver function, T_½ and AUC of amlodipine are increased. There are no dosing recommendations for the drug. Amlodipine should be started at the lowest dose and precautions should be taken both at the beginning of treatment and when increasing the dose. In patients with severe hepatic impairment, the dose should be increased gradually, ensuring close monitoring of the clinical condition.

Elderly patients

In elderly patients, dose increases should be given with caution (see Sections “Administration and Doses” and “Pharmacological Properties. Pharmacokinetics”).

Renal failure

Patients with renal insufficiency can take amlodipine at 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/GOCMP

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

Cancel syndrome

Despite the absence of withdrawal syndrome in BMCCs, discontinuation of treatment with Dalneva^® should preferably be done gradually, reducing the drug dose. Amlodipine does not prevent the development of withdrawal when beta-adrenoblockers are stopped abruptly.

Peripheral edema

Mild to moderate peripheral edema was the most common adverse event of amlodipine in clinical trials. The incidence of peripheral edema increased with increasing dose (with amlodipine 2.5 mg, 5 mg and 10 mg daily, edema occurred in 1.8%, 3% and 10% of patients, respectively). Peripheral edema associated with amlodipine use should be carefully differentiated from symptoms of progression of left ventricular heart failure.

Other

It is necessary to maintain dental hygiene and see a dentist (to prevent sore, bleeding and gum hyperplasia).

Perindopril

Elevated sensitivity/angioneurotic edema (Quincke’s edema)

When using ACE inhibitors, including perindopril, the development of angioedema of the face, lips, tongue, vocal folds, and/or larynx may occur in rare cases. This may occur at any time. If these symptoms occur, the use of Dalneva^® should be stopped immediately and the patient should be observed until the signs of oedema have completely disappeared.If angioedema only affects the face and lips, its manifestations usually disappear on their own or antihistamines may be used to treat their symptoms. Angioedema accompanied by swelling of the tongue or larynx may cause airway obstruction and may be fatal. If these symptoms develop, epinephrine (adrenaline) 1:1000 (0.3 or 0.5 ml) subcutaneously injected immediately and/or airway patency assured. The patient should be under medical supervision until the symptoms completely and permanently disappear.

In rare cases, intestinal angioedema (angioedema of the intestine) develops against the background of ACE inhibitor therapy. Patients present with abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding angioedema of the face and with a normal serum C1-esterase concentration. Diagnosis is made by abdominal computed tomography, ultrasound or at the time of surgery. Symptoms disappear after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered when making a differential diagnosis (see section “Side effects”).

The concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus), or DPP-IV (gliptins, including vildagliptin) increases the risk of angioedema (e.g., upper airway or tongue edema, with or without respiratory impairment) (see section “Interaction with other medicinal products”).

Caution should be exercised when initiating therapy with racecadotril, mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus), or gliptins, including vildagliptin, when used concurrently with ACE inhibitors.

Anaphylactoid reactions during desensitization procedures

There have been isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with Hymenoptera venom. In the same patients, anaphylactoid reactions were avoided by temporary withdrawal of ACE inhibitors, but anaphylactoid reactions occurred again if the drug was accidentally taken.

Anaphylactoid reactions during LDL apheresis with dextran sulfate

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions when performing LDL apheresis with dextran sulfate. To prevent anaphylactoid reactions, ACE inhibitor therapy should be temporarily stopped before each LDL apheresis procedure with dextran sulfate.

Neutropenia/agranulocytosis, thrombocytopenia and anemia

In patients taking ACE inhibitors, there may be cases of neutropenia/agranulocytosis, thrombocytopenia and anemia. In patients with normal renal function in the absence of other aggravating factors neutropenia is rare.

Perindopril should be used with special caution in patients with systemic connective tissue diseases, against the background of taking immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function.

Some patients had 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 leukocytes in the blood. Patients should inform the physician about any signs of infectious diseases (e.g., sore throat, fever).

Renovascular Hypertension

Patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney are at increased risk for arterial hypotension and renal failure with ACE inhibitor therapy. Taking diuretics may be an additional risk factor. Deterioration of renal function may be observed even with a small change in serum creatinine concentration, even in patients with unilateral renal artery stenosis.

Double RAAS blockade

There is evidence that concomitant use of ACE inhibitors, ARA II or aliskiren increases the risk of arterial hypotension, hyperkalemia and renal function impairment (including acute renal failure). Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal insufficiency (FFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. If therapy with dual RAAS blockade is considered absolutely necessary, it should be performed only under strict medical supervision and with regular monitoring of renal function, plasma electrolyte content and BP. ACE inhibitors usage simultaneously with APA II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see section “Contraindications”).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are usually not susceptible to hypotensive drugs whose action is based on inhibition of the RAAS. Therefore it is not recommended to use this medicine.

Arterial hypotension

ACE inhibitors can cause a sharp decrease in BP. Symptomatic arterial hypotension rarely develops in patients without comorbidities. The risk of significant BP decrease is increased in patients with decreased blood pressure, which may be observed against the background of diuretic therapy, with strict salt-free diet, hemodialysis, diarrhea and vomiting, as well as in patients with severe AH with high renin activity (see sections “Interaction with other medicinal products” and “Side effects”). In patients with increased risk of symptomatic arterial hypotension, BP, renal function and serum potassium content during therapy with the drug Dalneva^®.

A similar approach is used in patients with angina and cerebrovascular disease in whom severe arterial hypotension can lead to myocardial infarction or cerebrovascular events.

If arterial hypotension develops, the patient should be transferred to the supine position with elevated legs. If necessary, the circulatory blood pressure should be replenished by intravenous injection of 0.9% sodium chloride solution. Transient arterial hypotension is not an obstacle for further drug administration. After the RBC and BP recovery, the treatment can be continued.

Mitral stenosis/aortic stenosis/GOCMP

Perindopril, like other ACE inhibitors, should be prescribed with caution in patients with left ventricular outflow tract obstruction (aortic stenosis, GOCMP) and in patients with mitral stenosis. Amlodipine is contraindicated in patients with left ventricular outflow tract obstruction.

Kidney function disorder

Patients with renal insufficiency (KC less than 60 ml/min) are recommended to choose individual doses of perindopril and amlodipine (see section “Dosage and administration”). These patients require regular monitoring of potassium content and serum creatinine concentration (see section “Side effects”).

Patients with bilateral renal artery stenosis or artery stenosis of the uniciliary artery may have increased serum urea and creatinine concentrations during ACE inhibitor therapy, which usually subsides with therapy reversal. This effect is more often noted in patients with renal insufficiency. The additional presence of renovascular hypertension causes an increased risk of severe arterial hypotension and renal failure in these patients. Some patients with AH without signs of renal vascular lesions may have increased serum urea and creatinine concentrations, especially when concomitant administration of perindopril with a diuretic, usually minor and transient. More often this effect is observed in patients with previous renal dysfunction.

Liver function disorder

In rare

Contraindications
Contraindications
High sensitivity to perindopril or other ACE inhibitors, amlodipine or other dihydropyridine derivatives, or excipients in the drug.
Anhioneurotic edema (Quincke’s edema) in anamnesis (including against the other ACE inhibitors).
Hereditary/idiopathic angioedema.
Simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes and/or moderate to severe renal function impairment (GFR < 60 ml/min/1.73 m² body surface area) (see See sections “Interaction with other medicinal products” and “Pharmacological properties. Pharmacodynamics”).
Simultaneous use with ARA II in patients with diabetic nephropathy (see “Special Indications.

– Concomitant use with neutral endopeptidase inhibitors (such as those containing sacubitril) due to the high risk of angioedema.
Extracorporeal therapy leading to blood contact with negatively charged surfaces (see “Interaction with other drugs”).

>Veep bilateral renal artery stenosis or artery stenosis of the only functioning kidney (see Special Instructions).
Severe arterial hypotension (systolic BP less than 90 mm Hg.
Shock (including cardiogenic).
Obstruction of the left ventricular exit tract (eg, clinically significant aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
Renal failure (creatinine clearance [CK] less than 60 ml/min).
Pregnancy and breastfeeding.
Age under 18 years of age (efficacy and safety not established).

Overdose
Overdose
No information about overdose with Dalneva^®.

Amlodipine

Information on amlodipine overdose is limited.

Symptoms: expressed BP decrease with possible development of reflex tachycardia and excessive peripheral vasodilation (risk of severe and persistent arterial hypotension, including with the development of shock and death).

Treatment: Gastric lavage, administration of activated carbon (especially in the first 2 hours after overdose), maintenance of cardiovascular function, elevation of the lower extremities, control of blood pressure and diuresis, symptomatic and supporting therapy. To restore vascular tone – the use of vasoconstrictors (if there are no contraindications for their use), to eliminate the effects of calcium channel blockade – intravenous injection of calcium gluconate solution. Hemodialysis is ineffective.

Perindopril

The data on perindopril overdose is limited.

Symptoms: expressed BP decrease, shock, water-electrolyte imbalance, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness, and coughing.

treatment:the emergency measures are limited to the elimination of the drug from the body: gastric lavage and/or administration of activated charcoal, followed by the restoration of the BAC.

Pregnancy use
Pregnancy use
Dalneva^® drug is contraindicated in pregnancy.

Dalneva^®drug is not recommended for use during breastfeeding. The significance of therapy for the mother should be evaluated to decide whether to stop breastfeeding or to discontinue the drug.
Pregnancy

Amlodipine

The safety of amlodipine in pregnancy has not been established.

In experimental animal studies fetotoxic and embryotoxic effects of the drug are established when used in high doses. Its use during pregnancy is possible only if there is no safer alternative and when the disease is more risky for the mother and the fetus.

Perindopril

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

There is currently no conclusive epidemiologic evidence of teratogenic risk when taking ACE inhibitors in the first trimester of pregnancy. However, a small increase in the risk of fetal abnormalities cannot be ruled out. If pregnancy is planned, the drug Dalneva^® should be discontinued and other hypotensive agents approved for use in pregnancy should be prescribed. If pregnancy is established, therapy with ACE inhibitors should be immediately discontinued and, if necessary, other therapy should be prescribed.

It is known that exposure of the fetus to ACE inhibitors in the second and third trimesters of pregnancy can lead to impaired fetal development (reduced renal function, oligohydramnion, delayed ossification of the skull bones) and development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia).

If the patient received ACE inhibitors in the second or third trimester of pregnancy, an ultrasound scan is recommended to evaluate the skull bones and fetal/fetal renal function.

Newborns whose mothers received ACE inhibitors during pregnancy should be under close medical supervision due to the risk of arterial hypotension (see Sections “Contraindications” and “Special Instructions”).

Breastfeeding period

Amlodipine

Amlodipine is excreted with breast milk. The proportion of the maternal dose received by the infant was estimated with an interquartile range of 3-7%, but not more than 15%. The effect of amlodipine on neonates is unknown. The decision to continue/continue therapy or breastfeeding should be made considering the benefit of breastfeeding for the infant and the benefit of amlodipine for the mother.

Perindopril

Due to the lack of information regarding the use of perindopril during breastfeeding, taking perindopril is not recommended; it is preferable to follow an alternative treatment with a more studied safety profile during breastfeeding, especially when feeding newborn or preterm infants.
Similarities
Similarities
Prestance
Additional information
Weight 0.020 kg
Shelf life
3 years. Do not use the drug after the expiration date.
Conditions of storage
At a temperature not exceeding 25°C, in the original package. Store out of reach of children.
Manufacturer
KRKA-RUS, Russia
Medication form
pills
Brand
KRKA-RUS