Corsaval

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CORSAVAL (CORSAVAL)

Composition:

Active substances: sacubitril (sacubitril) and valsartan (valsartan);

1 tablet 50 mg contains sacubitril sodium, equivalent to sacubitril 24 mg, and valsartan disodium, equivalent to valsartan 26 mg;

Excipients: microcrystalline cellulose, hydroxypropylcellulose, crospovidone, talc, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: Opadry II 85F18422 white (polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), macrogol 4000, talc).

1 tablet 100 mg contains sacubitril sodium, equivalent to sacubitril 49 mg, and valsartan disodium, equivalent to valsartan 51 mg;

Excipients: microcrystalline cellulose, hydroxypropylcellulose, crospovidone, talc, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: Opadry II 85F240088 pink (polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), macrogol 4000, talc, iron oxide red (E 172), iron oxide yellow (E 172)).

1 tablet 200 mg contains sacubitril sodium, equivalent to sacubitril 97 mg, and valsartan disodium, equivalent to valsartan 103 mg;

Excipients: microcrystalline cellulose, hydroxypropylcellulose, crospovidone, talc, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating: Opadry II 85F240088 pink (polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E 171), macrogol 4000, talc, iron oxide red (E 172), iron oxide yellow (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

CorSaval 50 mg: oval, biconvex film-coated tablets of white color, with imprint «S7V» on one side and «L1» on the other.

CorSaval 100 mg: oval, biconvex film-coated tablets of pink color, with imprint «S7V» on one side and «M2» on the other.

CorSaval 200 mg: oval, biconvex film-coated tablets of pink color, with imprint «S7V» on one side and «H3» on the other.

Pharmacotherapeutic group. Medicinal products affecting the renin-angiotensin system. Angiotensin II antagonists, other combinations. ATC code C09DX04.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

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

Valsartan, by selectively blocking AT1 receptors, inhibits the detrimental 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, stimulation of cell growth and proliferation, and may lead to impaired cardiovascular function.

Pharmacodynamic effects of sacubitril and valsartan were evaluated after single and multiple doses in healthy volunteers and in patients with chronic heart failure. Observed effects were consistent with the dual mechanism of action involving simultaneous neprilysin inhibition and RAAS blockade. In a 7-day study in patients with reduced left ventricular ejection fraction (LVEF), where valsartan was used as control, treatment with sacubitril/valsartan resulted in a statistically significant, short-term increase in natriuresis, increased urinary cGMP concentration, and reduced plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), compared to valsartan. In a 21-day study in patients with reduced LVEF, sacubitril/valsartan treatment led to statistically significant increases in urinary concentrations of atrial natriuretic peptide (ANP) and cGMP, as well as plasma cGMP levels, along with reductions in plasma concentrations of NT-proBNP, aldosterone, and endothelin-1 (compared to baseline). Additionally, sacubitril/valsartan treatment blocked AT1 receptors, as evidenced by increased plasma renin activity and concentration. In the PARADIGM-HF trial, the sacubitril/valsartan combination produced a greater reduction in plasma NT-proBNP concentration and a more pronounced increase in urinary B-type natriuretic peptide (BNP) and cGMP levels compared to enalapril. BNP is a substrate for neprilysin, whereas NT-proBNP is not. Therefore, NT-proBNP, unlike BNP, can be used as a biomarker for monitoring patients with heart failure receiving sacubitril/valsartan (see section "Special warnings and precautions for use").

In a QTc interval study in healthy male volunteers, single 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). After two weeks of daily administration of 194 mg sacubitril/206 mg valsartan in healthy volunteers, CSF concentration of Aβ 1-38 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.

Dosages of 50 mg, 100 mg, or 200 mg are sometimes referenced in certain sources as 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg of the medicinal product.

PARADIGM-HF

PARADIGM-HF was a multinational, randomized, double-blind trial involving 8,442 patients comparing sacubitril/valsartan with enalapril in adults 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 standard 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, severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²), or severe hepatic impairment were excluded during screening and thus not included in the prospective study.

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

Patients were required to discontinue ACEIs or ARBs, then enter a sequential, single-blind run-in phase during which they received enalapril 10 mg twice daily, followed by single-blind treatment with sacubitril/valsartan 100 mg twice daily, titrated up to 200 mg twice daily (see section "Adverse Reactions" regarding discontinuation during this phase). Subsequently, patients were randomized into the double-blind phase of the study, receiving either sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily (sacubitril/valsartan: n=4,209; enalapril: n=4,233). The mean age of the study population was 64 years, with 19% aged 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 sacubitril/valsartan group, 76% of patients continued 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% continued on the target dose of 10 mg twice daily (mean daily dose: 18.9 mg).

Compared to enalapril, sacubitril/valsartan significantly reduced the risk of cardiovascular death or hospitalization for heart failure (21.8% in the investigational drug group vs. 26.5% in the enalapril group). The absolute risk reduction for cardiovascular death or hospitalization for heart failure was 4.7% (3.1% reduction in cardiovascular death and 2.8% reduction in first hospitalization for heart failure). The relative risk reduction compared to enalapril was 20%. The beneficial effect was evident early after initiation and persisted throughout the study period. Both active components of the drug contributed to this effect. The incidence of sudden death, which accounted for 45% of all cardiovascular deaths, was reduced by 20% in the sacubitril/valsartan group compared to the enalapril group (hazard ratio [HR] 0.80, p=0.0082). The incidence of death due to worsening pump failure, which accounted for 26% of cardiovascular deaths, was reduced by 21% in the investigational drug group compared to enalapril (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.

Sacubitril/valsartan improved survival, with a significant 2.8% reduction in all-cause mortality (sacubitril/valsartan: 17%, enalapril: 19.8%). The relative risk reduction compared to enalapril was 16% (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 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.

The 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 never 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, and subsequently to the target dose of 200 mg twice daily over a 3- or 6-week period. A greater proportion of patients who had not previously received ACE inhibitors or ARBs or had received low-dose therapy (equivalent to <10 mg enalapril/day) achieved and maintained the sacubitril/valsartan 200 mg dose level when titrated over 6 weeks (84.8%) compared to 3 weeks (73.6%). Overall, 76% of patients reached and remained on the target dose of sacubitril/valsartan 200 mg twice daily without interruption of treatment 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 patient groups with heart failure.

Pharmacokinetics.

Valsartan in the form of a complex salt contained in sacubitril/valsartan has higher bioavailability compared to valsartan contained 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.

Following oral administration, the medicinal product Corsaval dissociates into valsartan and the inactive prodrug form of sacubitril. Sacubitril is further metabolized to the active metabolite LBQ657. Maximum plasma concentration (Cmax) is reached within 2 hours, 1 hour, and 2 hours, respectively. Absolute bioavailability of sacubitril and valsartan exceeds 60% and 23%, respectively. Following twice-daily administration of Corsaval, steady-state concentrations of sacubitril, LBQ657, and valsartan are achieved within three days. There is no statistically significant accumulation of sacubitril and valsartan at steady state, whereas accumulation of LBQ657 exceeds the concentration after single-dose administration by a factor of 1.6. Administration of the medicinal product with food does not have a clinically significant effect on systemic exposure of sacubitril, LBQ657, and valsartan. Corsaval may be administered independently of food intake.

Distribution.

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

Metabolism.

Sacubitril is rapidly converted to LBQ657 by carboxylesterase 1b and 1c, after which LBQ657 is not significantly metabolized. Valsartan is minimally metabolized, with only approximately 20% of the administered dose recovered as metabolites. A hydroxylated metabolite was detected in plasma at low concentrations (<10%). Since both sacubitril and valsartan are minimally metabolized by CYP450 isoenzymes, changes in their pharmacokinetics when co-administered with drugs affecting CYP450 isoenzymes are unlikely.

Elimination.

Following oral administration of Corsaval, 52–68% of sacubitril (predominantly as LBQ657) and approximately 13% of valsartan and its metabolites are excreted in urine; 37–48% of sacubitril (predominantly as LB657) and 86% of valsartan and its metabolites are excreted in feces.

Sacubitril, LBQ657, and valsartan are eliminated from plasma with mean half-lives (T1/2) 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 over the entire dose range of Corsaval from 50 mg to 200 mg.

Pharmacokinetics in specific patient groups.

Elderly patients. Exposure to LBQ657 and valsartan in patients aged 65 years and older is higher by 42% and 30%, respectively, compared to 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); this was the largest patient group enrolled in the PARADIGM-HF study. Exposure to valsartan was similar in patients with moderate and severe renal impairment compared to those with mild renal impairment. Studies in patients undergoing 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 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 sex. Pharmacokinetics (sacubitril, LBQ657, and valsartan) were 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 of the medicinal product.
• Concomitant use with ACE inhibitors (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use"). The medicinal product may be administered if at least 36 hours have elapsed since discontinuation of the ACE inhibitor.
• History of angioedema associated with previous use of ACE inhibitors or ARBs (see section "Special precautions for use").
• Hereditary or idiopathic angioedema (see section "Special precautions for use").
• Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or patients with renal impairment (eGFR <60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").
• Severe hepatic impairment, biliary cirrhosis, and cholestasis (see section "Dosage and administration").
• Second and third trimesters 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. Concomitant use of the medicinal product Korsavale with ACE inhibitors is contraindicated, as dual inhibition of neprilysin (NEP) and ACE increases the risk of angioedema. Treatment with Korsavale must not be initiated earlier than 36 hours after the last dose of an ACE inhibitor. Therapy with an ACE inhibitor should not be started earlier than 36 hours after the last dose of Korsavale (see sections "Contraindications" and "Dosage and administration").

Aliskiren. Concomitant use of Korsavale 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 Korsavale with direct renin inhibitors such as aliskiren is not recommended (see section "Special precautions for use"). The combination of Korsavale and aliskiren may be associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function, including acute renal failure (see sections "Contraindications" and "Special precautions for use").

Concomitant use is not recommended.

Korsavale contains valsartan; therefore, this medicinal product must not be used concomitantly with other medicinal products containing ARBs (see section "Special precautions for use"). 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, Korsavale may increase systemic exposure to OATP1B1 and OATP1B3 substrates, particularly statins. Concomitant administration of Korsavale increased Cmax of atorvastatin and its metabolites by 2-fold and AUC by 1.3-fold. Therefore, caution should be exercised when administering Korsavale concomitantly with statins.

Phosphodiesterase-5 inhibitors, including sildenafil. In patients with marked hypertension receiving Korsavale (at steady-state), single-dose administration of sildenafil enhanced the antihypertensive effect compared to Korsavale monotherapy. Therefore, patients receiving Korsavale should use sildenafil or other phosphodiesterase-5 inhibitors with caution.

Potassium. Concomitant use of potassium-sparing diuretics (e.g., 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 and serum creatinine levels. In patients receiving Korsavale concomitantly with these medicinal products, regular monitoring of serum potassium levels is recommended (see section "Special precautions for use").

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 renal impairment, concomitant use of Korsavale and NSAIDs increases the risk of renal dysfunction. In patients receiving Korsavale concomitantly with NSAIDs, monitoring of renal function is recommended (see section "Special precautions for use").

Lithium-containing 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. The potential for drug interaction between Korsavale and lithium preparations has not been studied. Therefore, combination of these agents is not recommended. If such combination is necessary, careful monitoring of serum lithium levels is required. The risk of lithium toxicity may be increased when diuretics are used concomitantly.

Furosemide. Concomitant use of Korsavale and furosemide does not affect the pharmacokinetics of Korsavale, but reduces Cmax and AUC of furosemide by 50% and 28%, respectively. Although total urine volume is not significantly altered, urinary sodium excretion is reduced over 4 and 24 hours following 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 sacubitril/valsartan.

Nitrates, e.g., nitroglycerin. No drug interaction between Korsavale and intravenous nitroglycerin for blood pressure reduction has been observed. When nitroglycerin and Korsavale were used concomitantly, heart rate differed by 5 beats per minute compared to nitroglycerin monotherapy. A similar effect on heart rate was observed when sacubitril/valsartan was administered with sublingual, oral, or transdermal nitrates. Overall, 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 sacubitril/valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g., rifampicin, cyclosporine), OAT1 (e.g., tenofovir, cidofovir), or MRP2 (e.g., ritonavir) may increase systemic exposure to LBQ657 or valsartan. Caution should be exercised when initiating or discontinuing concomitant use of Korsavale with these medicinal products.

Metformin. Concomitant use of sacubitril/valsartan 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 taking metformin should be evaluated before initiating treatment with Korsavale.

Minor interactions.

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

Cytochrome CYP450 interactions. In vitro metabolism studies indicate that the likelihood of drug interactions mediated by cytochrome P450 isoenzymes is very low, as metabolism of sacubitril/valsartan via CYP450 enzymes is limited. Korsavale does not induce or inhibit CYP450 enzymes.

Special precautions for use.

Double blockade of the RAAS.

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

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

Corzaval contains valsartan; therefore, this medicinal product must not be used in combination with other medicinal products containing ARBs (see sections "Method of administration and dosage" 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 sacubitril/valsartan during clinical trials (see section "Adverse reactions"), particularly in patients aged ≥65 years, patients with renal 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 Corzaval. In case of hypotension, temporary dose reduction or discontinuation of Corzaval therapy is recommended (see section "Method of administration and dosage"). Adjustment of diuretic dosage, concomitant antihypertensive agents, and evaluation of other causes of hypotension (e.g., hypovolemia) should be considered. The likelihood of pronounced blood pressure reduction is generally higher in patients with hypovolemia, which may result from concomitant diuretic use, adherence to a low-salt diet, diarrhea, or vomiting. Low serum sodium levels and/or reduced circulating blood volume (CBV) should be corrected prior to initiating Corzaval therapy, provided this does not lead to a risk of CBV overload.

Renal impairment.

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

Renal function impairment.

Use of this medicinal product, as with any other agent acting on the RAAS, may lead to deterioration of renal function. The risk is increased in cases of dehydration or concomitant use of NSAIDs (see section "Interaction with other medicinal products and other forms of interaction"). In case of clinically significant renal function impairment, dose reduction of Corzaval should be considered.

Hyperkalemia.

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

Angioedema.

Cases of angioedema have been reported during treatment with sacubitril/valsartan. If angioedema occurs, Corzaval must be discontinued immediately, and appropriate treatment and monitoring should be initiated until complete and sustained resolution of all symptoms. The medicinal product must not be re-administered. In cases of confirmed angioedema limited to the face and lips, the condition usually resolved spontaneously, although antihistamines facilitated symptom relief.

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 must be initiated, such as administration of 1 mg/mL adrenaline solution (0.3–0.5 mL), and/or securing airway patency.

Patients with a history of angioedema have not been studied. Due to their higher risk of developing angioedema, Corzaval should be prescribed to such patients with extreme caution. Corzaval is contraindicated in patients with a history of angioedema during ACE inhibitor or ARB therapy, or with hereditary or idiopathic angioedema (see section "Contraindications").

Patients of non-Black race are more susceptible to developing angioedema (see section "Adverse reactions").

Patients with renal artery stenosis.

Corzaval may cause increased 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 chronic heart failure NYHA functional class IV.

Caution is advised when using Corzaval in patients with chronic heart failure NYHA functional class IV, 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 Corzaval, as it is a substrate for neprilysin (see section "Pharmacodynamics").

Patients with hepatic impairment.

Clinical experience with the use of the medicinal product in patients with moderate hepatic impairment (Child-Pugh class B) or with aspartate aminotransferase/alanine aminotransferase (AST/ALT) values exceeding the upper limit of normal by more than two times is limited. These patients are more sensitive to the drug's effects, and its safety profile has not been established. Therefore, the medicinal product should be prescribed with caution in such patients (see sections "Pharmacokinetics" and "Method of administration and dosage"). Corzaval 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.

Use of Corzaval is not recommended during the first trimester of pregnancy. The medicinal product is contraindicated during the second and third trimesters of pregnancy (see section "Contraindications").

Valsartan. Epidemiological data on teratogenic risk associated with ACE inhibitors during the first trimester of pregnancy are inconclusive, but a certain increase in risk cannot be excluded. Despite the lack of controlled epidemiological data on teratogenicity associated with ARBs, similar risks may exist with the use of this class of medicinal products. Except when continued ARB therapy is necessary, 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 needed. It is known that ARB therapy during the second and third trimesters induces fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If ARB medicinal products were used from the second trimester of pregnancy, renal and skull ultrasound examinations are recommended. Newborns whose mothers received ARBs should be closely monitored for the development of hypotension (see section "Contraindications").

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

Corzaval. Data on the use of Corzaval in pregnant women are lacking. Animal studies with sacubitril/valsartan have shown reproductive toxicity.

Breastfeeding period.

It is unknown whether Corzaval is excreted in human breast milk. The components of the medicinal product—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 Corzaval on human reproductive function are lacking. Studies in male and female rats have shown impaired reproductive function.

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 or operating machinery.

Method of Administration and Dosage.

The medicinal product is intended for oral administration. The time of administration of Corzaval is independent of food intake (see section "Pharmacokinetics"). Tablets should be swallowed whole with a glass of water.

Dosage.

The recommended initial dose is 1 tablet of 100 mg twice daily, except in situations described below. The dose should be doubled after 2–4 weeks of treatment so that the dose becomes 1 tablet of 200 mg twice daily, provided the patient tolerates it well.

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

Information on treatment of patients who are not taking ACE inhibitors or ARBs, or are taking them at low doses, is limited. Therefore, for this patient category, 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. Corzaval 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, the medicinal product should not be initiated unless at least 36 hours have passed since discontinuation of the ACE inhibitor.

Valsartan in the form of a complex salt contained in the medicinal product Corzaval has higher bioavailability compared to valsartan contained in other tablet formulations (see section "Pharmacokinetics").

If a patient misses a dose, the next dose should be taken at the scheduled time.

Dosage in Specific Patient Populations.

Elderly Patients.

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

Patients with Renal Impairment.

Dose adjustment is not required in patients with mild renal impairment (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 the use of the medicinal product in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) (see section "Pharmacodynamics"), sacubitril/valsartan should be initiated with caution at an initial dose of 50 mg twice daily. There is no experience with the use of Corzaval in patients with end-stage renal disease; therefore, administration of the medicinal product is not recommended in these patients.

Patients with Hepatic Impairment.

Dose adjustment is not required in patients with mild hepatic impairment (Child-Pugh class A). Clinical experience with the use of this medicinal product in patients with moderate hepatic impairment (Child-Pugh class B) or with AST/ALT levels twice the upper limit of normal is limited. The medicinal product should be used with caution in these patients. The recommended initial dose is 50 mg twice daily (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use"). Corzaval is contraindicated in severe hepatic impairment, biliary cirrhosis, or cholestasis (Child-Pugh class C) (see section "Contraindications").

Children.

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

Overdose.

There is insufficient data on overdose of this medicinal product in humans. Single doses of up to 1200 mg and multiple doses of up to 900 mg were well tolerated in healthy volunteers.

Symptoms. The most likely symptom of overdose is pronounced hypotension due to the antihypertensive effect of the active substances.

Treatment. Symptomatic treatment is recommended. The likelihood of removing the drug via hemodialysis is very low due to its high plasma protein binding.

Adverse Reactions

The following adverse reactions have been reported with the use of the medicinal product Korsaval: hypotension, hyperkalemia, and renal dysfunction (see section "Special Warnings and Precautions for Use"). There have been reports of angioedema in patients receiving sacubitril/valsartan (see "Description of Selected Adverse Reactions").

The safety of sacubitril/valsartan in patients with chronic heart failure was evaluated in the pivotal phase III PARADIGM-HF trial, in which patients received either sacubitril/valsartan 200 mg twice daily (n=4203) or enalapril 10 mg once daily (n=4229). Patients randomized to the sacubitril/valsartan group received treatment for up to 24 months; 3271 patients received therapy for more than one year.

In the PARADIGM-HF study, patients who had previously received ACE inhibitors and/or ARBs were administered enalapril and sacubitril/valsartan (mean 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, 1102 patients (10.5%) were permanently discontinued from the study: 5.6% due to adverse reactions, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%), and hypotension (1.4%). During the sacubitril/valsartan 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 hyperkalemia (1.3%). Given 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 sacubitril/valsartan (10.7%) and in 516 patients receiving enalapril (12.2%).

Adverse events are classified by system organ class and frequency (in decreasing order): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000). Within each category, adverse reactions are listed in decreasing order of severity.

Table 2

List of Adverse Reactions

* See "Description of selected adverse reactions."

Description of selected adverse reactions.

Angioedema Angioedema has been reported in patients receiving sacubitril/valsartan. In the PARADIGM-HF study, angioedema developed in 0.5% of patients receiving sacubitril/valsartan compared with 0.2% of patients receiving enalapril. A higher incidence of angioedema was observed in black patients receiving sacubitril/valsartan (2.4%) and enalapril (0.5%) (see section "Special precautions"). Hyperkalemia and serum potassium. During the PARADIGM-HF study, hyperkalemia and serum potassium concentration > 5.4 mmol/L were observed in 11.6% and 19.7% of patients receiving sacubitril/valsartan, 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 mmHg and a decrease from baseline of >20 mmHg) were recorded in 17.6% and 4.76% of patients receiving sacubitril/valsartan, 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 sacubitril/valsartan and in 11.5% of patients receiving enalapril.

Reporting of 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 professionals and patients, as well as their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. No special storage conditions required. Keep out of the reach and sight of children.

Packaging. 7 tablets in a blister; 4 blisters in a cardboard box, or 14 tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription-only.

Manufacturers.

Sintón Chile Ltda.

Manufacturer's address and location of its business operations.

El Castaño No. 145, Lampa, Santiago, 0000, Chile