Uperio

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT UPERIO (UPERIO®)

Composition:

Active substances: sacubitril and valsartan;

One 50 mg tablet contains: 24.3 mg of sacubitril and 25.7 mg of valsartan (as a complex of sodium 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).

One 100 mg tablet contains: 48.6 mg of sacubitril and 51.4 mg of valsartan (as a complex of sodium 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).

One 200 mg tablet contains: 97.2 mg of sacubitril and 102.8 mg of valsartan (as a complex of sodium 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).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Uperio, 50 mg: oval, biconvex film-coated tablets, from almost white to white with a violet tint, with beveled edges, without a break line, marked with "NVR" on one side and "LZ" on the other.

Uperio, 100 mg: oval, biconvex film-coated tablets of light yellow color, with beveled edges, without a break line, marked with "NVR" on one side and "L1" on the other.

Uperio, 200 mg: oval, biconvex film-coated tablets of light pink color, with beveled edges, without a break line, marked with "NVR" on one side and "L11" on the other.

Pharmacotherapeutic group. Medicinal products affecting the renin-angiotensin system. Angiotensin II antagonists, other combinations.

ATC code C09DX04.

Pharmacological properties.

Pharmacodynamics.

The pharmacodynamic effects of sacubitril and valsartan were evaluated after single and multiple doses of the medicinal product in healthy volunteers and in patients with chronic heart failure. The observed effects were consistent with the mechanism of action of the active substance combination, which involves simultaneous inhibition of neprilysin and blockade of the renin-angiotensin-aldosterone system (RAAS). In a 7-day study involving patients with reduced left ventricular ejection fraction (LVEF), in which valsartan was used as control, treatment with sacubitril and valsartan resulted in a statistically significant short-term increase in natriuresis, increased urinary cyclic guanosine monophosphate (cGMP) concentration, and decreased plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), compared to valsartan. In a 21-day study in patients with reduced LVEF, treatment with sacubitril and valsartan led to a statistically significant increase in urinary concentrations of atrial natriuretic peptide (ANP) and cGMP, as well as increased plasma cGMP concentration, and reductions in plasma concentrations of NT-proBNP, aldosterone, and endothelin-1 (compared to baseline). Additionally, treatment with sacubitril and valsartan blocks the AT1 receptor, as evidenced by increased plasma renin activity and concentration. In the PARADIGM-HF trial, the sacubitril/valsartan combination caused a greater reduction in plasma NT-proBNP concentration and a more pronounced increase in urinary brain natriuretic peptide (BNP) and cGMP concentrations compared to enalapril. While BNP is a substrate for neprilysin, NT-proBNP is not. Therefore, unlike BNP, NT-proBNP can be used as a biomarker for monitoring patients with heart failure receiving sacubitril/valsartan (see section "Special instructions").

In a QTc interval study in healthy male volunteers, single-dose administration of Yuperio 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 Yuperio at a dose of 194 mg sacubitril/206 mg valsartan once daily for two weeks in healthy volunteers, the concentration of Aβ 1-38 in cerebrospinal fluid increased, while concentrations of Aβ 1-40 and Aβ 1-42 in CSF remained unchanged. The clinical significance of this finding is unknown.

Clinical efficacy and safety

The dosages of 50 mg, 100 mg, or 200 mg of the medicinal product are indicated in some sources as 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg of the medicinal product, respectively.

PARADIGM-HF

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

Prior to enrollment, patients were receiving standard heart failure therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE inhibitors/ARBs) (>99%), beta-blockers (94%), mineralocorticoid receptor antagonists (58%), and diuretics (82%). The mean duration of follow-up was 27 months, with patients receiving treatment for up to 4.3 years.

Patients were required to discontinue ACE inhibitors or ARBs, followed by a sequential, single-blind run-in period during which they received enalapril 10 mg twice daily, then single-blind treatment with Yuperio 100 mg twice daily, up-titrated to 200 mg twice daily (see section "Adverse reactions" regarding discontinuation during this period). Subsequently, they were randomized into the double-blind treatment period, receiving either Yuperio 200 mg twice daily or enalapril 10 mg twice daily (Yuperio: n = 4,209; enalapril: n = 4,233).

The mean age of the study population was 64 years, with 19% aged ≥75 years. At randomization, 70% of patients had NYHA class II chronic 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 Yuperio group, 76% of patients remained on the target dose of 200 mg twice daily until 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 until the end of the study (mean daily dose: 18.9 mg).

Yuperio significantly reduced the risk of cardiovascular death or hospitalization due to heart failure compared to enalapril (21.8% in the investigational drug group vs. 26.5% in the enalapril group). The absolute risk reduction for cardiovascular death or hospitalization due to heart failure was 4.7% (3.1% reduction in risk of cardiovascular death and 2.8% reduction in risk of first hospitalization due to heart failure). The relative risk reduction compared to enalapril was 20%. The effect was evident early in treatment and persisted throughout the study period. Both active components of the medicinal product contributed to the observed benefit. The incidence of sudden death, which accounted for 45% of all cardiovascular deaths, was reduced by 20% in the investigational drug group compared to the enalapril group (hazard ratio [HR] 0.80, p = 0.0082). The incidence of heart failure death, which accounted for 26% of cardiovascular deaths, was reduced by 21% in the investigational drug group compared to the enalapril group (HR 0.79, p = 0.0338).

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

Yuperio improved survival, with a significant 2.8% reduction in all-cause mortality (Yuperio: 17%, enalapril: 19.8%). The relative risk reduction was 16% compared to enalapril (see Table 1).

Table 1. Treatment effect based on the primary composite endpoint, its components, and all-cause mortality over a mean follow-up duration of 27 months.

Parameters	Entresto N = 4187* n (%)	Enalapril N = 4212* n (%)	Risk ratio (95 % Cl)	Relative risk reduction	p-value ***
Composite endpoint of cardiovascular death and hospitalization for heart failure*	914 (21.83)	1117 (26.52)	0.80 (0.73, 0.87)	20 %	0.0000002
Individual components of the primary composite endpoint
Cardiovascular death**	558 (13.33)	693 (16.45)	0.80 (0.71, 0.89)	20 %	0.00004
First hospitalization for heart failure	537 (12.83)	658 (15.62)	0.79 (0.71, 0.89)	21 %	0.00004
Secondary endpoints
Total mortality	711 (16.98)	835 (19.82)	0.84 (0.76, 0.93) 0.0005	16 %	0.0005

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

** The term "cardiovascular death" includes all fatal events up to the data cutoff date regardless of prior hospitalization of the patient.

*** One-sided p-value.

TITRATION STUDY

TITRATION was a 12-week safety and tolerability study involving 538 patients with chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction < 35%) who had either not previously received ACE inhibitors or ARBs, or had received ACE inhibitors or ARBs at various doses prior to enrollment. Patients initially received sacubitril/valsartan 50 mg twice daily, then the dose was increased to 100 mg twice daily, followed by a target dose of 200 mg twice daily over a 3- or 6-week period.

A higher proportion of patients who had not previously received ACE inhibitors or ARBs or who had received low-dose therapy (equivalent to < 10 mg enalapril/day) achieved the sacubitril/valsartan dose of 200 mg and remained at this level when dose escalation occurred over 6 weeks (84.8%) compared to 3 weeks (73.6%). Overall, 76% of patients reached the target dose of sacubitril/valsartan 200 mg twice daily and remained on this dose without interruption or dose reduction over 12 weeks.

Children

The European Medicines Agency has deferred the obligation to submit the results of studies with one or more pediatric populations with heart failure.

Mechanism of Action

Sacubitril/valsartan demonstrates a dual mechanism of action as a neprilysin inhibitor and angiotensin receptor blocker by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657—the active metabolite of sacubitril—and blocking angiotensin II type 1 (AT1) receptors via valsartan. The additional beneficial cardiovascular effects of sacubitril/valsartan in patients with heart failure are attributed to LBQ657 enhancing peptides degraded by neprilysin, particularly natriuretic peptides (NPs), while valsartan suppresses the negative effects of angiotensin II. NPs exert their effects by activating membrane-bound receptors coupled to guanylyl cyclase, leading to increased intracellular cyclic guanosine monophosphate (cGMP) levels, resulting in vasodilation, increased natriuresis and diuresis, enhanced glomerular filtration rate and renal blood flow, suppression of renin and aldosterone release, reduced sympathetic activity, and exerting anti-hypertrophic and anti-fibrotic effects.

Valsartan, by selectively blocking AT1 receptors, inhibits the adverse effects of angiotensin II on the cardiovascular system and kidneys, and also blocks angiotensin II-dependent aldosterone release. This prevents sustained activation of the renin-angiotensin-aldosterone system (RAAS), which causes vasoconstriction, renal sodium and water retention, cellular growth stimulation, proliferation, and may lead to cardiovascular dysfunction.

Pharmacokinetics

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

Absorption

After oral administration, sacubitril/valsartan dissociates into valsartan and sacubitril, a prodrug. Sacubitril is further metabolized to the active metabolite LBQ657. Peak plasma concentrations of these substances are reached at 2 hours, 1 hour, and 2 hours, respectively. Absolute bioavailability of sacubitril and valsartan exceeds 60% and 23%, respectively.

At steady state following twice-daily administration of sacubitril/valsartan, equilibrium concentrations of sacubitril, LBQ657, and valsartan are achieved within three days. There is no statistically significant accumulation of sacubitril and valsartan at steady state; however, accumulation of LBQ657 exceeds that after single-dose administration by a factor of 1.6. Food intake does not clinically significantly alter systemic exposure to sacubitril, LBQ657, or valsartan. Sacubitril/valsartan can be administered regardless of food intake.

Distribution

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

Metabolism

Sacubitril is rapidly converted to LBQ657 by carboxylesterase 1b and 1c; LBQ657 is subsequently not significantly metabolized. Valsartan is minimally metabolized, with only about 20% of the administered dose recovered as metabolites. A hydroxylated metabolite is detected in plasma at low concentrations (< 10%).

Since both sacubitril and valsartan are minimally metabolized by cytochrome P450 isoenzymes, changes in their pharmacokinetics when co-administered with drugs affecting CYP450 isoenzymes are unlikely.

In vitro metabolism studies indicate a very low potential for drug interactions mediated by cytochrome CYP450 isoenzymes, as the metabolism of sacubitril/valsartan via CYP450 enzymes is limited. Sacubitril/valsartan does not induce or inhibit CYP450 enzymes.

Elimination

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

Sacubitril, LBQ657, and valsartan are eliminated from plasma with mean elimination half-lives (T_1/2) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.

Linearity/Non-linearity

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

Pharmacokinetics in Specific Patient Populations

Elderly Patients. Exposure to LBQ657 and valsartan in patients over 65 years of age is 42% and 30% higher, respectively, than in younger patients.

Renal Impairment. A correlation was observed 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) renal impairment was 1.4 and 2.2 times higher, respectively, compared to patients with mild renal impairment (60 mL/min/1.73 m² ≤ eGFR < 90 mL/min/1.73 m²)—the largest patient group in the PARADIGM-HF trial. Exposure to valsartan was similar in patients with moderate and severe renal impairment compared to those with mild impairment. Studies in patients on hemodialysis have not been conducted. However, since LBQ657 and valsartan are highly protein-bound, their removal during hemodialysis is unlikely.

Hepatic Impairment. In patients with mild and moderate hepatic impairment, exposure to sacubitril increased by 1.5 and 3.4 times, LBQ657 by 1.5 and 1.9 times, and valsartan by 1.2 and 2.1 times, respectively, compared to healthy volunteers. However, in patients with mild or moderate hepatic impairment, exposure to free (unbound) concentrations of LBQ657 increased by 1.47 and 3.08 times, respectively, and exposure to free concentrations of valsartan increased by 1.09 and 2.20 times, respectively, compared to healthy volunteers. Sacubitril/valsartan has not been studied in patients with severe hepatic impairment, biliary cirrhosis, or cholestasis (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Effect of Gender. The pharmacokinetics of sacubitril/valsartan (sacubitril, LBQ657, and valsartan) are similar in men and women.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Concomitant use with ACE inhibitors (see sections «Special precautions» and «Interaction with other medicinal products and other forms of interaction»). YUPELIO may be administered if at least 36 hours have elapsed since the last dose of an ACE inhibitor.
• History of angioedema associated with previous use of ACE inhibitors or ARBs (see section «Special precautions»).
• Hereditary or idiopathic angioedema (see section «Special precautions»).
• Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or in patients with renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections «Special precautions» and «Interaction with other medicinal products and other forms of interaction»).
• Severe hepatic impairment, biliary cirrhosis, and cholestasis (see section «Dosage and administration»).
• Pregnancy or planned pregnancy (see section «Use during pregnancy or breastfeeding»).

Interaction with other medicinal products and other forms of interaction.

Concomitant use is contraindicated

ACE inhibitors. Concomitant use of YUPELIO with ACE inhibitors is contraindicated, as dual inhibition of neprilysin (NEP) and ACE increases the risk of angioedema. Initiation of YUPELIO therapy must not occur earlier than 36 hours after the last dose of an ACE inhibitor. Initiation of ACE inhibitor therapy must not occur earlier than 36 hours after the last dose of YUPELIO (see sections «Dosage and administration» and «Contraindications»).

Aliskiren. Concomitant use of YUPELIO with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus and in patients with renal impairment (eGFR < 60 mL/min/1.73 m²) (see section «Contraindications»). Combination of YUPELIO with direct renin inhibitors such as aliskiren is not recommended (see section «Special precautions»). The combination of YUPELIO and aliskiren may potentially be associated with a higher incidence of adverse reactions such as hypotension, hyperkalaemia, and impaired renal function (including acute renal failure) (see sections «Contraindications» and «Special precautions»).

Concomitant use not recommended

YUPELIO contains valsartan; therefore, it should not be used concomitantly with other medicinal products containing ARBs (see section «Special precautions»).

Concomitant use requires precautions

OATP1B1 and OATP1B3 substrates (HMG-CoA reductase inhibitors), e.g., statins. In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Consequently, YUPELIO may increase systemic exposure to substrates of OATP1B1 and OATP1B3, particularly statins. Concomitant administration of YUPELIO increased Cmax of atorvastatin and its metabolites by 2-fold and AUC by 1.3-fold. Therefore, caution should be exercised when administering YUPELIO concomitantly with statins. No clinically significant interaction was observed with concomitant use of simvastatin and YUPELIO.

Phosphodiesterase-5 inhibitors, including sildenafil. In patients with marked elevation of arterial pressure (BP) receiving YUPELIO (at steady-state), single-dose administration of sildenafil enhanced the antihypertensive effect compared to YUPELIO monotherapy. For this reason, sildenafil or other phosphodiesterase-5 inhibitors should be used with caution in patients receiving YUPELIO.

Potassium. Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone), potassium supplements, potassium-containing salt substitutes, or other drugs (e.g., heparin) may lead to increased serum potassium levels and serum creatinine levels. In patients receiving YUPELIO concomitantly with these agents, regular monitoring of serum potassium levels is recommended (see section «Special precautions»).

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, concomitant use of YUPELIO and NSAIDs increases the risk of worsening renal function.

In patients receiving YUPELIO concomitantly with NSAIDs, monitoring of renal function is recommended (see section «Special precautions»).

Lithium preparations. Reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors or angiotensin II receptor antagonists, including YUPELIO. Therefore, combination of these drugs is not recommended. If such combination is necessary, careful monitoring of serum lithium levels is required. The risk of lithium toxicity may increase if diuretics are also used.

Furosemide. Concomitant use of YUPELIO and furosemide does not affect the pharmacokinetics of YUPELIO, but reduces Cmax and AUC of furosemide by 50% and 28%, respectively. While urine volume is not significantly altered, urinary sodium excretion was reduced over 4 and 24 hours after concomitant administration. The mean daily dose of furosemide did not change compared to baseline dose by the end of the PARADIGM-HF study in patients receiving YUPELIO.

Nitrates, e.g., nitroglycerin. No drug interaction between YUPELIO and intravenous nitroglycerin for blood pressure reduction has been observed. When nitroglycerin and YUPELIO were used concomitantly, heart rate differed by 5 beats per minute compared to nitroglycerin monotherapy. A similar effect on heart rate was observed when YUPELIO was administered with sublingual, oral, or transdermal nitrates. In general, dose adjustment is not 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 YUPELIO with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g., rifampicin, cyclosporine), OAT1 (e.g., tenofovir, cidofovir), or MRP2 (e.g., ritonavir) may lead to increased systemic exposure to LBQ657 or valsartan. Caution should be exercised when initiating or discontinuing concomitant use of YUPELIO with these agents.

Metformin. Concomitant use of YUPELIO and metformin resulted in a 23% reduction in Cmax and AUC of metformin. The clinical significance of these findings is unknown. Therefore, the clinical status of patients receiving metformin should be evaluated before initiating YUPELIO.

Minor interactions

Clinically significant drug interactions were not observed during concomitant use of YUPELIO with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol, or the combination of levonorgestrel/ethinylestradiol.

Special precautions for use.

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

Combination of Entresto with ACE inhibitors is contraindicated due to increased risk of angioedema (see section "Contraindications"). Entresto must not be taken until at least 36 hours have passed since the last dose of an ACE inhibitor. After discontinuation of Entresto, ACE inhibitors should not be initiated earlier than 36 hours after the last dose of Entresto (see sections "Dosage and administration", "Contraindications", and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of Entresto with direct renin inhibitors, particularly aliskiren, is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). The combination of Entresto with medicinal products containing aliskiren is contraindicated in patients with diabetes or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Entresto contains valsartan; therefore, it should not be used concomitantly with other medicinal products containing ARBs (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

Hypotension

Treatment should not be initiated if systolic blood pressure (SBP) is < 100 mm Hg. Patients with SBP < 100 mm Hg have not been studied (see section "Pharmacodynamics"). Cases of symptomatic hypotension have been reported in patients receiving Entresto during clinical trials (see section "Adverse reactions"), particularly in patients aged ≥ 65 years, patients with kidney disease, and patients with low SBP (< 112 mm Hg). Blood pressure should be monitored routinely at the beginning of therapy or during dose titration of Entresto. In case of hypotension, temporary dose reduction or discontinuation of Entresto is recommended (see section "Dosage and administration"). Consideration should be given to adjusting the dose of diuretics and concomitant antihypertensive agents, as well as to other potential causes of hypotension (e.g., hypovolemia). The likelihood of pronounced hypotension is generally higher in patients with existing hypovolemia, which may be caused by concomitant use of diuretics, adherence to a low-salt diet, or conditions such as diarrhea or vomiting. Low serum sodium levels and/or reduced circulating blood volume (CBV) should be corrected prior to initiating Entresto, provided this does not lead to risk of excessive CBV.

Renal impairment

Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild to moderate renal impairment are at increased risk of developing hypotension (see section "Dosage and administration"). Clinical experience with use of the medicinal product in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) is extremely limited, and these patients are at high risk of hypotension (see section "Dosage and administration"). There is no experience with use of Entresto in patients with end-stage renal disease; use in such patients is not recommended.

Worsening renal function

Use of Entresto, as with any other agent acting on the RAAS, may lead to deterioration of renal function. Risk is increased in the presence of 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 worsening of renal function, consideration should be given to reducing the dose of Entresto.

Hyperkalemia

Treatment should not be initiated if serum potassium level is > 5.4 mmol/L. Therapy with Entresto increases the risk of hyperkalemia, although hypokalemia may also occur (see section "Adverse reactions"). Regular monitoring of serum potassium levels is recommended, particularly in patients with risk factors such as renal impairment, diabetes mellitus, hypoaldosteronism, high-potassium diet, or use of mineralocorticoid receptor antagonists (see section "Dosage and administration"). In case of clinically significant hyperkalemia, adjustment of concomitant medications, temporary dose reduction, or discontinuation of therapy is recommended. Discontinuation of therapy is recommended if serum potassium exceeds 5.4 mmol/L.

Angioedema

Cases of angioedema have been reported during treatment with Entresto. If angioedema occurs, Entresto should be discontinued immediately, and appropriate treatment and monitoring should be initiated until complete and sustained resolution of symptoms. Re-administration of the medicinal product is not recommended. In cases of confirmed angioedema limited to the face and lips, the condition usually resolves spontaneously, although antihistamines may help alleviate symptoms.

Angioedema associated with laryngeal edema may be fatal. In cases where swelling involves the tongue, vocal cords, or larynx, potentially leading to airway obstruction, immediate appropriate treatment is required, such as administration of epinephrine solution 1 mg/mL (0.3–0.5 mL), and/or securing airway patency.

Patients with a history of angioedema have not been studied. Because such patients are at high risk of developing angioedema, Entresto should be prescribed to this patient group with extreme caution. Entresto is contraindicated in patients with a history of angioedema during treatment with an ACE inhibitor or ARB, or with hereditary or idiopathic angioedema (see section "Contraindications").

Patients of African descent are at increased risk of developing angioedema (see section "Adverse reactions").

Patients with renal artery stenosis

Entresto may increase serum urea and creatinine concentrations in patients with unilateral or bilateral renal artery stenosis. The medicinal product should be used with caution in patients with renal artery stenosis, with regular monitoring of renal function.

Patients with NYHA class IV chronic heart failure

Caution is required when using Entresto in patients with NYHA class IV chronic heart failure, as clinical data in this patient group are limited.

B-type natriuretic peptide (BNP)

BNP is not a reliable biomarker of heart failure in patients receiving Entresto, as it is a substrate of neprilysin (see section "Pharmacodynamics").

Patients with hepatic impairment

Clinical experience with use of the medicinal product in patients with moderate hepatic impairment (Child-Pugh class B) or with aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels more than twice the upper limit of normal is limited. These patients may be more sensitive to the effects of the medicinal product, and safety has not been established. Therefore, the medicinal product should be used with caution in such patients (see sections "Dosage and administration" and "Pharmacokinetics"). Entresto is contraindicated in patients with severe hepatic impairment (Child-Pugh class C), biliary cirrhosis, or cholestasis (see section "Contraindications").

Psychiatric disorders

Psychiatric disorders such as hallucinations, paranoia, and sleep disturbances have been observed during treatment with sacubitril/valsartan and were considered related to the medicinal product. If such events occur, discontinuation of sacubitril/valsartan therapy should be considered.

Use during pregnancy or breastfeeding

Pregnancy

The medicinal product should not be used during pregnancy or in women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, therapy should be discontinued immediately and replaced with another medicinal product approved for use during pregnancy.

Valsartan. Epidemiological evidence regarding teratogenic risk associated with ACE inhibitors during the first trimester of pregnancy is inconclusive; however, a certain increase in risk cannot be excluded. Although there are no controlled epidemiological data on teratogenicity associated with ARBs, similar risks may exist with use of this class of medicinal products. Unless continued ARB therapy is required, women planning pregnancy should be switched to alternative antihypertensive agents with a well-established safety profile during pregnancy. ARB therapy should be discontinued as soon as pregnancy is confirmed, and alternative therapy should be initiated if necessary. It is known that ARB therapy during the second and third trimesters may cause fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If ARBs have been used during the second trimester of pregnancy, ultrasound examination of fetal kidneys and skull bone development is recommended. Newborns whose mothers received ARBs should be closely monitored for the development of hypotension (see section "Contraindications").

Sacubitril. Data on use of sacubitril in pregnant women are lacking. Animal studies have shown reproductive toxicity.

Entresto. Data on use of Entresto in pregnant women are lacking. Animal studies with Entresto have shown reproductive toxicity.

Breastfeeding

It is unknown whether Entresto is excreted in human breast milk. Components of Entresto – sacubitril and valsartan – were excreted in milk in lactating rats. Due to the potential risk of adverse reactions in breastfed infants, use of the medicinal product during breastfeeding is not recommended.

Fertility

Data on the effect of Entresto on human fertility are lacking. During studies in male and female rats, reproductive function impairments were observed.

Ability to influence reaction speed when driving or operating machinery

Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.

Method of Administration and Dosage

The medicinal product is intended for oral administration. The time of administration of Uptril does not depend on food intake (see section "Pharmacokinetics"). Tablets should be swallowed whole with a glass of water.

Dosage

The recommended initial dose of Uptril is one 100 mg tablet twice daily, except in the situations described below. The dose should be doubled after 2–4 weeks of treatment, so that the dose becomes one 200 mg tablet twice daily, provided the patient tolerates it well.

If patients develop intolerance (systolic blood pressure (SBP) ≤ 95 mm Hg, symptomatic hypotension, hyperkalemia, or renal impairment), it is recommended to adjust concomitant therapy, temporarily reduce the dose, or discontinue Uptril treatment (see section "Special Warnings and Precautions for Use").

Information on treatment of patients who are not taking ACE inhibitors or ARBs, or who are taking them at low doses, is limited. Therefore, for this category of patients, the recommended initial dose is 50 mg twice daily, with gradual dose escalation (doubling the daily dose once every 3–4 weeks).

Initiating treatment is not recommended in patients with serum potassium levels > 5.4 mmol/L or SBP < 100 mm Hg (see section "Special Warnings and Precautions for Use"). An initial dose of 50 mg twice daily is recommended for patients with SBP ≥ 100–110 mm Hg. Uptril should not be used concomitantly with an ACE inhibitor or ARB. Due to the potential risk of angioedema with concomitant use of an ACE inhibitor, Uptril should not be initiated unless at least 36 hours have passed since discontinuation of the ACE inhibitor.

The valsartan complex salt contained in Uptril has higher bioavailability compared to valsartan contained in other tablet formulations (see section "Pharmacokinetics").

If a patient misses a dose, they should take the next dose at the scheduled time. Tablets should not be split or crushed.

Dosage in Specific Patient Populations

Elderly Patients

Dosage should be determined based on renal function in elderly patients.

Patients with Renal Impairment

No dose adjustment is required in patients with mild renal impairment (estimated glomerular filtration rate (eGFR) 60–90 mL/min/1.73 m²). An initial dose of 50 mg twice daily is recommended for patients with moderate renal impairment (eGFR 30–60 mL/min/1.73 m²). Due to limited clinical experience with use in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) (see section "Pharmacodynamics"), Uptril should be prescribed with caution at an initial dose of 50 mg twice daily. There is no experience with the use of Uptril in patients with end-stage renal disease, and administration in such cases is not recommended.

Patients with Hepatic Impairment

No dose adjustment of Uptril is required in patients with mild hepatic impairment (Child–Pugh class A). Clinical experience in patients with moderate hepatic impairment (Child–Pugh class B) or with AST/ALT levels two times above the upper limit of normal is limited. Uptril should be used with caution in these patients; the recommended initial dose is 50 mg twice daily (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Uptril is contraindicated in patients with severe hepatic impairment, biliary cirrhosis, or cholestasis (Child–Pugh class C) (see section "Contraindications").

Children

Safety and efficacy of Uptril in children (under 18 years of age) have not been established. Data are lacking.

Overdose

There is insufficient data on overdose of Uptril in humans.

Single doses of Uptril up to 1200 mg and multiple doses up to 900 mg were well tolerated in healthy volunteers.

The most likely manifestation of overdose is pronounced hypotension due to the antihypertensive effect of the active substances. In such cases, symptomatic treatment is recommended. Hemodialysis is unlikely to remove the drug due to its high plasma protein binding.

Adverse reactions

During treatment with YUPRIO, the most commonly reported adverse reactions were hypotension (17.6%), hyperkalaemia (11.6%), and renal dysfunction (10.1%) (see section "Special precautions"). There have been reports of angioedema (0.5%) in patients taking YUPRIO (see "Description of selected adverse reactions").

The safety of YUPRIO in patients with chronic heart failure was evaluated in the pivotal phase III PARADIGM-HF study, in which patients received YUPRIO 200 mg twice daily (n = 4,203) or enalapril 10 mg once daily (n = 4,229). Patients randomized to the YUPRIO group received treatment for up to 24 months; 3,271 patients received therapy for more than one year.

In the PARADIGM-HF study, patients who had previously received ACE inhibitors and/or ARBs were given enalapril and YUPRIO (median duration of exposure 15 and 29 days, respectively) during a run-in phase prior to the randomized double-blind period. During the enalapril run-in phase, 1,102 patients (10.5%) were permanently discontinued from the study: 5.6% due to adverse reactions, most commonly renal dysfunction (1.7%), hyperkalaemia (1.7%), and hypotension (1.4%). During the YUPRIO run-in phase, 10.4% of patients were permanently discontinued: 5.9% due to adverse reactions, most commonly renal dysfunction (1.8%), hypotension (1.7%), and hyperkalaemia (1.3%). Considering discontinuations during the initial run-in phase, the adverse reaction frequencies presented in Table 2 below may be lower than those expected in clinical practice.

During the double-blind period of the PARADIGM-HF study, treatment was discontinued due to adverse reactions in 450 patients receiving YUPRIO (10.7%) and in 516 patients receiving enalapril (12.2%).

Adverse reactions are classified by organ system and frequency (in descending order): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency category, adverse effects are listed in order of decreasing severity.

Table 2. List of adverse reactions

System organ	Adverse reactions	Frequency category
Blood and lymphatic system	Anaemia	Common
Immune system	Hypersensitivity	Uncommon
Metabolism and nutrition	Hyperkalaemia*	Very common
	Hypokalaemia	Common
	Hypoglycaemia	Common
	Hyponatraemia	Uncommon
Nervous system	Dizziness	Common
	Headache	Common
	Syncope	Common
	Postural dizziness	Uncommon
Ear and labyrinthine disorders	Vertigo	Common
Vascular	Hypotension*	Very common
	Orthostatic hypotension	Common
Respiratory, thoracic and mediastinal	Cough	Common
Gastrointestinal	Diarrhoea	Common
	Nausea	Common
	Gastritis	Common
Skin and subcutaneous tissue	Pruritus	Uncommon
	Rash	Uncommon
	Angioneurotic oedema*	Uncommon
Renal and urinary	Renal dysfunction*	Very common
	Renal failure (including acute renal failure)	Common
General disorders	Fatigue	Common
	Asthenia	Common
Psychiatric disorders	Hallucinations**	Rare
	Sleep disorders	Rare
	Paranoia	Very rare

* See below "Description of selected adverse reactions".

** Including auditory and visual hallucinations

Description of selected adverse reactions

Angioedema

Angioedema has been reported in patients taking Entresto. In the PARADIGM-HF study, angioedema occurred in 0.5% of patients receiving Entresto compared to 0.2% of patients receiving enalapril. A higher incidence of angioedema was observed in black patients receiving Entresto (2.4%) and enalapril (0.5%) (see section "Special precautions for use").

Hyperkalemia and serum potassium

During the PARADIGM-HF study, hyperkalemia and serum potassium concentrations > 5.4 mmol/L were observed in 11.6% and 19.7% of patients receiving Entresto, and in 14.0% and 21.1% of patients receiving enalapril, respectively.

Blood pressure

During the PARADIGM-HF study, hypotension and clinically significant low systolic blood pressure (< 90 mm Hg and a decrease from baseline > 20 mm Hg) were reported in 17.6% and 4.76% of patients receiving Entresto, and in 11.9% and 2.67% of patients receiving enalapril, respectively.

Renal function impairment

During PARADIGM-HF, renal function impairment developed in 10.1% of patients receiving Entresto and in 11.5% of patients receiving enalapril.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging. 14 tablets per blister; 2 or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Novartis Farma S.p.A./Novartis Farma S.p.A.
2. Lek Pharmaceuticals d.d./Lek Pharmaceuticals d.d.

Manufacturer's address and site of operations.

1. Via Provinciale Schito 131, 80058 Torre Annunziata (NA), Italy / Via Provinciale Schito 131, 80058 Torre Annunziata (NA), Italy.

2. Trimlini 2d, Lendava/lendva, 9220, Slovenia / Trimlini 2d, Lendava/lendva, 9220, Slovenia.