Dalneva, tablets 5 mg+8 mg 30 pcs

hypotensive combination therapy (angiotensin-converting enzyme inhibitor [ACE] + slow calcium channel blocker [CCB])

Indications

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

Active ingredient

Composition

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

Active substances:

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

Auxiliaries:

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

How to take, the dosage

Orally, one tablet once a day, preferably in the morning before a meal.

The dose of the drug Dalneva® is adjusted after previously adjusted doses of individual drug components: perindopril and amlodipine in patients with AH and stable angina pectoris.

If therapeutic necessity, the dose of the drug Dalneva® can be changed based on 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.

Interaction

Amlodipine

Unrecommended drug combinations

Dantrolene (intravenous administration)

Fatal ventricular fibrillation and collapse have been reported in laboratory animals against verapamil administration and intravenous dantrolene accompanied by hyperkalemia. Due to the risk of hyperkalemia, concomitant use of PBMCs, including amlodipine, should be excluded in patients with malignant hyperthermia as well as during treatment of malignant hyperthermia.

Drug combinations, require special attention

Isoenzyme inducers CYP3A4: Concomitant use with CYP3A4 isoenzyme inducers may alter the plasma concentration of amlodipine. Therefore it is necessary to monitor BP and adjust the dose both during and after their concomitant use, especially in case of use with potent inducers of CYP3A4 isoenzyme (e.g. rifampicin, St. John’s Wort preparations).

Inhibitors of the isoenzyme CYP3A4: Simultaneous administration of amlodipine and potent to moderate CYP3A4 isoenzyme inhibitors (protease inhibitors, antifungal drugs of the azole group, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in significant increases in plasma amlodipine concentration. Clinical manifestations of these pharmacokinetic abnormalities may be more pronounced in elderly patients. Due to this clinical condition monitoring and dose adjustment may be required.

Patients taking amlodipine concomitantly with clarithromycin are at increased risk of arterial hypotension. Patients taking perindopril concomitantly with clarithromycin should be monitored closely.

Drug combinations., require attention

Amlodipine increases the antihypertensive effects of hypertensive drugs.

Tacrolimus:Tacrolimus risk increases serum concentrations when used simultaneously with amlodipine. To avoid the development of toxic effects of tacrolimus concomitantly using these drugs it is necessary to monitor the serum concentration of tacrolimus and adjust the dose if necessary.

Cyclosporine: There have been no studies examining the interaction of cyclosporine with amlodipine in healthy volunteers or other populations, with the exception of kidney transplant patients, in whom there has been variability in increasing the lowest plasma concentrations of cyclosporine (on average, 0% to 40%). The possibility of controlling serum concentration of cyclosporine in patients after kidney transplantation during concomitant use with amlodipine should be considered. If necessary, the dose of cyclosporine should be decreased.

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

The simultaneous use of amlodipine and consumption of grapefruit or grapefruit juice is not recommended due to the possible increased bioavailability of amlodipine in some patients, which in turn may increase the effects of BP reduction.

Inhibitors tTOR(mammalianTargetofRapamycinmammalian target of rapamycin: MTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of the CYP3A isoenzyme. Amlodipine is a weak inhibitor of CYP3A isoenzyme. When used concomitantly with mTOR inhibitors, amlodipine may increase their exposure.

Clarithromycin: clarithromycin is a CYP3A4 isoenzyme inhibitor. There is an increased risk of arterial hypotension in patients concomitantly using clarithromycin with amlodipine. Close monitoring of patients is recommended when using amlodipine concomitantly with clarithromycin.

Simultaneous use of beta-adrenoblockers (bisoprolol, metoprolol) and the alpha- and beta-adrenoblocker carvedilol in CHF: increases the risk of arterial hypotension and worsening 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 concomitant CHF.

Concurrent use of amlodipine may increase systemic plasma exposure to tasonermine. In such cases, regular monitoring of plasma concentrations of tasonermine is necessary and dose adjustment if necessary.

Other drug combinations

Calcium preparations can reduce the effect of BMCC.

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, T½ 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.

Synopsis

Tablets 5 mg + 4 mg:

Round, slightly biconvex, beveled tablets, white to almost white.

Tablets 10 mg + 4 mg:

Capsule-shaped, biconvex tablets with a ridge on one side, white to almost white.

Tablets 5 mg + 8 mg:

Round, biconvex, beveled tablets, white to almost white.

Tablets 10 mg + 8 mg:

Round, biconvex, beveled tablets, with a bevel on one side, white to almost white.

Contraindications

– 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”).

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, elevated position of the lower extremities, control of the 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 circulatory blood pressure.

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 is recommended to evaluate the skull bone 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 neonates or premature babies.

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