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Composition:


active ingredients: sacubitril and Valsartan;


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


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


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


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


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


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


Dosage form. Film-coated tablets.


Basic physical and chemical properties:


Huperio 50 mg: Oval, biconvex film-coated tablets of purple-white color, with beveled edges, without risk, embossed with "NVR" on one side and "LZ" on the other side.


Yuperio 100 mg: Oval, biconvex film-coated tablets of light yellow color, with beveled edges, without risk, embossed with "NVR" on one side and "L1" on the other side.


Yuperio 200 mg: Oval, biconvex film-coated tablets of light pink color, with beveled edges, without risk, embossed with "NVR" on one side and "L11" on the other side.


Pharmacotherapeutic group. Drugs that affect the renin-angiotensin system. Angiotensin II antagonists, other combinations.


ATX code C09D X04.


Pharmacological properties.


Pharmacodynamics.


The pharmacodynamic effects of sacubitril and valsartan were evaluated after single and repeated administration of the drug in healthy volunteers, as well as in patients with chronic heart failure. The observed effects corresponded to the mechanism of action of the complex of active substances, which consists in simultaneous inhibition of neprilysin and blockade of the renin-angiotensin-aldosterone system (RAAS). In a seven-day study involving patients with reduced left ventricular ejection fraction (EF), in which valsartan was used as a control, the use of sacubitrile and Valsartan caused a statistically significant short-term increase in natriuresis, an increase in the concentration of cyclic guazine monophosphate (cGMP) in the urine, and a decrease in the concentration of atrial natriuretic peptide (MR-proANP) and the N-terminal fragment of the brain natriuretic peptide precursor (NT-proBNP) in blood plasma (compared to valsartan). In a 21-day study in patients with reduced left ventricular FV, the use of sacubitril and Valsartan caused a statistically significant increase in the concentration of atrial natriuretic peptide (ANP) and cGMP in the urine and the concentration of cGMP in blood plasma, as well as a decrease in plasma concentrations of NT-proBNP, aldosterone and endothelin-1 (compared to baseline). In addition, the use of sacubitrile and Valsartan blocks the AT1 receptor, which is indicated by an increase in the activity and concentration of renin in blood plasma. In the PARADIGM-HF study, the sacubitril and Valsartan complex caused a more pronounced decrease in the concentration of NT-proBNP in blood plasma and a more significant increase in the concentrations of cerebral natriuretic peptide (BNP) and cGMP in urine than enalapril. Therefore, NT-proBNP, unlike BNP, can be used as a biomarker during the follow-up of patients with heart failure receiving a complex of sacubitril and Valsartan (see the section "application features").


In a study of the QTc interval in healthy male volunteers, a single dose of Juperio at dosages of 194 mg of sacubitril/ 206 mg of valsartan and 583 mg of sacubitril/ 617 mg of valsartan did not affect cardiac repolarization.


Neprilysin is one of several enzymes involved in the metabolism of amyloid-β (Aß) in the brain and cerebrospinal fluid (CMR). When using Huperio at a dosage of 194 mg of sacubitril/ 206 mg of valsartan once a day for two weeks in healthy volunteers, the concentration of Aß 1-38 in the cerebrospinal fluid increased; while the concentration of Aß 1-40 and 1-42 in the CMR did not change in any way. The clinical significance of this fact is unknown.


Clinical efficacy and safety


Dosage-50 mg, 100 mg or 200 mg of the drug are indicated in some sources as 24 mg/ 26 mg, 49 mg/ 51 mg and 97 mg/ 103 mg of the drug.


PARADIGM-HF


PARADIGM-HF is a multinational, randomized, double-blind study involving 8,442 patients, which compared Huperio and enalapril taken by adult patients with chronic heart failure, Class II–IV according to the New York Heart Association (NYHA) classification, and a reduced ejection fraction (left ventricular ejection fraction [FVLSH] ≤ 40%, later adjusted to ≤ 35 %) in addition to other drugs prescribed for heart failure. The primary endpoint was combined – death due to cardiovascular pathology or hospitalization due to heart failure. Patients with systolic blood pressure (Sat 2) and severe hepatic impairment were excluded from screening and, as a result, did not complete a prospective study.


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


Patients were required to stop therapy with ACE inhibitors or ARBs, after which they were included in a sequential, simple blind period of administration and received enalapril 10 mg twice a day, then simple blind therapy Huperio 100 mg twice a day, with an increase to 200 mg twice a day (see the section "adverse reactions" for discontinuation of therapy during this period). They were then randomized to participate in a double – blind study period, during which they received either Yuperio 200 mg or enalapril 10 mg twice daily (Yuperio: n = 4,209; enalapril: n = 4,233).


The average age of patients in the study population was 64 years, and 19% were aged 75 years and older. At the time of randomization, 70% of patients had NYHA Class II chronic heart failure, 24% had NYHA Class III chronic heart failure, and 0.7% had NYHA Class IV chronic heart failure. The mean LVEF was 29%; 963 (11.4%) patients had baseline LVEF > 35% and ≤ 40%.


In the Huperio group, 76% of patients remained on the target dose of 200 mg twice daily until the end of the study (the average daily dose is 375 mg). In the enalapril Group, 75% of patients remained on the target dose of 10 mg twice daily until the end of the study (the average daily dose is 18.9 mg).


Juperio compared to enalapril statistically significantly reduced the risk of death due to cardiovascular pathology or the risk of hospitalization due to heart failure (21.8% in the study drug group versus 26.5% in the enalapril group). The absolute reduction in the risk of death due to cardiovascular pathology or the risk of hospitalization due to heart failure was 4.7 % (3.1%-reduced the risk of death due to cardiovascular pathology and 2.8% – reduced the risk of primary hospitalization due to heart failure). The relative risk reduction compared to enalapril was 20 %. The effect was noted in the early stages of drug use and persisted throughout the entire 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 due to cardiovascular pathology, in the study drug group decreased by 20% compared to the enalapril group (hazard ratio, HR) 0.80, p = 0.0082). The incidence of contractile insufficiency of the heart, which was the cause of death in 26% of cases due to cardiovascular pathology, in the group of the studied drug decreased by 21% compared to that in the enalapril group (HR 0.79, p = 0.0338).


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

TITRARION research


TITRATION is 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


A larger number of patients who have not previously received ACE inhibitors or ARBs or have received low-dose therapy (equivalent to


Children


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


Mechanism of action


Huperio demonstrates the mechanism of action of a non – lysine receptor antagonist inhibitor by simultaneously inhibiting non-lysine (neutral endopeptidase; NEP) via lbq657, the active metabolite of sacubitrile, and blocking angiotensin II type 1 (AT1) receptors with valsartan. The additional positive effect of Huperio on the cardiovascular system in patients with heart failure is explained by the fact that LBQ657 activates peptides that break down under the influence of neprilisin, in particular natriuretic peptides (NP), while valsartan suppresses the negative effects of angiotensin II. NPS manifest their effect by activating membrane-bound receptors associated with guanyl cyclase, which leads to an increase in the concentration of cyclic guanosine monophosphate (cGMP) and causes symptoms of vasodilation, increased natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, decreased sympathetic activity, and also has antihypertrophic and antifibrotic effects.


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


Pharmacokinetics.


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


Suction


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


After applying Huperio twice a day, steady-state concentrations of sacubitril, LBQ657 and valsartan are reached within three days. There is no statistically significant accumulation of sacubitrile and Valsartan at steady state; at the same time, the accumulation of LBQ657 exceeds the concentration with a single application by 1.6 times. Taking the drug with a meal does not have a clinically significant effect on the systemic effects of sacubitril, LBQ657 and Valsartan. Huperio can be taken regardless of food intake.


Distribution


Sacubitril, LBQ657, and Valsartan bind strongly to plasma proteins (94-97 %). LBQ657 slightly penetrates the blood-brain barrier (0.28 %). The average apparent volume of distribution of valsartan and sacubitrile was 75 and 103 liters, respectively.


Metabolism


Sacubitril is rapidly converted to LBQ657 under the influence of lb and lc carboxylesterase; in addition, LBQ657 is not significantly metabolized. Valsartan is metabolized to a small extent, only about 20% of the administered dose is detected as metabolites. The hydroxyl metabolite was detected in the blood plasma in insignificant concentrations ( 10%).


Since both sacubitril and valsartan are minimally metabolized with the participation of cytochrome CYP450 isoenzymes, a change in their pharmacokinetics in the case of simultaneous use of drugs that affect CYP450 isoenzymes is unlikely.


Output


After oral administration of Juperio, 52-68% of sacubitril (mainly in the form of LBQ657) and approximately 13% of valsartan and its metabolites are excreted in the urine; 37-48% of sacubitril (mainly in the form of LBQ657) and 86% of valsartan and its metabolites are excreted in the faeces.


Sacubitril, LBQ657, and valsartan are eliminated from plasma with an average Half-Life (T1/2) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.


Linearity/nonlinearity


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


Pharmacokinetics in certain groups of patients


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


Impaired renal function. There was a correlation between renal function and systemic exposure to LBQ657 in patients with mild or severe renal impairment. The effect of LBQ657 in patients with moderate (30 mL/min/1.73 m2 ≤ rscf 2) and severe impairment (15 mL/min/1.73 m2 ≤ rscf 2) was 1.4 and 2.2 times higher than in patients with mild renal impairment (60 mL/min/1.73 m2 ≤ rscf 2) – this is the largest group of patients who participated in the PARADIGM-HF study). The effect of valsartan was similar in patients with moderate to severe renal impairment compared to patients with mild renal impairment. Studies involving patients undergoing hemodialysis have not been conducted. However, LBQ657 and valsartan are largely bound to plasma proteins, so their elimination during hemodialysis is unlikely.


Impaired liver function. In patients with mild to moderate hepatic impairment, sacubitril exposure increased 1.5 and 3.4 times, LBQ657 – 1.5 and 1.9 times, and Valsartan – 1.2 and 2.1 times, respectively, compared to that in healthy volunteers. However, in patients with mild to moderate hepatic impairment, exposure to free concentrations of LBQ657 increased 1.47 and 3.08 times, respectively, and exposure to free concentrations of valsartan increased 1.09 and 2.20 times, respectively, compared to healthy volunteers. Yuperio has not been studied in patients with severe hepatic impairment, biliary cirrhosis, or cholestasis (see the sections "contraindications" and "application features").


Influence of gender. The pharmacokinetics of Huperio (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.


* Concomitant use with ACE inhibitors (see sections "features of Use" and "interactions with other drugs and other types of interactions"). Yuperio can be taken if at least 36 hours have passed since the ACE inhibitor was discontinued.


* A history of angioedema with ACE inhibitors or ARBs (see the section "special instructions for use").


* Hereditary or idiopathic angioedema (see the section "application features").


* Concomitant use with drugs containing aliskiren in patients with diabetes mellitus or patients with impaired renal function (rshkf 2) (see sections "features of Use" and "interactions with other drugs and other types of interactions").


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


* Second and third trimesters of pregnancy (see the section "use during pregnancy or lactation").


Interactions with other drugs and other types of interactions.


Combined use is contraindicated.


ACE inhibitors. Concomitant use of Yuperio with ACE inhibitors is contraindicated, since simultaneous inhibition of neprilisin (NEP) and Ace increases the risk of angioedema. Yuperio therapy should be started no earlier than 36 hours after taking the last dose of an ACE inhibitor. ACE inhibitor therapy should begin no earlier than 36 hours after the last dose of Huperio (see sections "dosage and administration" and "Contraindications").


Aliskiren. Concomitant use of Yuperio with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and patients with impaired renal function (rshkf 2) (see the section "contraindications"). The combination of Huperio and direct renin inhibitors, such as aliskiren, is not recommended (see the section "special instructions for use"). The combination of Huperio and aliskiren is potentially associated with a higher frequency of adverse reactions, such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure) (see the sections "contraindications" and "application features").


Joint use is undesirable.


Huperio contains valsartan, so it should not be used with other drugs containing sconces (see the section "special applications").


Joint use requires precautions.


OATP1B1 and OATP1B3 substrates (HMG-CoA reductase inhibitors), such as statins. In vitro data indicate that sacubitril inhibits the oatp1b1 and OATP1B3 transporters. As a consequence, Huperio may increase systemic exposure to OATP1B1 and OATP1B3 substrates, in particular statins. Concomitant use of Yuperio increased the Cmax of atorvastatin and its metabolites by 2 times, and the AUC – by 1.3 times. Therefore, caution should be exercised when using Huperio concomitantly with statins.


Phosphodiesterase 5 inhibitors, including sildenafil. In patients with a marked increase in blood pressure (BP) receiving the drug Yuperio (until the equilibrium concentration is reached), a single use of sildenafil increased the antihypertensive effect compared to the use of the drug Yuperio as monotherapy. For this reason, patients receiving Huperio should use sildenafil or another type 5 phosphodiesterase inhibitor with caution.

Potassium. Concomitant use of potassium-sparing diuretics (Triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements or potassium-containing table salt substitutes, and other medications (e.g. heparin) may lead to increased serum potassium and serum creatinine levels. In patients receiving Juperio simultaneously with these drugs, it is recommended to regularly monitor the content of potassium in the blood serum (see the section "features of 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 impaired renal function, concomitant use of Yuperio and nonsteroidal anti-inflammatory drugs increases the risk of impaired renal function.


In patients receiving Yuperio concomitantly with nonsteroidal anti-inflammatory drugs, it is recommended to monitor renal function (see the section "special instructions for use").


Lithium preparations. Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors or angiotensin II receptor antagonists.  Therefore, the combination of these drugs is not recommended. If this combination is necessary, careful monitoring of serum lithium levels is required. When using diuretics, the risk of toxic effects of lithium may increase.


Furosemide. Concomitant use of Yuperio and furosemide does not affect the pharmacokinetics of Yuperio, but reduces the Cmax and AUC of Furosemide by 50% and 28%, respectively. While the volume of urine did not change significantly, urinary sodium excretion decreased within 4 and 24 hours after simultaneous administration. The average daily dose of Furosemide did not change compared to the baseline dose until the end of the PARADIGM-HF study in patients treated with Huperio.


Nitrates, such as nitroglycerin. There was no drug interaction between Huperio and nitroglycerin administered intravenously to lower blood pressure. In the case of simultaneous use of nitroglycerin and Huperio, the heart rate was accompanied by a difference of 5 beats per minute compared to the use of nitroglycerin alone as monotherapy. A similar effect on heart rate was observed when Huperio was taken with sublingual, oral, or transdermal nitrates. In general, no dose adjustment is required.


OATP and MRP2 transporters. The active metabolite of sacubitrile (LBQ657) and valsartan are substrates of OATP1B1, OATP1B3, OAT1, and OAT3; valsartan is also a substrate of MRP2. Thus, concomitant use of Huperio with OATP1B1, OATP1B3, OAT3 inhibitors (e.g. rifampicin, cyclosporine), OAT1 (e.g. tenofovir, cidofovir), or MRP2 (e.g. ritonavir) may lead to increased systemic exposure to LBQ657 or valsartan. Caution should be exercised at the beginning and at the time of completion of the combined use of Huperio and these drugs.


Metformin. Concomitant use of Huperio and metformin resulted in a 23% decrease in the Cmax and AUC of metformin. The clinical significance of these data is unknown. Therefore, before starting treatment with Huperio, patients taking metformin should be evaluated for their clinical condition.


Minor interactions


No clinically significant drug interactions were observed with the use of Huperio and digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol, or the Levonorgestrel/Ethinyl Estradiol combination.


In vitro metabolic studies show that the probability of drug interactions mediated by cytochrome CYP 450 isoenzymes is extremely low, since the metabolism of Huperio via CYP450 enzymes is limited. Huperio does not activate or inhibit CYP450 enzymes.


Application features.


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


The combination of Huperio with ACE inhibitors is contraindicated due to the increased risk of angioedema (see the section "contraindications"). Yuperio should not be taken until 36 hours have passed since the last dose of an ACE inhibitor was taken. After discontinuation of Yuperio therapy, ACE inhibitors should not be started earlier than 36 hours after the last dose of Yuperio (see the sections "dosage and administration", "contraindications" and "interactions with other drugs and other types of interactions").


It is not recommended to use Huperio concomitantly with direct renin inhibitors, in particular with aliskiren (see the section "interactions with other drugs and other types of interactions"). The combination of Juperio with drugs containing aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (rshkf 2) (see sections "contraindications" and "interactions with other drugs and other types of interactions").


Huperio contains valsartan, so it should not be used with other drugs containing ARBs (see the sections "dosage and Administration" and "interactions with other drugs and other types of interactions").


Hypotension


Treatment should not be initiated if the SAT is not ≥ 100 mm Hg. St. patients with sat


Impaired renal function


Screening of patients with heart failure should always include an assessment of renal function. Patients with mild to moderate renal impairment are significantly more likely to develop hypotension (see the section "dosage and administration"). There is extremely limited clinical experience with the use of the drug in patients with severe renal impairment (rscf 2), who have a high risk of developing hypotension (see the section "dosage and administration"). There is no experience of using Yuperio in patients with impaired renal function in the end stage of kidney disease, and the use of the drug in this case is not recommended.


Deterioration of renal function


The use of Huperio, as well as any other drug that acts on RAAS, can lead to deterioration of renal function. The risk increases with dehydration or concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) (see the section "interactions with other drugs and other types of interactions"). In case of clinically significant deterioration of renal function, consideration should be given to reducing the dose of Yuperio.


Hyperkalemia


Treatment should not be initiated if the serum potassium level is > 5.4 mmol/L. Yuperio therapy increases the risk of hyperkalemia, and hypokalemia may also occur (see the section "adverse reactions"). It is recommended to regularly monitor serum potassium levels, especially in patients with risk factors such as impaired renal function, diabetes mellitus or hypoaldosteronism, or a diet high in potassium, as well as taking mineralocorticoid antagonists (see the section "dosage and administration"). If clinically significant hyperkalemia develops, it is recommended to adjust the dose of concomitant medications or temporarily reduce the dose, or discontinue therapy. Discontinuation of therapy is recommended if the serum potassium level is > 5.4 mmol/L.


Angioedema


Against the background of the use of the drug Yuperio, cases of angioedema have been noted. If angioedema occurs, Huperio should be discontinued immediately and appropriate treatment and monitoring of the patient should be prescribed until all symptoms disappear completely and permanently. The drug should not be reused. In cases of confirmed angioedema that spread only to the face and lips, this condition usually went away on its own, although prescribing antihistamines helped relieve symptoms.


Angioedema, accompanied by laryngeal edema, can be fatal. In cases where edema spreads to the tongue, vocal folds or larynx, which can lead to airway obstruction, appropriate treatment should be initiated immediately, for example, the introduction of an epinephrine solution of 1 mg/ 1 ml (0.3–0.5 ml), and/or ensure airway patency.


Patients with a history of angioedema were not studied. Given that they have a high risk of developing angioedema, it is recommended to prescribe Huperio to this category of patients with great caution. Yuperio is contraindicated in patients with a history of angioedema with the use of an ACE inhibitor or ARBs, or hereditary or idiopathic angioedema (see the section "contraindications").


Patients of the black race are more likely to develop angioedema (see the section "adverse reactions").


Patients with renal artery stenosis


Huperio 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, regularly monitoring renal function.


Patients with NYHA functional Class IV chronic heart failure


Caution should be exercised when using Huperio in patients with NYHA functional Class IV chronic heart failure, as data on clinical use in this category of patients are limited.


B-type natriuretic peptide (BNP)


BNP is not an appropriate biomarker of heart failure in patients treated with Huperio, as it is a non-lysine substrate (see Section "pharmacodynamics").

Patients with hepatic insufficiency


Experience in clinical use of the drug in patients with moderate hepatic impairment (Child – Pugh Class B) or with values of aspartate aminotransferase/ alanine aminotransferase (AST/ALT) exceeding the upper limit of normal by two times is limited. Patients in this category are more sensitive to the effects of the drug, and the degree of safety for them has not been established. As a result, it is necessary to prescribe the drug with caution to such patients (see the section "dosage and administration" and "pharmacokinetics"). Yuperio is contraindicated in patients with severe hepatic impairment (Child – Pugh Class C), biliary cirrhosis, or cholestasis (see Section "contraindications").


Use during pregnancy or lactation.


Pregnancy


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


Valsartan. Epidemiological data on the risk of teratogenicity due to exposure to ACE inhibitors during the first trimester of pregnancy are not definitive; however, some increase in this risk cannot be excluded. Despite the lack of controlled epidemiological data on teratogenicity associated with ARBs, similar risks may exist when using this class of drugs. In cases where it is necessary to continue therapy for ARBs, patients planning pregnancy should be transferred to alternative antihypertensive drugs that have a proven safety profile for use during pregnancy. Treatment with ARBs should be discontinued immediately after pregnancy and, if necessary, alternative therapy should be prescribed. It is known that ARBs therapy during the second and third trimester provokes fetotoxicity (decreased renal function, oligohydramnion, slowing ossification of the skull) and neonatal toxicity (renal failure, hypotension, hyperkalemia).


If ARBs have been used since the second trimester of pregnancy, it is recommended to perform an ultrasound examination of the kidneys and the condition of the skull bones. Newborns whose mothers have taken ARBs should be carefully monitored for the development of hypotension (see the section "contraindications").


Sacubitrile. There are no data on the use of sacubitrile in pregnant women. Animal studies have revealed reproductive toxicity.


Huperio. There are no data on the use of Yuperio in pregnant women. Animal studies using Huperio have revealed reproductive toxicity.


Breastfeeding


It is not known whether Huperio is excreted in breast milk. The components of Juperio-sacubitril and valsartan – were isolated with milk in lactating rats. Given the potential risk of adverse reactions in breastfed children, it is not recommended to use the drug during breast-feeding.


Reproductive function


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


Ability to influence the reaction rate when driving vehicles or other mechanisms.


Due to the possible occurrence of dizziness or increased fatigue, caution should be exercised when driving vehicles or working with other mechanisms.


Dosage and administration.


The drug is intended for oral administration. The time of taking the drug Yuperio does not depend on the time of meal (see the section "pharmacokinetics"). Tablets should be swallowed whole and washed down with a glass of water.


Dosage


The recommended starting dose of Yuperio is 1 tablet of 100 mg 2 times a day, except for the situations described below. The dose should be doubled after 2-4 weeks of administration in such a way that the dose is one tablet of 200 mg twice a day, provided that the patient is well tolerated.


If patients develop intolerance (systolic blood pressure (sat) ≤ 95 mm Hg). symptomatic hypotension, hyperkalemia, impaired renal function) it is recommended to adjust the combination therapy, temporarily reduce the dose, or discontinue therapy with Huperio (see the section "application features").


Information on the treatment of patients who do not take ACE inhibitors or ARBs, or take them in low doses, is limited. Therefore, for this category of patients, the recommended initial dose is 50 mg 2 times a day with a slow increase in the dose (doubling the daily dose 1 time in 3-4 weeks).


It is not recommended to start treatment in patients with serum potassium levels > 5.4 mmol/L or with sat


Valsartan, in the form of a complex salt contained in Yuperio, has a higher bioavailability compared to valsartan contained in other tablet preparations (see the section "pharmacokinetics").


If the patient has missed taking the drug, he should take the next dose at the appointed time.


Dosage for individual patient groups


Elderly patients


Dosage is determined taking into account renal function in elderly patients.


Patients with impaired renal function


For patients with mild renal impairment (estimated glomerular filtration rate (rscf) 60-90 mL/min/1.73 m2), no dose adjustment is required. An initial dose of 50 mg twice daily is recommended for patients with moderate renal impairment (rscf 30-60 mL/min/1.73 m2). Given the limited clinical experience of using the drug in patients with severe renal impairment (rshkf 2) (see the section "pharmacodynamics"), Yuperio is recommended to be prescribed with caution at an initial dose of 50 mg 2 times a day.  There is no experience of using Yuperio in patients with end-stage kidney disease, and taking the drug in this case is not recommended.


Patients with impaired liver function


For patients with mild hepatic impairment (Child – Pugh Class A), No dose adjustment of Huperio is required. Clinical experience with patients with moderate hepatic impairment (Child – Pugh Class B) or with AST/ALT values twice the upper limit of normal is limited. Yuperio should be used with caution in this category of patients; the recommended starting dose is 50 mg 2 times a day (see the sections "features of Use" and "pharmacokinetics").


Huperio is contraindicated in severe hepatic insufficiency, biliary cirrhosis of the liver, or cholestasis (Child – Pugh Class C) (see Section "contraindications").


Children.


The safety and efficacy of Yuperio in children (under 18 years of age) have not been established. No data available.


Overdose.


There are insufficient data on overdose of the drug Yuperio in humans.


Single use of the drug at a dose of 1200 mg and multiple use at a dose of 900 mg in healthy volunteers was well tolerated.


The most likely symptom of overdose is a pronounced decrease in blood pressure due to the antihypertensive effect of active substances. In this case, symptomatic treatment is recommended. The probability of drug withdrawal during hemodialysis is extremely low due to the high binding to plasma proteins.


Adverse reactions.


Adverse reactions such as hypotension, hyperkalemia, and impaired renal function were most often reported during Yuperio therapy (see Section "application specifics"). There have been reports that patients taking Huperio have developed angioedema (see "description of individual adverse events").


The safety of using Huperio in patients with chronic heart failure was evaluated in the basic Phase III PARADIGM-HF study, in which patients received Huperio 2 times a day 200 mg (n = 4,203) or enalapril 10 mg (N = 4,229). Patients randomized to the Huperio group were treated for 24 months; 3,271 patients received therapy for more than one year.

Angioedema


Patients taking Huperio have been reported to develop angioedema. In the PARADIGM-HF study, angioedema developed in 0.5% of patients treated with Huperio, compared to 0.2% of patients treated with enalapril. A higher incidence of angioedema was observed in black patients treated with Huperio (2.4 %) and enalapril (0.5 %) (see the section "application features").


Hyperkalemia and serum potassium


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


Blood pressure


Hypotension and clinically significant low systolic blood pressure ( 20 mm Hg) during the PARADIGM-HF study. St.) were observed in 17.6% and 4.76% of patients treated with Huperio, and in 11.9% and 2.67% of patients treated with enalapril, respectively.


Impaired renal function


During PARADIGM-HF, renal dysfunction developed in 10.1% of patients treated with Huperio and 11.5% of patients treated with enalapril.


Reports of suspected adverse reactions


It is important to report adverse reactions after registering the drug. This allows you to monitor the benefit/risk balance of using the drug. Health professionals are asked to report any adverse reactions through the National Reporting System.


Expiration date. 36 months.

Tags: Uperio® [Valsartan, Sacubitrile]