Euperio film-coated tablets 50 mg blister No. 28

Instructions for use: Euperio film-coated tablets 50 mg blister No. 28

Warehouse

active ingredients: sacubitril and valsartan;

1 tablet of 50 mg contains: 24.3 mg of sacubitril and 25.7 mg of valsartan (as a complex of the sodium salt of sacubitril and valsartan);

excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide, hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide, red (E 172), iron oxide, black (E 172).

1 tablet of 100 mg contains: 48.6 mg of sacubitril and 51.4 mg of valsartan (as a complex of the sodium salt of sacubitril and valsartan);

excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide, hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide, red (E 172), iron oxide, yellow (E 172).

1 tablet of 200 mg contains: 97.2 mg of sacubitril and 102.8 mg of valsartan (as a complex of the sodium salt of sacubitril and valsartan);

excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide, hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide, red (E 172), iron oxide, black (E 172).

Dosage form

Film-coated tablets.

Main physicochemical properties:

Euperio 50 mg: oval, biconvex, film-coated tablets of violet-white color, with beveled edges, without a score, embossed with “NVR” on one side and “LZ” on the other side.

Euperi 100 mg: oval, biconvex, film-coated tablets of light yellow color, with beveled edges, without a score, embossed with “NVR” on one side and “L1” on the other side.

Euperio 200 mg: oval, biconvex, film-coated tablets of light pink color, with beveled edges, without a score, embossed with “NVR” on one side and “L11” on the other side.

Pharmacotherapeutic group

Medicinal products that affect the renin-angiotensin system. Angiotensin II antagonists, other combinations.

ATX code C09D X04.

Pharmacological properties

Pharmacodynamics.

The pharmacodynamic effects of sacubitril and valsartan were evaluated after single and multiple doses in healthy volunteers and patients with chronic heart failure. The observed effects were consistent with the mechanism of action of the active substance complex, which consists in the simultaneous inhibition of neprilysin and blockade of the renin-angiotensin-aldosterone system (RAAS). In a seven-day study in patients with reduced left ventricular ejection fraction (LVEF) in which valsartan was used as a control, sacubitril and valsartan caused a statistically significant short-term increase in natriuresis, an increase in urinary cyclic guanosine monophosphate (cGMP) concentration, and a decrease in plasma concentrations of atrial natriuretic peptide (MR-proANP) and N-terminal fragment of the precursor of brain natriuretic peptide (NT-proBNP) (compared to valsartan). In a 21-day study in patients with reduced left ventricular ejection fraction, sacubitril/valsartan caused statistically significant increases in urinary atrial natriuretic peptide (ANP) and cGMP and plasma cGMP concentrations, and decreases in plasma NT-proBNP, aldosterone, and endothelin-1 concentrations (compared to baseline). In addition, sacubitril/valsartan blocks the AT1 receptor, as indicated by increases in plasma renin activity and concentrations. In the PARADIGM-HF study, sacubitril/valsartan caused a greater decrease in plasma NT-proBNP and a greater increase in urinary brain natriuretic peptide (BNP) and cGMP concentrations than enalapril. While BNP is a substrate for neprilysin, NT-proBNP is not. Therefore, NT-proBNP, unlike BNP, can be used as a biomarker in the monitoring of patients with heart failure receiving a complex of sacubitril and valsartan (see section "Special instructions").

In a QTc study in healthy male volunteers, single doses of Euperior at doses of 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization.

Neprilysin is one of several enzymes involved in the metabolism of amyloid-β (Aβ) in the brain and cerebrospinal fluid (CSF). Following administration of 194 mg sacubitril/206 mg valsartan once daily for two weeks in healthy volunteers, the concentration of Aβ 1-38 in the CSF increased; however, the concentration of Aβ 1-40 and 1-42 in the CSF did not change. The clinical significance of this finding is unknown.

Clinical efficacy and safety

Dosages – 50 mg, 100 mg, or 200 mg of the drug are listed in some sources as 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg of the drug.

PARADIGM-HF is a multinational, randomized, double-blind study of 8,442 patients comparing Euperior and enalapril in adult patients with chronic heart failure, New York Heart Association (NYHA) class II–IV, and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%, later corrected to ≤ 35%) in addition to other heart failure medications. The primary endpoint was a composite of cardiovascular death or hospitalization for heart failure. Patients with systolic blood pressure (SBP) < 100 mm Hg. age, with severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2) and with severe hepatic impairment were excluded from screening and, as a result, did not undergo the prospective study.

Prior to study entry, patients were receiving standard treatment regimens that included angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE/ARBs) (>99%), beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). The median follow-up period was 27 months, with patients receiving therapy for up to 4.3 years.

Patients were required to discontinue ACE inhibitor or ARB therapy and then entered a sequential, single-blinded run-in period and received enalapril 10 mg twice daily, followed by single-blind treatment with Euperior 100 mg twice daily, uptitrated to 200 mg twice daily (see section 4.8 for discontinuation during this period). They were then randomised to a double-blind period in which they received either Euperior 200 mg or enalapril 10 mg twice daily (Euperio: n=4,209; enalapril: n=4,233).

The mean age of the study population was 64 years, with 19% being 75 years or older. At randomization, 70% of patients had NYHA class II heart failure, 24% had class III, and 0.7% had class IV. The mean LVEF was 29%; 963 (11.4%) patients had baseline LVEF >35% and ≤40%.

In the Euperito group, 76% of patients remained on the target dose of 200 mg twice daily by the end of the study (mean daily dose – 375 mg). In the enalapril group, 75% of patients remained on the target dose of 10 mg twice daily by the end of the study (mean daily dose – 18.9 mg).

Euperito compared with enalapril statistically significantly reduced the risk of death due to cardiovascular pathology or the risk of hospitalization due to heart failure (21.8% in the study drug group versus 26.5% in the enalapril group). The absolute reduction in the risk of death due to cardiovascular pathology or the risk of hospitalization due to heart failure was 4.7% (3.1% - reduction in the risk of death due to cardiovascular pathology and 2.8% - reduction in the risk of primary hospitalization due to heart failure). The relative reduction in the risk compared with enalapril was 20%. The effect was observed in the early stages of drug use and was maintained throughout the study period. The development of the effect was facilitated by both active components of the drug. The incidence of sudden death, which accounted for 45% of all cardiovascular deaths, was reduced by 20% in the study drug group compared with the enalapril group (hazard ratio (HR) 0.80, p = 0.0082). The incidence of heart failure, which was the cause of 26% of cardiovascular deaths, was reduced by 21% in the study drug group compared with the enalapril group (HR 0.79, p = 0.0338).

This risk reduction was consistently observed in subgroups by gender, age, race, place of residence, NYHA class (II/III), ejection fraction, renal function, history of diabetes or hypertension, heart failure therapy, and atrial fibrillation.

Euperior increased survival along with a significant reduction in overall mortality of 2.8% (Euperor 17%, enalapril 19.8%). The relative risk reduction was 16% compared with enalapril (see Table 1).

Table 1.

Treatment effect as determined by the primary composite endpoint, its components, and all-cause mortality over a median follow-up of 27 months

*The primary endpoint was defined as the time to first occurrence of cardiovascular death and hospitalization for heart failure.

**The concept of "death due to cardiovascular pathology" includes all deaths up to the date of data collection, regardless of the patient's previous hospitalization.

*** One-sided p-value.

TITRARION study.

TITRATION is a 12-week safety and tolerability study in 538 patients with chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction < 35%) who were naïve to ACE inhibitors or ARBs or who were taking ACE inhibitors or ARBs at various doses prior to enrollment. Patients initially received Euperio 50 mg twice daily, then the dose was increased to 100 mg twice daily, then to a target dose of 200 mg twice daily over a 3- or 6-week period.

A greater proportion of patients who were ACE-inhibitor or ARB-naïve or on low-dose therapy (equivalent to < 10 mg enalapril/day) achieved and remained at the 200 mg dose of Euperio until dose escalation within 6 weeks (84.8%) compared to 3 weeks (73.6%). Overall, 76% of patients achieved and remained at the target dose of Euperio 200 mg twice daily without interruption or dose reduction within 12 weeks.

Children.

The European Medicines Agency has postponed the deadline for the mandatory submission of study results in one or more groups of pediatric patients with heart failure.

Mechanism of action.

Euperio demonstrates the mechanism of action of a neprilysin receptor antagonist inhibitor by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of sacubitril, and blocking angiotensin II type 1 (AT1) receptors with valsartan. The additional beneficial effect of Euperio on the cardiovascular system in patients with heart failure is explained by the fact that LBQ657 activates peptides that are degraded by neprilysin, in particular natriuretic peptides (NPs), while valsartan inhibits the negative effects of angiotensin II. NPs exert their effect by activating membrane-bound receptors associated with guanyl cyclase, which leads to an increase in the concentration of cyclic guanosine monophosphate (cGMP) and causes symptoms of vasodilation, increased natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and also has antihypertrophic and antifibrotic effects.

Valsartan, by selectively blocking AT1 receptors, suppresses the negative effects of angiotensin II on the cardiovascular system and kidneys, and also blocks angiotensin II-dependent release of aldosterone. This prevents persistent activation of the renin-angiotensin-aldosterone system (RAAS), which causes vasoconstriction, sodium and water retention by the kidneys, activation of cell growth and proliferation, and can also lead to impaired cardiovascular function.

Pharmacokinetics.

Valsartan, in the form of a complex salt contained in Euperio, has a higher bioavailability compared to valsartan contained in other tablet preparations; 26 mg, 51 mg and 103 mg of valsartan in Euperio are equivalent, respectively, to 40 mg, 80 mg and 160 mg of valsartan in other tablets.

Absorption

After oral administration, Euperior is dissociated into valsartan and the inactive form (prodrug) sacubitril. Sacubitril is further metabolized to the active metabolite LBQ657. Peak plasma concentrations are reached after 2 hours, 1 hour, and 2 hours, respectively. The absolute bioavailability of sacubitril and valsartan exceeds 60% and 23%, respectively.

After twice daily administration of Euperio, steady-state concentrations of sacubitril, LBQ657, and valsartan are reached within three days. There is no statistically significant accumulation of sacubitril or valsartan at steady state; however, accumulation of LBQ657 is 1.6-fold higher than that observed with a single dose. Administration with food has no clinically significant effect on the systemic exposure of sacubitril, LBQ657, or valsartan. Euperio can be taken without regard to meals.

Distribution

Sacubitril, LBQ657, and valsartan are highly bound to plasma proteins (94–97%). LBQ657 crosses the blood-brain barrier to a limited extent (0.28%). The mean apparent volume of distribution for valsartan and sacubitril was 75 and 103 liters, respectively.

Metabolism

Sacubitril is rapidly transformed to LBQ657 by carboxylesterases lb and lc; LBQ657 is not further metabolized significantly. Valsartan is metabolized to a minor extent, with only about 20% of the administered dose recovered as metabolites. A hydroxyl metabolite was detected in plasma at low concentrations (< 10%).

Since both sacubitril and valsartan are minimally metabolized by cytochrome CYP450 isoenzymes, changes in their pharmacokinetics are unlikely when drugs that affect CYP450 are coadministered.

Following oral administration of Euperito, 52–68% of sacubitril (predominantly as LBQ657) and approximately 13% of valsartan and its metabolites are excreted in the urine; 37–48% of sacubitril (predominantly as LBQ657) and 86% of valsartan and its metabolites are excreted in the feces.

Sacubitril, LBQ657, and valsartan are eliminated from plasma with mean half-lives (T1/2) of approximately 1.43 h, 11.48 h, and 9.90 h, respectively.

Linearity/nonlinearity

The pharmacokinetics of sacubitril, LBQ657, and valsartan were approximately linear over the entire dose range of Euperior, from 50 mg to 200 mg.

Pharmacokinetics in certain patient groups

Elderly patients: Exposures of LBQ657 and valsartan in patients over 65 years of age are higher than in
42% and 30%, respectively, than in younger patients.

Renal impairment. There was a correlation between renal function and systemic exposure to LBQ657 in patients with mild or severe renal impairment. Exposure to LBQ657 in patients with moderate (30 mL/min/1.73 m2 ≤ eGFR < 60 mL/min/1.73 m2) and severe (15 mL/min/1.73 m2 ≤ eGFR < 30 mL/min/1.73 m2) impairment was 1.4- and 2.2-fold higher compared to patients with mild renal impairment (60 mL/min/1.73 m2 ≤ eGFR < 90 mL/min/1.73 m2), the largest patient group included in the PARADIGM-HF study. Exposure to valsartan was similar in patients with moderate and severe renal impairment compared to patients with mild impairment. Studies in patients undergoing hemodialysis have not been conducted. However, LBQ657 and valsartan are highly bound to plasma proteins, and therefore their removal during hemodialysis is unlikely.

Hepatic impairment. In patients with mild to moderate hepatic impairment, exposure to sacubitril was increased 1.5- and 3.4-fold, LBQ657 was increased 1.5- and 1.9-fold, and valsartan was increased 1.2- and 2.1-fold, respectively, compared to healthy volunteers. However, in patients with mild to moderate hepatic impairment, exposure to free concentrations of LBQ657 was increased 1.47- and 3.08-fold, respectively, and exposure to free concentrations of valsartan was increased 1.09- and 2.20-fold, respectively, compared to healthy volunteers. Euperior has not been studied in patients with severe hepatic impairment, biliary cirrhosis, or cholestasis (see sections 4.3 and 4.4).

Effect of gender: The pharmacokinetics of Euperio (sacubitril, LBQ657, and valsartan) were similar in men and women.

Indication

Treatment of chronic heart failure in adult patients with reduced left ventricular ejection fraction.

Contraindication

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use with ACE inhibitors (see sections “Special instructions for use” and “Interaction with other medicinal products and other types of interactions”). Euperio can be taken if at least 36 hours have passed since the ACE inhibitor was discontinued.

History of angioedema with ACE inhibitors or ARBs (see section "Special warnings and precautions for use").

Hereditary or idiopathic angioedema (see section "Special warnings and precautions for use").

Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR < 60 ml/min/1.73 m2) (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”).

Severe hepatic impairment, biliary cirrhosis and cholestasis (see section "Method of administration and dosage").

Second and third trimester of pregnancy (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions

Concomitant use is contraindicated.

ACE inhibitors. The concomitant use of Euperio with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE increases the risk of angioedema. Euperio therapy should be initiated no earlier than 36 hours after the last dose of an ACE inhibitor. ACE inhibitor therapy should be initiated no earlier than 36 hours after the last dose of Euperio (see sections “Method of administration and dosage” and “Contraindications”).

Aliskiren. The concomitant use of Euperior with aliskiren-containing products is contraindicated in patients with diabetes mellitus and in patients with renal impairment (eGFR < 60 ml/min/1.73 m2) (see section 4.3). The combination of Euperior with direct renin inhibitors such as aliskiren is not recommended (see section 4.4). The combination of Euperior with aliskiren is potentially associated with a higher frequency of adverse reactions such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) (see sections 4.4 and 4.4).

Concomitant use is undesirable.

Euperio contains valsartan and should not be used with other drugs containing ARBs (see section "Special warnings and precautions for use").

OATP1B1 and OATP1B3 substrates (HMG-CoA reductase inhibitors), such as statins. In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. As a result, Euperio may increase systemic exposure to OATP1B1 and OATP1B3 substrates, including statins. Co-administration of Euperio increased the Cmax of atorvastatin and its metabolites by 2-fold and the AUC by 1.3-fold. Therefore, caution should be exercised when Euperio is co-administered with statins.

Phosphodiesterase type 5 inhibitors, including sildenafil. In patients with severe hypertension receiving Euperio (until steady state is reached), single administration of sildenafil increased the antihypertensive effect compared to Euperio monotherapy. Therefore, sildenafil or another phosphodiesterase type 5 inhibitor should be used with caution in patients receiving Euperio.

Potassium. Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements or potassium-containing salt substitutes, other drugs (e.g. heparin) may lead to increases in serum potassium and serum creatinine. In patients receiving Euperio concomitantly with these drugs, regular monitoring of serum potassium is recommended (see section 4.4).

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors. In elderly patients, patients with hypovolemia (including those receiving diuretics), or patients with impaired renal function, the simultaneous use of Euperior and NSAIDs increases the risk of worsening renal function.

In patients receiving Euperio concomitantly with nonsteroidal anti-inflammatory drugs, it is recommended to monitor renal function (see section "Special warnings and precautions for use").

Lithium preparations. Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors or angiotensin II receptor antagonists. The possibility of drug interactions between Euperito and lithium preparations has not been studied. Therefore, the combination of these drugs is not recommended. If such a combination is necessary, careful monitoring of serum lithium levels is required. The risk of lithium toxicity may be increased when diuretics are used.

Furosemide. Co-administration of Uperio and furosemide did not affect the pharmacokinetics of Uperio, but reduced the Cmax and AUC of furosemide by 50% and 28%, respectively. While urine volume was not significantly altered, urinary sodium excretion was reduced at 4 and 24 hours after co-administration. The mean daily dose of furosemide was unchanged from baseline through the end of the PARADIGM-HF study in patients receiving Uperio.

Nitrates, such as nitroglycerin. No drug interaction has been observed between Euperior and nitroglycerin, which is administered intravenously to lower blood pressure. When nitroglycerin and Euperior were used together, the heart rate was reduced by 5 beats per minute compared to nitroglycerin alone. Similar effects on heart rate were observed when Euperior was taken with sublingual, oral or transdermal nitrates. In general, no dose adjustment is required.

OATP and MRP2 transporters. The active metabolite of sacubitril (LBQ657) and valsartan are substrates of OATP1B1, OATP1B3, OAT1 and OAT3; valsartan is also a substrate of MRP2. Therefore, concomitant use of Euperio with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, cyclosporine), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may result in increased systemic exposure to LBQ657 or valsartan. Caution should be exercised when initiating and discontinuing concomitant use of Euperio and these agents.

Metformin. Concomitant use of Euperior and metformin resulted in a 23% decrease in metformin Cmax and AUC. The clinical significance of these findings is unknown. Therefore, patients taking metformin should be evaluated for clinical status before initiating Euperior treatment.

Minor interactions.

Clinically significant drug interactions were not observed when using Euperior and digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or the combination of levonorgestrel/ethinyl estradiol.

CYP 450 Interactions: In vitro metabolism studies indicate that the potential for drug interactions mediated by cytochrome CYP 450 isoenzymes is extremely low, as the metabolism of Euperior by CYP450 enzymes is limited. Euperior does not induce or inhibit CYP450 enzymes.

Application features

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

The concomitant use of Euperio with direct renin inhibitors, in particular aliskiren, is not recommended (see section 4.5). The combination of Euperio with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 ml/min/1.73 m2) (see sections 4.3 and 4.5).

Euperito contains valsartan and should therefore not be used with other drugs containing ARBs (see sections “Method of administration and dosage” and “Interaction with other medicinal products and other types of interactions”).

Hypotension.

Treatment should not be initiated unless the systolic blood pressure is ≥ 100 mm Hg. Patients with systolic blood pressure < 100 mm Hg have not been studied (see section 5.1). Symptomatic hypotension has been reported in patients treated with Euperio in clinical trials (see section 4.8), particularly in patients ≥ 65 years of age, patients with renal disease, and patients with low systolic blood pressure (< 112 mm Hg). Blood pressure should be monitored routinely during initiation of therapy or during titration of Euperio. In the event of hypotension, it is recommended to temporarily reduce the dose or discontinue Euperio (see section 4.2). The need for dose adjustments of diuretics, concomitant antihypertensive agents, and other causes of hypotension (e.g., hypovolemia) should be considered. The likelihood of a pronounced decrease in blood pressure is generally higher in patients with hypovolemia, which may be caused by concomitant use of diuretics, adherence to a low-salt diet, the presence of diarrhea or vomiting. Low blood sodium and/or reduced circulating blood volume (BVC) should be corrected before starting therapy with Euperito, provided that this does not lead to a risk of BVC overload.

Kidney dysfunction

The assessment of renal function in patients with heart failure should always include assessment of renal function. Patients with mild to moderate renal impairment are at increased risk of hypotension (see section 4.2). There is very limited clinical experience in patients with severe renal impairment (eGFR < 30 ml/min/1.73 m2), who are at high risk of hypotension (see section 4.2). There is no experience with the use of Euperior in patients with end-stage renal disease and its use is not recommended.

Deterioration of kidney function.

The use of Euperior, as with any drug that acts on the RAAS, may lead to a deterioration in renal function. The risk is increased by dehydration or concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) (see section "Interaction with other medicinal products and other forms of interaction"). In case of clinically significant deterioration in renal function, a dose reduction of Euperior should be considered.

Hyperkalemia.

Treatment should not be initiated if serum potassium levels are > 5.4 mmol/l. Therapy with Euperior increases the risk of hyperkalaemia, and hypokalaemia may also occur (see section 4.8). Regular monitoring of serum potassium is recommended, especially in patients with risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism, or a diet high in potassium, or taking mineralocorticoid antagonists (see section 4.2). In the event of clinically significant hyperkalaemia, dose adjustment of concomitant medicinal products or temporary dose reduction or discontinuation of therapy is recommended. Discontinuation of therapy is recommended if serum potassium levels are > 5.4 mmol/l.

Angioedema.

Cases of angioedema have been reported with the use of Euperio. If angioedema occurs, Euperio should be discontinued immediately and appropriate treatment and monitoring should be instituted until all symptoms have resolved. The drug should not be re-administered. In cases of confirmed angioedema involving only the face and lips, this condition usually resolved spontaneously, although antihistamines have been shown to alleviate symptoms.

Angioedema with laryngeal oedema can be fatal. In cases where the oedema involves the tongue, glottis or larynx, which may lead to airway obstruction, appropriate treatment should be initiated immediately, e.g. administration of adrenaline 1 mg/1 ml (0.3-0.5 ml), and/or airway management should be ensured.

Patients with a history of angioedema have not been studied. Given that they are at high risk of developing angioedema, it is recommended that Euperio be prescribed to this category of patients with great caution. Euperio is contraindicated in patients with a history of angioedema associated with the use of an ACE inhibitor or ARB, or with hereditary or idiopathic angioedema (see section "Contraindications").

Patients of the Negroid race are more prone to developing angioedema (see section "Adverse reactions").

Euperior may cause an increase in serum urea and creatinine concentrations in patients with unilateral or bilateral renal artery stenosis. The drug should be used with caution in patients with renal artery stenosis, with regular monitoring of renal function.

Patients with chronic heart failure of NYHA functional class IV.

Caution should be exercised when administering Euperito to patients with chronic heart failure of NYHA functional class IV, as clinical data on this category of patients are limited.

B-type natriuretic peptide (BNP).

BNP is not a suitable biomarker for heart failure in patients treated with Euperior, as it is a substrate of neprilysin (see section 5.1).

Patients with liver failure.

Clinical experience in patients with moderate hepatic impairment (Child-Pugh class B) or with aspartate aminotransferase/alanine aminotransferase (AST/ALT) values exceeding two times the upper limit of normal is limited. Patients in this category are more sensitive to the effects of the drug, and the degree of safety for them has not been established. As a result, caution should be exercised when prescribing the drug to such patients (see sections “Dosage and administration” and “Pharmacokinetics”). Euperior is contraindicated in patients with severe hepatic impairment (Child-Pugh class C), biliary cirrhosis or cholestasis (see section “Contraindications”).

Use during pregnancy or breastfeeding

Pregnancy.

It is not recommended to use Euperio during the first trimester of pregnancy. The drug is contraindicated for use during the second and third trimesters of pregnancy (see section "Contraindications").

Valsartan. Epidemiological evidence regarding the risk of teratogenicity due to exposure to ACE inhibitors during the first trimester of pregnancy is not conclusive; however, some increase in this risk cannot be excluded. Although there are no controlled epidemiological data on teratogenicity associated with ARBs, similar risks may exist with this class of medicinal products. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. ARB therapy should be stopped as soon as pregnancy is diagnosed, and, if appropriate, alternative therapy should be started. ARB therapy during the second and third trimesters is known to induce fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

If ARBs have been used from the second trimester of pregnancy, ultrasound examination of the kidneys and skull is recommended. Newborns whose mothers have taken ARBs should be closely monitored for the development of hypotension (see section 4.3).

Sacubitril: There are no data from the use of sacubitril in pregnant women. Animal studies have shown reproductive toxicity.

Euperior. There are no data on the use of Euperior in pregnant women. Animal studies with Euperior have shown reproductive toxicity.

Breastfeeding.

It is not known whether Euperio is excreted in human milk. The components of Euperio, sacubitril and valsartan, were excreted in the milk of lactating rats. Given the potential risk of adverse reactions in breast-fed infants, the use of the drug during breastfeeding is not recommended.

Reproductive function.

There are no data on the effect of Euperio on human reproductive function. During studies of the drug on male and female rats, reproductive function disorders were found.

Ability to influence reaction speed when driving vehicles or other mechanisms

Due to the possible occurrence of dizziness and