Uperio (Tablets) Instructions for Use

Marketing Authorization Holder

Novartis Overseas Investments AG (Switzerland)

Manufactured By

Novartis Singapore Pharmaceutical Manufacturing Pte. Ltd. (Singapore)

Or

Novartis Farma S.p.A. (Italy)

Or

Novartis Neva, LLC (Russia)

Packaging and Quality Control Release

NOVARTIS FARMA, S.p.A. (Italy)

Or

NOVARTIS NEVA, LLC (Russia)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

C09DX04 (Valsartan and sacubitril)

Active Substances

Valsartan (Rec.INN registered by WHO)

Sacubitril (Rec.INN registered by WHO)

Dosage Forms

	Uperio	Film-coated tablets, 50 mg (25.7 mg+24.3 mg): 28 or 56 pcs.
		Film-coated tablets, 100 mg (51.4 mg+48.6 mg): 28 or 56 pcs.
		Film-coated tablets, 200 mg (102.8 mg+97.2 mg): 28 or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white with a purple tint, oval, biconvex, with a bevel, without a score; engraved with “LZ” on one side and “NVR” on the other.

Excipients: microcrystalline cellulose, hypromellose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide.

Shell composition white shell premix (hypromellose, titanium dioxide (E171), macrogol 4000, talc), red shell premix (hypromellose, iron oxide red dye (E172), macrogol 4000, talc), black shell premix (hypromellose, iron oxide black dye (E172), macrogol 4000, talc).

14 pcs. – blisters (2) – cardboard packs^×.
14 pcs. – blisters (4) – cardboard packs^×.

Film-coated tablets light yellow, oval, biconvex, with a bevel, without a score; engraved with “L1” on one side and “NVR” on the other.

Excipients: microcrystalline cellulose, hypromellose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide.

Shell composition white shell premix (hypromellose, titanium dioxide (E171), macrogol 4000, talc), yellow shell premix (hypromellose, iron oxide yellow dye (E172), macrogol 4000, talc), red shell premix (hypromellose, iron oxide red dye (E172), macrogol 4000, talc).

14 pcs. – blisters (2) – cardboard packs^×.
14 pcs. – blisters (4) – cardboard packs^×.

Film-coated tablets light pink, oval, biconvex, with a bevel, without a score, engraved with “L11” on one side and “NVR” on the other.

Excipients: microcrystalline cellulose, hypromellose, crospovidone, magnesium stearate, talc, colloidal silicon dioxide.

Shell composition white shell premix (hypromellose, titanium dioxide (E171), macrogol 4000, talc), red shell premix (hypromellose, iron oxide red dye (E172), macrogol 4000, talc), black shell premix (hypromellose, iron oxide black dye (E172), macrogol 4000, talc).

14 pcs. – blisters (2) – cardboard packs^×.
14 pcs. – blisters (4) – cardboard packs^×.

^× the presence of primary opening control on the cardboard pack is allowed.

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, other combinations

Pharmacological Action

Mechanism of action

The action of the drug Uperio is mediated by a new mechanism, namely the simultaneous suppression of neprilysin (neutral endopeptidase, NEP) activity by sacubitrilat (the active metabolite of sacubitril) and blockade of angiotensin II type 1 receptors (AT₁) by valsartan, which is an angiotensin II receptor antagonist (ARB).

Under the influence of sacubitrilat, the amount of peptides degraded by neprilysin (such as natriuretic peptides (NPs)) increases, which, with the simultaneous suppression of the negative effects of angiotensin II by valsartan, causes complementary beneficial effects of sacubitril and valsartan 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 cyclic guanosine monophosphate (cGMP) concentration, causing symptoms of 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 the AT₁ receptor, 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.

Pharmacodynamics

The pharmacodynamic effects of the sacubitril and valsartan complex included in the drug were evaluated after its 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 in the simultaneous inhibition of neprilysin and blockade of the RAAS.

In a 7-day study in patients with reduced left ventricular ejection fraction (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 plasma concentration 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, the use of sacubitril and valsartan caused a statistically significant increase in the concentration of atrial natriuretic peptide (ANP) and urinary cGMP 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 greater increase in urinary brain natriuretic peptide (BNP) and cGMP concentrations than enalapril. While BNP is a substrate for neprilysin, NT-proBNP is not, so 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, Uperio reduced levels of NT-proBNP, troponin, soluble ST2 (sST2) and increased urinary cGMP concentration compared to valsartan.

In a thorough QT_c interval study in healthy male volunteers, single doses of the sacubitril and valsartan complex at 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 the use 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 sacubitril and valsartan 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 primary 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 drug’s use 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, decreased by 20% in the study drug group compared to the enalapril group (OR 0.80, p=0.008). The incidence of development of myocardial contractile insufficiency, which was the cause of death in 26% of cases from cardiovascular causes, decreased by 21% in the study drug group compared to that in the enalapril group (OR 0.79, p=0.0004).

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

The antihypertensive effect of the drug Uperio was evaluated in two randomized, double-blind, active-controlled, 8-week studies evaluating the efficacy and safety of the drug Uperio compared with olmesartan (CLCZ696A2315 and CLCZ696A1306) in more than 2500 adult patients, of which more than 1700 patients received Uperio. Both studies demonstrated not only comparable but superior efficacy in reducing mean sitting systolic BP (msSBP) for both doses – Uperio 200 mg once daily (2.3 and 5.0 mm Hg in each study, respectively) and Uperio 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 sacubitril and valsartan complex dissociates into sacubitril, which is then metabolized to form the metabolite sacubitrilat, and valsartan; plasma concentrations of these substances peak at 0.5 h, 2 h, and 1.5 h, respectively. The absolute bioavailability of sacubitril and valsartan after oral administration is ≥60% and 23%, respectively. Valsartan in the Uperio formulation has higher bioavailability compared to other tablet formulations.

When taking the sacubitril and valsartan complex twice daily, C_ss of sacubitril, sacubitrilat, and valsartan are reached within 3 days. No statistically significant accumulation of sacubitril and valsartan at steady state is noted; meanwhile, the accumulation of sacubitrilat exceeds the concentration after a single dose by 1.6 times. After a single daily dose of Uperio, C_ss of sacubitril, sacubitrilat, and valsartan are reached within 5 days without accumulation of sacubitril and valsartan and with 1.2-fold accumulation of sacubitrilat. Taking the sacubitril and valsartan complex with food did not have a clinically significant effect on the systemic exposure parameters of sacubitril, sacubitrilat, and valsartan. The reduction in valsartan exposure when taking the sacubitril and valsartan complex with food is not accompanied by a clinically significant reduction in therapeutic effect. The time of taking the sacubitril and valsartan complex does not depend on the time of food intake.

Distribution

The sacubitril and valsartan complex is largely bound to plasma proteins (94-97%). Comparison of plasma and CSF exposures shows that sacubitrilat penetrates the BBB 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 to 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 sacubitril and valsartan are minimally metabolized by cytochrome CYP450 isoenzymes, a change in their pharmacokinetics when co-administered with drugs affecting CYP450 isoenzymes seems unlikely.

Elimination

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

Sacubitril, sacubitrilat, and valsartan are eliminated from plasma with mean T_1/2 of approximately 1.43 h, 11.48 h, and 9.90 h, respectively.

Linearity/non-linearity

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

Pharmacokinetics in special clinical cases

Patients over 65 years

Exposure to sacubitrilat and valsartan in these patients increases by 42% and 30%, respectively, compared to younger patients. However, this is not accompanied by clinically significant effects and, therefore, does not require dose adjustment.

Children and adolescents under 18 years

The use of the drug in patients of this category has not been studied.

Patients with renal impairment

A correlation between renal function and AUC was observed for sacubitrilat, but no such correlation was observed for valsartan. In patients with mild (estimated glomerular filtration rate (eGFR) 89-60 ml/min/1.73 m²) and moderate renal impairment (59-30 ml/min/1.73 m²), 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 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 drug Uperio 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 sacubitrilat and valsartan 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, exposure to sacubitril increased by 1.5 and 3.4 times, respectively. Exposure to sacubitrilat – by 1.5 and 1.9 times, 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 drug is not required.

In patients with heart failure and moderate hepatic impairment (Child-Pugh class B), the recommended initial dose of the drug 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 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 sacubitril and valsartan complex (sacubitril, sacubitrilat, and valsartan) 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 due to heart failure. The maximum risk reduction is observed in patients with left ventricular ejection fraction below normal;
• essential arterial hypertension.

ICD codes

Dosage Regimen

The drug is taken orally. The time of taking Uperio does not depend on the time of food intake.

Heart failure

The target (maximum daily) dose of Uperio is 200 mg (102.8 mg + 97.2 mg) twice daily. The recommended starting dose of Uperio is 100 mg (51.4 mg + 48.6 mg) twice daily. Depending on tolerance, the dose of Uperio 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 ACE inhibitors or ARBs, or who have received these drugs in low doses, therapy with Uperio 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).

Uperio can be used no earlier than 36 hours after discontinuation of an ACE inhibitor, because simultaneous use may lead to the development of angioedema.

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

If signs of intolerance to Uperio develop (clinically significant decrease in blood pressure, hyperkalemia, impaired renal function), a temporary dose reduction or adjustment of the dose of concomitant medications should be considered.

Essential arterial hypertension

The recommended starting dose of Uperio is 200 mg once daily. In patients with inadequate blood pressure control at a dose of 200 mg once daily, it can be increased to 400 mg once daily. In patients with arterial hypertension and heart failure, the dose recommended for heart failure (200 mg twice daily) is recommended. Uperio 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 (eGFR 60-90 mL/min/1.73 m²) or moderate renal impairment (eGFR 30-60 mL/min/1.73 m²), no dose adjustment is required (see section “Pharmacological action”).

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

The safety and efficacy of Uperio in patients with essential arterial hypertension and severe renal impairment (eGFR <30 mL/min/1.73 m²) have not been established (see section “Pharmacological action”).

Patients with hepatic impairment

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment of Uperio is required.

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

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

Children and adolescents under 18 years of age

There are no data on the safety and efficacy of Uperio in children and adolescents. Not recommended for use in children under 18 years of age.

Patients over 65 years of age

In patients over 65 years of age, no dose adjustment is required.

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 studies. Of these, 5085 received Uperio therapy for at least 1 year.

PARADIGM-HF

The safety of Uperio in patients with chronic heart failure with LVEF <40% was evaluated in the main phase 3 PARADIGM-HF study, which compared groups receiving Uperio 200 mg twice daily (n=4203) or enalapril 10 mg (n=4229).

When assessing safety, the duration of therapy in patients with chronic heart failure was up to 4.3 years, with an average duration of intake of 24 months.

Discontinuation of therapy due to adverse events (AEs) was required in 10.71% of patients receiving Uperio and in 12.20% receiving the comparator drug. The phenomena most often associated with dose adjustment or discontinuation of therapy were: arterial hypotension, hyperkalemia, and impaired renal function. The identified adverse drug reactions (ADRs) corresponded to the pharmacological characteristics of Uperio and the comorbidities present in the patients.

The frequency of adverse reactions (ARs) did not depend on gender, age, or race.

ADRs are listed according to the MedDRA system-organ class. Within each system-organ class, ADRs are distributed by frequency of occurrence in order of decreasing significance. The following criteria were used to assess frequency: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000), including individual reports; frequency unknown - since information about these ADRs was obtained in the post-registration period from spontaneous reports and reports in the literature, it is not always possible to accurately assess the frequency of occurrence and the causal relationship with the drug, for these reactions "frequency unknown" is indicated).

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.

PARAGON-HF

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

Essential arterial hypertension

The safety of Uperio in patients with essential arterial hypertension was evaluated in clinical studies involving more than 7000 patients with hypertension (more than 3500 patients received Uperio).

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

ADRs are classified by system-organ classes, and then by frequency, starting with the most frequent, using the following categories: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10000 to <1/1000); very rare (<1/10000), including individual reports. Within each frequency group, ADRs are grouped in descending order of severity.

Nervous system disorders: common – dizziness.

Contraindications

• Hypersensitivity to sacubitril or to valsartan, as well as to other excipients included in the drug;
• Simultaneous use with ACE inhibitors, as well as the period of 36 hours after discontinuation of ACE inhibitors;
• History of angioedema during previous therapy with ACE inhibitors or ARBs;
• Hereditary angioedema;
• Simultaneous use with drugs containing aliskiren in patients with diabetes mellitus or with moderate or severe renal impairment (eGFR <60 mL/min/1.73 m²);
• Severe hepatic impairment (Child-Pugh class C), biliary cirrhosis and cholestasis;
• Childhood and adolescence under 18 years of age due to lack of data on efficacy and safety;
• Pregnancy and pregnancy planning;
• Period of breastfeeding;
• Simultaneous use with other drugs containing ARBs, because the drug contains valsartan.

With caution

• Severe renal impairment (eGFR <30 mL/min/1.73 m²), including in patients on hemodialysis or undergoing hemodialysis (eGFR <15 mL/min/1.73 m²) due to lack of safety data in these patients;
• Bilateral renal artery stenosis;
• Hypovolemia, which may be caused by diuretic therapy, low-salt diet, diarrhea, or vomiting;
• Simultaneous use with drugs that can increase serum potassium levels (e.g., potassium-sparing diuretics, potassium preparations);
• Simultaneous use with statins, PDE5 inhibitors;
• History of angioedema due to lack of data on the use of the drug in these patients (patients of Black race may be more susceptible to the risk of angioedema).

Use in Pregnancy and Lactation

Patients and patients with preserved reproductive potential, contraception (if applicable)

Female patients with preserved reproductive potential should be informed about the possible 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 directly act on the RAAS, Uperio should not be used during pregnancy. The action of Uperio is mediated by blockade of angiotensin II 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, the patient should discontinue the drug and inform her attending physician.

Breastfeeding

It is unknown whether Uperio passes into human breast milk. Since preclinical studies have noted the excretion of sacubitril and valsartan in the milk of lactating rats, it is not recommended to use Uperio during breastfeeding. The decision to discontinue breastfeeding or to discontinue Uperio treatment 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 Uperio on male and female fertility. In studies of Uperio in animals, no decrease in fertility was noted.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment (Child-Pugh class C), biliary cirrhosis and cholestasis.

In patients with mild hepatic impairment (Child-Pugh class A), no dose adjustment is required.

Use in Renal Impairment

The drug should be prescribed with caution in severe renal impairment (eGFR <30 mL/min/1.73 m²), including in patients on hemodialysis or undergoing hemodialysis (eGFR <15 mL/min/1.73 m²) due to lack of safety data in these patients; in bilateral renal artery stenosis.

In patients with mild (eGFR 60-90 mL/min/1.73 m²) or moderate renal impairment (eGFR 30-60 mL/min/1.73 m²), no dose adjustment is required.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

In patients over 65 years of age, no dose adjustment is required.

Special Precautions

Marked decrease in blood pressure

Cases of clinically significant arterial hypotension have been observed in patients receiving Uperio. If arterial hypotension occurs, consideration should be given to adjusting the dose of diuretics, concomitant antihypertensive agents, as well as eliminating the causes of arterial hypotension (e.g., hypovolemia). If, despite these measures, arterial hypotension persists, the dose of Uperio should be reduced or the drug should be temporarily discontinued. Complete withdrawal 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, a low-salt diet, diarrhea, or vomiting. Before starting Uperio, sodium levels should be corrected and/or blood volume should be replenished.

Renal impairment

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

Hyperkalemia

Like any other drug acting on the RAAS, Uperio may increase the risk of hyperkalemia. In a comparative safety and efficacy study (compared with enalapril), clinically significant hyperkalemia was rare; Uperio 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 Uperio. 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 Uperio. If angioedema occurs, Uperio should be discontinued immediately and appropriate treatment should be initiated, with patient observation until all symptoms have completely and permanently resolved. Uperio should not be re-administered. In cases of confirmed angioedema where the edema 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 edema extends to the tongue, vocal cords, or larynx, which may lead to airway obstruction, appropriate treatment should be initiated immediately, e.g., subcutaneous administration of epinephrine (adrenaline) solution 1:1000 (0.3-0.5 mL), and/or appropriate measures to ensure airway patency should be taken.

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

Patients of Black race may be more susceptible to the risk of angioedema.

Patients with renal artery stenosis

Like other drugs acting on the RAAS, Uperio 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 vehicles and mechanisms

There are no data on the effect of the drug on the ability to drive vehicles and/or mechanisms. Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or working with mechanisms.

Overdose

Data on overdose of Uperio in humans are insufficient. Single administration of the drug at a dose of 1200 mg and multiple administration at a dose of 900 mg (14 days) in healthy volunteers was accompanied by good tolerability.

Symptoms the most likely symptom of overdose is arterial hypotension due to the antihypertensive effect of the drug.

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

Drug Interactions

Contraindicated drug combinations

ACE inhibitors

Uperio is contraindicated for simultaneous use with ACE inhibitors, because inhibition of neprilysin simultaneously with the use of an ACE inhibitor may increase the risk of angioedema. Uperio can be used no earlier than 36 hours after discontinuation of an ACE inhibitor. An ACE inhibitor can be used no earlier than 36 hours after the last dose of Uperio.

Aliskiren

Concomitant use of the drug Uperio with aliskiren-containing preparations is contraindicated in patients with diabetes mellitus or with impaired renal function (eGFR <60 ml/min/1.73 m²) and is not recommended in other patients.

Not Recommended Drug Combinations

Angiotensin II Receptor Antagonists

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

Drug Combinations Requiring Consideration of Interaction

HMG-CoA Reductase Inhibitors (Statins)

Research data indicate that sacubitril inhibits the activity of OATP1B1 and OATP1B3 transporters. The drug Uperio may increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. In patients receiving the drug Uperio concomitantly with atorvastatin, the C_max of atorvastatin and its metabolites in plasma increased up to 2-fold, and AUC up to 1.3-fold. Caution should be exercised when using statins concomitantly with the drug Uperio. No clinically significant drug interaction was observed with the concomitant use of the drug Uperio with simvastatin.

Sildenafil

In patients with marked hypertension receiving the drug Uperio (prior to reaching C_ss), a single dose of sildenafil enhanced the antihypertensive effect compared to the use of the drug Uperio in monotherapy. For this reason, sildenafil or another PDE5 inhibitor should be used with caution in patients receiving the drug Uperio.

Potential Drug Interaction Requiring Consideration

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 the drug Uperio concomitantly with these drugs, regular monitoring of serum potassium is recommended.

NSAIDs, including selective COX-2 inhibitors

Use of the drug Uperio concomitantly with NSAIDs in patients older than 65 years, in patients with hypovolemia (including those receiving diuretics), and in patients with impaired renal function may increase the risk of worsening renal function. In patients receiving the drug Uperio concomitantly with NSAIDs, renal function should be monitored when initiating and during this treatment regimen and when it is changed.

Lithium preparations

The possibility of a drug interaction between the drug Uperio and lithium preparations has not been studied. Concomitant use of lithium preparations with ACE inhibitors and ARBs II has been associated with a reversible increase in serum lithium concentrations and a consequent increase in toxic manifestations.

In patients receiving the drug Uperio together with lithium preparations, it is recommended to carefully monitor serum lithium levels. 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 the drug Uperio concomitantly with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g., rifampicin and cyclosporine) or MRP2 (e.g., ritonavir), the systemic exposure of sacubitrilat or valsartan, respectively, may increase. Caution is required when initiating and discontinuing concomitant use of the drug Uperio and these groups of drugs.

Absence of Significant Drug Interaction

No clinically significant interaction was identified when the drug Uperio was used in combination with furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, metformin, omeprazole, carvedilol, intravenous nitroglycerin, or the combined preparation of levonorgestrel and ethinylestradiol. Interaction with atenolol, indomethacin, glibenclamide (glyburide), or cimetidine when used concomitantly with the drug Uperio is not expected.

Interaction with Cytochrome P450 Isoenzymes

Available studies demonstrate that the likelihood of a drug interaction mediated by cytochrome CYP450 isoenzymes is low, as the complex of active substances is minimally metabolized via CYP450 isoenzymes. The complex of active substances of the drug Uperio 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) to protect from moisture, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years. Do not use after the expiration date.

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.