Akrivario (Tablets) Instructions for Use

ATC Code

C09DX04 (Valsartan and Sacubitril)

Active Substances

Valsartan (Rec.INN registered by WHO)

Sacubitril (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Angiotensin II receptor antagonist in combination with a neprilysin inhibitor

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists, combinations; angiotensin II receptor antagonists, other combinations

Pharmacological Action

Mechanism of action

The drug Akrivario contains a salt complex of the anionic forms of valsartan and sacubitril, sodium cations, and water molecules in a molar ratio of 1:1:3:2.5, respectively.

The action of the combination of valsartan and sacubitril is mediated by a new mechanism, namely, simultaneous blockade of angiotensin II type 1 (AT1) receptors by valsartan, which is an ARB II, and suppression of neprilysin (neutral endopeptidase [NEP]) activity by sacubitrilat (the active metabolite of sacubitril), which leads to an increase in the number of peptides degraded by neprilysin (such as natriuretic peptides [NP]), which, with simultaneous suppression of the negative effects of angiotensin II by valsartan, determines the complementary beneficial effects of valsartan and sacubitril on the state of the cardiovascular system and kidneys in patients with heart failure. NPs activate membrane-bound guanylyl cyclase-coupled receptors, leading to an increase in the concentration of cyclic guanosine monophosphate (cGMP), causing vasodilation, increased natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, suppression of renin and aldosterone release, reduced sympathetic activity, as well as 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 aldosterone release. This prevents persistent activation of the RAAS, which causes vasoconstriction, sodium and water retention by the kidneys, activation of cell growth and proliferation, and subsequent maladaptive remodeling of the cardiovascular system.

Pharmacodynamic effects

The pharmacodynamic effects of the valsartan and sacubitril complex were evaluated after single and multiple administration in healthy volunteers, as well as in patients with chronic heart failure. The observed effects corresponded to the mechanism of action of the active substance complex, consisting of simultaneous inhibition of neprilysin and blockade of the RAAS. In a 7-day study in patients with reduced LVEF, in which valsartan was used as a control, the use of the sacubitril and valsartan complex led to a statistically significant short-term increase in natriuresis, an increase in urinary cGMP concentration, and a decrease in the concentration of mid-regional pro-atrial natriuretic peptide (MR-proANP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in plasma (compared to valsartan). In a 21-day study in patients with reduced LVEF, the use of sacubitril and valsartan caused a statistically significant increase in the concentration of atrial natriuretic peptide (ANP) and cGMP in urine and plasma cGMP concentration, as well as a decrease in plasma concentrations of NT-proBNP, aldosterone, and endothelin-1 (compared to baseline). Furthermore, the use of the sacubitril and valsartan complex blocks the AT₁ receptor, as indicated by an increase in plasma renin activity and concentration. In the PARADIGM-HF study, the sacubitril and valsartan complex caused a greater reduction in plasma NT-proBNP concentration and a more significant increase in brain natriuretic peptide (BNP) and urinary 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 for monitoring patients with heart failure receiving the sacubitril and valsartan complex. In the PARAGON-HF study, Akrivario reduced levels of NT-proBNP, troponin, soluble ST2 (sST2) and increased urinary cGMP concentration compared to valsartan.

In a thorough QTc interval study in healthy male volunteers, single administration of the sacubitril and valsartan complex at doses of 400 mg and 1200 mg did not affect myocardial repolarization.

Neprilysin is one of several enzymes involved in the metabolism of amyloid-β (Aβ) in the brain and cerebrospinal fluid (CSF). During administration of the sacubitril and valsartan complex at a dose of 400 mg once daily for 2 weeks in healthy volunteers, the concentration of Aβ 1-38 in the CSF increased; while the concentrations of Aβ 1-40 and 1-42 in the CSF did not change. The clinical significance of this fact is unknown.

In the PARADIGM-HF clinical trial, the use of the valsartan and sacubitril complex in patients with chronic heart failure statistically significantly reduced the risk of death from cardiovascular causes or hospitalization for heart failure (21.8% in the study drug group versus 26.5% in the enalapril group). The absolute risk reduction for death from cardiovascular causes or hospitalization for heart failure was 4.7% (3.1% for the risk of death from cardiovascular causes and 2.8% for the first hospitalization for heart failure). The relative risk reduction compared to enalapril was 20% (odds ratio [OR] 0.80; p=0.0000002). The effect was noted early in the use of the drug and persisted throughout the study period. Both active components of the drug contributed to the development of the effect. The incidence of sudden death, which accounted for 45% of all deaths from cardiovascular causes, in the study drug group decreased by 20% compared to the enalapril group (OR 0.80; p=0.008). The incidence of death due to worsening heart failure, which was the cause of death in 26% of cases from cardiovascular causes, in the study drug group decreased by 21% compared to that in the enalapril group (OR 0.79, p=0.0004).

In the PARAGON-HF study, the use of the valsartan and sacubitril combination reduced the frequency of the combined endpoint of total (first and recurrent) hospitalizations for heart failure and death from cardiovascular causes by 13% compared to valsartan (rate ratio [RR] 0.87; 95% confidence interval [CI] from 0.75 to 1.01; p=0.059). The treatment effect was primarily due to a reduction in the total number of heart failure hospitalizations in patients randomized to the valsartan and sacubitril combination group, by 15% (RR 0.85; 95% CI from 0.72 to 1.00). The valsartan and sacubitril combination reduced the frequency of the combined endpoint of total heart failure worsening (heart failure hospitalizations and urgent heart failure visits) and death from cardiovascular causes by 14% (RR 0.86; 95% CI from 0.75 to 0.99). In the analysis of the relationship between LVEF and outcomes in PARADIGM-HF and PARAGON-HF, patients with below-normal LVEF receiving the valsartan and sacubitril combination showed a greater risk reduction.

LVEF is a variable parameter that can change over time, and the normal range varies depending on patient characteristics and assessment method. Prescribing physicians should rely on clinical assessment when making treatment decisions. In both studies, the therapeutic effect of the valsartan and sacubitril combination was demonstrated early and persisted throughout all study periods.

The antihypertensive effect of the valsartan and sacubitril combination was evaluated in two randomized, double-blind, active-controlled 8-week efficacy and safety studies of the valsartan and sacubitril combination compared to olmesartan (CLCZ696A2315 and CLCZ696A1306) in more than 2500 adult patients, of which more than 1700 patients received the valsartan and sacubitril combination.

Both studies demonstrated not only comparable but superior efficacy in reducing mean sitting systolic blood pressure (msSBP) with both doses of the valsartan and sacubitril combination: 200 mg once daily (2.3 and 5.0 mm Hg in each study, respectively) and 400 mg once daily (3.5 and 7.0 mm Hg) compared to olmesartan 20 mg once daily. Corresponding results were observed for mean diastolic BP.

Pharmacokinetics

Absorption

After oral administration, the valsartan and sacubitril complex dissociates into valsartan and sacubitril, which is then metabolized to form the metabolite sacubitrilat; the plasma concentrations of these substances reach a maximum after 2, 0.5, and 1.5 hours, respectively. The absolute bioavailability of valsartan and sacubitril after oral administration is 23% and ≥ 60%, respectively. Valsartan as part of the drug Akrivario has higher bioavailability compared to other tablet forms.

When taking the sacubitril and valsartan complex twice daily, the C_ss of valsartan, sacubitril, and sacubitrilat are reached within 3 days.

No statistically significant accumulation of valsartan and sacubitril was noted at steady state; meanwhile, the accumulation of sacubitrilat exceeded the concentration after a single dose by 1.6 times. After a single daily dose of the valsartan and sacubitril combination, the C_ss of valsartan, sacubitril, and sacubitrilat are reached within 5 days without accumulation of valsartan and sacubitril, with a 1.2-fold accumulation of sacubitrilat. Taking the valsartan and sacubitril complex simultaneously with food did not have a clinically significant effect on the systemic exposure parameters of valsartan, sacubitril, and sacubitrilat. The reduction in valsartan exposure when taking the valsartan and sacubitril complex simultaneously with food is not accompanied by a clinically significant reduction in therapeutic effect. The time of taking the valsartan and sacubitril complex does not depend on the time of food intake.

Distribution

The valsartan and sacubitril complex is largely bound to plasma proteins (94-97%). Comparison of plasma and CSF exposures shows that sacubitrilat penetrates the blood-brain barrier to a small extent (0.28%). The apparent V_d of the complex ranges from 75 to 103 L.

Metabolism

Sacubitril is rapidly converted by enzymes into sacubitrilat, which is then not significantly metabolized. Valsartan is metabolized to a small extent, with only about 20% of the administered dose found as metabolites. A hydroxyl metabolite was found in plasma in low concentrations (10%).

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

Excretion

After oral administration, approximately 13% of valsartan and its metabolites, as well as 52-68% of sacubitril (mainly in the form of sacubitrilat), are excreted by the kidneys; 86% of valsartan and its metabolites, as well as 37-48% of sacubitril (mainly in the form of sacubitrilat), are excreted through the intestine.

Valsartan, sacubitril, and sacubitrilat are eliminated from plasma with mean T_1/2 of approximately 9.90, 1.43, and 11.48 hours, respectively.

Linearity (non-linearity)

In the studied dose range of the valsartan and sacubitril complex (50-400 mg), the pharmacokinetic parameters of valsartan, sacubitril, and sacubitrilat change proportionally to the dose.

Pharmacokinetic-pharmacodynamic relationship

Elderly patients

The exposure of valsartan and sacubitrilat in patients over 65 years of age increases by 30% and 42%, respectively, compared to younger patients. However, this is not accompanied by clinically significant effects and, therefore, does not require dose adjustment.

Patients with renal impairment

For sacubitrilat, a correlation was observed between renal function and AUC; no such correlation was observed for valsartan. In patients with mild (eGFR 89-60 ml/min/1.73 m²) and moderate (eGFR 59-30 ml/min/1.73 m²) renal impairment, the AUC of sacubitrilat was 2 times higher than in patients with normal renal function. In patients with mild and moderate renal impairment, dose adjustment of the drug Akrivario is not required.

In patients with severe renal impairment (eGFR < 30 ml/min/1.73 m²), the AUC of sacubitrilat increased by 2.7 times; in patients of this category, the recommended initial dose of the drug is 50 mg twice daily. Caution should be exercised when using the drug in patients with severe renal impairment due to limited relevant data.

The safety and efficacy of the valsartan and sacubitril combination in patients with essential arterial hypertension and severe renal failure (eGFR < 30 ml/min/1.73 m²) have not been established. There are no data on the use of the drug in patients on hemodialysis. However, both valsartan and sacubitrilat are largely bound to plasma proteins, so their effective removal from the blood by hemodialysis is unlikely.

Patients with hepatic impairment

In patients with mild and moderate hepatic impairment, the exposure of sacubitril increased by 1.5 and 3.4 times, respectively. The exposure of sacubitrilat increased by 1.5 and 1.9 times, and of valsartan by 1.2 and 2.1 times (compared to healthy volunteers). In patients with mild hepatic impairment (Child-Pugh class A), including patients with biliary obstruction, dose adjustment of the valsartan and sacubitril combination is not required.

In patients with heart failure and moderate hepatic impairment (Child-Pugh class B), the recommended initial dose of the drug Akrivario is 50 mg twice daily.

In patients with essential arterial hypertension and moderate hepatic impairment (Child-Pugh class B), the recommended initial dose of the drug Akrivario is 100 mg once daily. Due to the lack of data, use in patients with severe hepatic impairment is not recommended.

Ethnicity

The pharmacokinetics of the valsartan and sacubitril complex (valsartan, sacubitril, and sacubitrilat) in patients of different racial and ethnic groups do not differ significantly.

Gender

The pharmacokinetics of the sacubitril and valsartan complex (sacubitril, sacubitrilat, and valsartan) in men and women do not differ significantly.

Indications

• Chronic heart failure to reduce the risk of cardiovascular death and hospitalization for heart failure. The maximum risk reduction is observed in patients with left ventricular ejection fraction (LVEF) below normal;
• Essential arterial hypertension.

ICD codes

Dosage Regimen

Tablets

For oral use. The time of taking the drug Akrivario does not depend on the time of food intake.

Heart failure

The target (maximum daily) dose of the drug Akrivario is 200 mg (102.8 mg + 97.2 mg) twice daily. The recommended initial dose of the drug Akrivario is 100 mg (51.4 mg + 48.6 mg) twice daily. Depending on tolerance, the dose of Akrivario should be doubled every 2-4 weeks until the target (maximum daily) dose of 200 mg (102.8 mg + 97.2 mg) twice daily is reached.

In patients who have not previously received therapy with angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin II receptor antagonists (ARBs), or who have received these drugs in low doses, therapy with Akrivario should be started at a dose of 50 mg (25.7 mg + 24.3 mg) twice daily with a slow dose increase (doubling the daily dose once every 3-4 weeks).

The use of the drug Akrivario is possible no earlier than 36 hours after discontinuation of an ACE inhibitor, because simultaneous use may lead to the development of angioedema.

Since the drug Akrivario contains the ARB valsartan, it should not be used simultaneously with another drug containing an ARB.

If signs of intolerance to the drug Akrivario develop (clinically significant decrease in BP, hyperkalemia, impaired renal function), the issue of a temporary dose reduction or adjustment of the dose of concurrently used medications should be considered.

Essential arterial hypertension

The recommended initial dose of the drug Akrivario is 200 mg once daily. In patients with inadequate BP control when taking a dose of 200 mg once daily, it can be increased to 400 mg once daily. In patients with hypertension and heart failure, the dosing regimen for heart failure should be followed (200 mg twice daily). The drug Akrivario can be used as monotherapy or in combination with other antihypertensive agents, except for ACE inhibitors and ARBs.

Special patient groups

Patients with renal impairment

In patients with mild renal impairment (estimated glomerular filtration rate [eGFR] from 60 to 90 ml/min/1.73 m²) or moderate renal impairment (eGFR from 30 to 60 ml/min/1.73 m²), dose adjustment of the drug is not required (see section “Pharmacokinetics”).

In patients with heart failure and severe renal impairment (eGFR < 30 ml/min/1.73 m²), the recommended initial dose of the drug is 50 mg twice daily.

The safety and efficacy of the drug Akrivario in patients with essential arterial hypertension and severe renal impairment (eGFR < 30 ml/min/1.73 m²) have not been established (see section “Pharmacokinetics”).

Patients with hepatic impairment

In patients with mild hepatic impairment (Child-Pugh class A), dose adjustment of the drug Akrivario is not required.

The recommended initial dose of the drug in patients with heart failure and moderate hepatic impairment (Child-Pugh class B) is 50 mg twice daily. The recommended initial dose of the drug in patients with essential arterial hypertension and moderate hepatic impairment (Child-Pugh class B) is 100 mg once daily.

The drug Akrivario is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).

Elderly patients

No dose adjustment is required in patients over 65 years of age.

Children

The safety and efficacy of Akrivario in children and adolescents aged 0 to 18 years have not been established. Data are unavailable.

Adverse Reactions

Heart failure

A total of 6622 patients with heart failure participated in the PARADIGM-HF (compared with enalapril) and PARAGON-HF (compared with valsartan) clinical trials. Of these, 5085 received the combination of valsartan and sacubitril for at least 1 year.

PARADIGM-HF

The safety of the valsartan and sacubitril combination in patients with chronic heart failure with LVEF?40% was evaluated in the main phase 3 PARADIGM-HF study, which compared groups receiving the valsartan and sacubitril combination 200 mg twice daily (n=4203) or enalapril 10 mg (n=4229). In the safety assessment, the duration of therapy with the drug in patients with chronic heart failure was up to 4.3 years, with a mean treatment duration of 24 months. Discontinuation of therapy due to adverse reactions was required in 10.71% of patients receiving the valsartan and sacubitril combination and in 12.20% receiving the comparator drug. The events most frequently associated with dose adjustment or discontinuation of therapy were: arterial hypotension, hyperkalemia, and impaired renal function. The identified adverse reactions were consistent with the pharmacological characteristics of the valsartan and sacubitril combination and the comorbidities present in the patients. The frequency of adverse reactions did not depend on gender, age, or race.

PARAGON-HF

The safety of the valsartan and sacubitril combination in patients with chronic heart failure and LVEF ≥ 45% was evaluated in the main phase 3 PARAGON-HF study, which compared groups receiving the valsartan and sacubitril combination 200 mg twice daily (n=2419) or Valsartan 160 mg (n=2402). The safety profile of the valsartan and sacubitril combination was consistent with the safety profile in patients with heart failure with reduced ejection fraction.

Essential arterial hypertension

The safety of the valsartan and sacubitril combination in patients with essential arterial hypertension was evaluated in clinical studies involving more than 7000 patients with hypertension (more than 3500 patients received the valsartan and sacubitril combination).

In the pooled group of short-term double-blind controlled studies, 3272 patients received the valsartan and sacubitril combination for an average of 8 weeks, with dizziness occurring more frequently in patients receiving the valsartan and sacubitril combination than in patients receiving olmesartan.

Summary of adverse reactions

Adverse reactions are grouped by system-organ class with an indication of their frequency of occurrence according to the World Health Organization (WHO) classification: very common (≥1/10); common (≥1/100 but <1/10), uncommon (≥1/1000 but <1/100), rare (≥1/10000 but <1/1000), very rare (<1/10000); frequency unknown (cannot be estimated from available data). Adverse reactions within each system-organ class are listed in descending order of severity with an indication of their frequency of occurrence (within the same frequency category).

Immune system disorders frequency unknown – hypersensitivity (including skin rash, pruritus, anaphylaxis).

Metabolism and nutrition disorders: very common – hyperkalemia; common – hypokalemia.

Nervous system disorders: common – dizziness, headache; uncommon – orthostatic dizziness.

Ear and labyrinth disorders common – vertigo.

Vascular disorders very common – arterial hypotension; common – syncope, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders common – cough.

Gastrointestinal disorders: common – diarrhea, nausea.

Skin and subcutaneous tissue disorders uncommon – angioedema.

Renal and urinary disorders very common – impaired renal function; common – renal failure (including acute renal failure).

General disorders and administration site conditions common – increased fatigue, asthenia.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to sacubitril, valsartan or to any of the excipients included in the drug formulation;
• History of angioedema associated with previous therapy with ACE inhibitors or ARBs;
• Hereditary angioedema;
• Severe hepatic impairment (Child-Pugh class C), biliary cirrhosis and cholestasis;
• Concomitant use with ACE inhibitors, as well as within 36 hours after discontinuation of an ACE inhibitor;
• Concomitant use with drugs containing aliskiren in patients with diabetes mellitus or with moderate or severe renal impairment (eGFR < 60 ml/min/1.73 m²);
• Concomitant use with other drugs containing ARBs, because the drug contains Valsartan;
• Not recommended for use in children under 18 years of age due to lack of data on efficacy and safety;
• Pregnancy, pregnancy planning;
• Period of breastfeeding.

With caution

• Severe renal impairment (eGFR < 30 ml/min/1.73 m²), including patients on hemodialysis or undergoing hemodialysis (eGFR < 15 ml/min/1.73 m²), due to lack of safety data in this patient category;
• Bilateral renal artery stenosis;
• Hypovolemia, which may be caused by diuretic therapy, low-salt diet, diarrhea, or vomiting;
• Concomitant use with drugs that can increase serum potassium levels (e.g., potassium-sparing diuretics, potassium preparations);
• Concomitant use with statins, PDE type 5 inhibitors;
• History of angioedema due to lack of data on the use of the drug in this patient category; Black patients may be at higher risk of angioedema.

Use in Pregnancy and Lactation

Women of childbearing potential (contraception in women)

Women of childbearing potential should be informed about the potential consequences of using the drug during pregnancy, as well as the need to use reliable methods of contraception during treatment with the drug and for one week after its last dose.

Pregnancy

Like other drugs that act directly on the RAAS, the drug Valsartan + Sacubitril should not be used during pregnancy. The action of Valsartan + Sacubitril is mediated by blockade of ARB receptors, so the risk to the fetus cannot be excluded. In pregnant women taking Valsartan, cases of spontaneous abortion, oligohydramnios, and impaired renal function in newborns have been reported. If pregnancy occurs during treatment with the drug, the patient should discontinue the drug and inform her attending physician.

Breastfeeding

It is unknown whether Valsartan + Sacubitril passes into human breast milk. Since preclinical studies have noted the excretion of sacubitril and valsartan in the milk of lactating rats, the use of Valsartan + Sacubitril during breastfeeding is not recommended. The decision to discontinue breastfeeding or to discontinue treatment with Valsartan + Sacubitril and continue breastfeeding should be made taking into account the importance of its use for the mother.

Fertility

There are no data on the effect of Valsartan + Sacubitril on male and female fertility. In studies of Valsartan + Sacubitril in animals, no reduction in fertility was observed.

Use in Hepatic Impairment

The recommended starting dose of the drug in patients with heart failure and moderate hepatic impairment (Child-Pugh class B) is 50 mg twice daily. The recommended starting dose of the drug in patients with essential arterial hypertension and moderate hepatic impairment (Child-Pugh class B) is 100 mg once daily.

The drug Akrivario is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).

Use in Renal Impairment

No dose adjustment of the drug is required in patients with mild (eGFR from 60 to 90 ml/min/1.73 m²) or moderate (eGFR from 30 to 60 ml/min/1.73 m²) renal impairment.

In patients with heart failure and severe renal impairment (eGFR < 30 ml/min/1.73 m²), the recommended starting dose of the drug is 50 mg twice daily.

The safety and efficacy of Akrivario in patients with essential arterial hypertension and severe renal impairment (eGFR < 30 ml/min/1.73 m²) have not been established.

Pediatric Use

The safety and efficacy of Akrivario in children and adolescents aged 0 to 18 years have not been established. Data are unavailable.

Geriatric Use

No dose adjustment is required in patients over 65 years of age.

Special Precautions

Marked decrease in blood pressure

Cases of clinically significant arterial hypotension have been observed in patients receiving the valsartan and sacubitril combination. If arterial hypotension occurs, consideration should be given to adjusting the dose of diuretics, concomitant antihypertensive drugs, as well as eliminating the causes of arterial hypotension (e.g., hypovolemia). If, despite these measures, arterial hypotension persists, the dose of Valsartan + Sacubitril should be reduced or the drug should be temporarily discontinued. Permanent discontinuation of the drug is usually not required. The likelihood of arterial hypotension is generally higher in patients with hypovolemia, which may be caused by diuretic therapy, low-salt diet, diarrhea, or vomiting. Before starting Valsartan + Sacubitril, sodium levels should be corrected and/or blood volume should be replenished.

Impaired renal function

Like any other drug acting on the RAAS, Valsartan + Sacubitril may cause deterioration of renal function. In a comparative safety and efficacy study (compared with enalapril), clinically significant impairments of renal function were rare, and Valsartan + Sacubitril was discontinued due to such impairments less frequently (0.65%) than enalapril (1.28%). In case of clinically significant deterioration of renal function, consideration should be given to reducing the dose of Valsartan + Sacubitril. Caution should be exercised when using Valsartan + Sacubitril in patients with severe renal impairment.

Hyperkalemia

Like any other drug acting on the RAAS, Valsartan + Sacubitril may increase the risk of hyperkalemia. In a comparative safety and efficacy study (compared with enalapril), clinically significant hyperkalemia was rare; Valsartan + Sacubitril was discontinued due to hyperkalemia in 0.26% of patients, and enalapril in 0.35% of patients. Drugs that can increase serum potassium levels (e.g., potassium-sparing diuretics, potassium preparations) should be used with caution concomitantly with Valsartan + Sacubitril. In case of clinically significant hyperkalemia, measures such as reducing dietary potassium intake or adjusting the dose of concomitant drugs should be considered.

Regular monitoring of serum potassium is recommended, especially in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism, or a high-potassium diet.

Angioedema

Cases of angioedema have been observed during treatment with Valsartan + Sacubitril. If angioedema occurs, Valsartan + Sacubitril should be discontinued immediately and appropriate treatment should be initiated with patient observation until all symptoms have completely and permanently resolved. Valsartan + Sacubitril should not be re-administered. In cases of confirmed angioedema where the swelling was limited to the face and lips, the condition usually resolved without intervention, although antihistamines helped relieve symptoms.

Angioedema involving laryngeal edema can be fatal. In cases where swelling extends to the tongue, vocal cords, or larynx, which may lead to airway obstruction, appropriate treatment should be initiated immediately, such as subcutaneous administration of epinephrine (adrenaline) solution 1:1000 (0.3-0.5 ml), and/or appropriate measures should be taken to ensure airway patency.

The use of the drug is contraindicated in patients with a history of angioedema associated with previous therapy with ACE inhibitors or ARBs, as well as in patients with hereditary angioedema.

Black patients may be at higher risk of angioedema.

Patients with renal artery stenosis

Like other drugs acting on the RAAS, Valsartan + Sacubitril may cause an increase in serum urea and creatinine concentrations in patients with unilateral or bilateral renal artery stenosis. In patients with renal artery stenosis, the drug should be used with caution, with regular monitoring of renal function.

Effect on ability to drive and operate machinery

There are no data on the effect of Valsartan + Sacubitril on the ability to drive vehicles and/or operate machinery. Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.

Overdose

Symptoms data on overdose of the medicinal product containing the combination of valsartan and sacubitril in humans are insufficient. Single administration of the valsartan and sacubitril combination at a dose of 1200 mg and multiple administration at a dose of 900 mg (14 days) in healthy volunteers was well tolerated. The most likely symptom of overdose is arterial hypotension due to the antihypertensive effect of the drug.

Treatment symptomatic treatment is recommended. Removal of the active substances by hemodialysis is unlikely, since a significant portion of them is bound to plasma proteins.

Drug Interactions

Contraindicated drug interactions

ACE inhibitors

Valsartan + Sacubitril is contraindicated for concomitant use with ACE inhibitors, since inhibition of neprilysin concomitantly with the use of ACE inhibitors may increase the risk of angioedema. Use of Valsartan + Sacubitril is possible no earlier than 36 hours after discontinuation of an ACE inhibitor. Use of an ACE inhibitor is possible no earlier than 36 hours after the last dose of Valsartan + Sacubitril.

Aliskiren

Concomitant use of Valsartan + Sacubitril with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or with renal impairment (eGFR < 60 ml/min/1.73 m²) and is not recommended in other patients.

Not recommended drug interactions

Angiotensin receptor antagonists

Since one of the active substances of the drug is an ARB, concomitant use with another drug containing an ARB is not recommended.

Drug interactions to be considered

HMG-CoA reductase inhibitors (statins)

Study data indicate that Sacubitril inhibits the activity of OATP1B1 and OATP1B3 transporters. Valsartan + Sacubitril may increase the systemic exposure of substrates of OATP1B1 and OATP1B3, such as statins. In patients receiving Valsartan + Sacubitril concomitantly with atorvastatin, the C_max of atorvastatin and its metabolites in plasma increased up to 2 times, and AUC up to 1.3 times. Caution should be exercised when statins are used concomitantly with Valsartan + Sacubitril. No clinically significant drug interaction was observed when Valsartan + Sacubitril was used concomitantly with simvastatin.

Sildenafil

In patients with marked hypertension receiving Valsartan + Sacubitril (before reaching steady-state concentration), single use of sildenafil enhanced the antihypertensive effect compared with the use of Valsartan + Sacubitril in monotherapy. For this reason, in patients receiving Valsartan + Sacubitril, sildenafil or another PDE type 5 inhibitor should be used with caution.

Presumed drug interactions to be considered

Potassium

Concomitant use of potassium-sparing diuretics (e.g., triamterene and amiloride), mineralocorticoid antagonists (e.g., spironolactone and eplerenone), potassium preparations, or potassium-containing salt substitutes may cause an increase in serum potassium and creatinine concentrations. In patients receiving Valsartan + Sacubitril concomitantly with these drugs, regular monitoring of serum potassium is recommended.

NSAIDs, including selective COX-2 inhibitors

Use of Valsartan + Sacubitril concomitantly with NSAIDs in patients over 65 years of age, in patients with hypovolemia (including patients receiving diuretics), and in patients with renal impairment may increase the risk of deterioration of renal function. In patients receiving Valsartan + Sacubitril concomitantly with NSAIDs, renal function should be monitored when using such a regimen and when it is changed.

Lithium preparations

The possibility of a drug interaction between Valsartan + Sacubitril and lithium preparations has not been studied. When lithium preparations were used concomitantly with ACE inhibitors and ARBs, a reversible increase in serum lithium levels and an associated increase in toxic manifestations were observed.

In patients receiving Valsartan + Sacubitril together with lithium preparations, careful monitoring of serum lithium levels is recommended. If a diuretic drug is additionally used, the risk of lithium toxicity may increase.

Transporter proteins

The active metabolite of sacubitril (sacubitrilat) and Valsartan are substrates of the OATP1B1, OATP1B3, and OAT3 transporter proteins; Valsartan is also a substrate of the MRP2 transporter protein. In patients receiving Valsartan + Sacubitril concomitantly with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g., rifampicin and cyclosporine) or MPR2 (e.g., ritonavir), the systemic exposure of sacubitrilat or valsartan, respectively, may increase. Caution is required at the start and end of concomitant use of Valsartan + Sacubitril and this group of drugs.

Absence of Clinically Significant Drug Interactions

When the drug Valsartan + Sacubitril was used in combination with furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, metformin, omeprazole, carvedilol, intravenous nitroglycerin, or the combined preparation of levonorgestrel and ethinylestradiol, no clinically significant interaction was identified. No interaction with atenolol, indomethacin, glibenclamide (glyburide), or cimetidine is expected when used concomitantly with the drug Valsartan + Sacubitril.

Interaction with Cytochrome P450 Isoenzymes

Available studies demonstrate that the likelihood of a drug interaction mediated by cytochrome P450 (CYP450) isoenzymes is low, as the complex of active substances is minimally metabolized with the participation of CYP450 isoenzymes. The complex of active substances of the drug Valsartan + Sacubitril is not an inhibitor or inducer of CYP450 isoenzymes.

Storage Conditions

The drug should be stored out of the reach of children in the original packaging (blister or bottle in a carton) to protect from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.