Yupero (Uperio)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceValsartan + SacubitrylValsartan + Sacubitryl
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  • Yupero
    pills inwards 
    Novartis Pharma AG     Switzerland
    • Dosage form: & nbsp

    Film-coated tablets.

    Composition:

    1 tablet, film-coated, 50 mg (25.7 mg + 24.3 mg) contains:

    Active substance: sakubitrila and valsartan hydrate complex of sodium salts - 56.551 mg (in terms of the acid form of anhydrous 50 mg, which is equivalent to 24.3 mg of sakubitryla and 25.7 mg of valsartan); Excipients: cellulose microcrystalline - 91.449 mg, giprolose - 25,000 mg, crospovidone - 18,000 mg, magnesium stearate - 6,000 mg, talc - 2,000 mg, silicon colloidal dioxide - 1,000 mg; shell: Premix shell white - 7.957 mg (hypromellose - 5.681 mg, titanium dioxide - 1.138 mg, macroline 4000 - 0.569 mg, talc - 0.569 mg), premix shell red 0.019 mg (hypromellose 0.014 mg, iron oxide red oxide 0.003 mg, macrogol 4000 - 0.001 mg, talc 0.001 mg), black coat premix 0.024 mg (hypromellose 0.017 mg, iron oxide black oxide 0.003 mg, macrogol 4000 0.002 mg, talc 0.002 mg).

    1 a film coated tablet, 100 mg (51.4 mg + 48.6 mg) contains:
    Active substance: sakubitrile and valsartan hydrate complex of sodium salts - 113.103 mg (in terms of the acid form of anhydrous 100 mg, which is equivalent to 48.6 mg of saccitrile and 51.4 mg of valsartan); Excipients: cellulose microcrystalline - 34,897 mg, giprolose - 25,000 mg, crospovidone - 18,000 mg, magnesium stearate - 6,000 mg, talc - 2,000 mg, silicon colloidal dioxide - 1,000 mg; shell: premix shell white - 7.732 mg (hypromellose - 5.521 mg, titanium dioxide - 1.106 mg, macroline 4000 - 0.553 mg, talc - 0.553 mg), premix coat yellow - 0.256 mg (hypromellose - 0.183 mg, iron oxide yellow oxide - 0.037 mg, macrogol 4000 0.018 mg, talc 0.018 mg), red coat premix 0.012 mg (hypromellose 0.009 mg, iron oxide red oxide 0.002 mg, macrogol 4000 0.001 mg, talc 0.001 mg).

    1 tablet, film-coated, 200 mg (102.8 mg + 97.2 mg) contains:
    Active substance: sakubitrile and valsartan hydrate complex of sodium salts - 226,206 mg (in terms of the acidic form of anhydrous 200 mg, which is equivalent to 97.2 sakubitrila and 102.8 mg of valsartan; Excipients: cellulose microcrystalline - 69,794 mg, giprolose - 50,000 mg, crospovidone - 36,000 mg, magnesium stearate - 12,000 mg, talc - 4,000 mg, silicon dioxide colloid - 2,000 mg; shell: premix shell white - 11.796 mg (hypromellose - 8.422 mg, titanium dioxide - 1.687 mg, macroline 4000 - 0.843 mg, talc - 0.843 mg), premix shell red - 0.168 mg (hypromellose 0.120 mg, iron oxide red oxide 0.024 mg, Macrogol 4000 - 0.012 mg, talc 0.012 mg), black coat premix 0.036 mg (hypromellose - 0.026 mg, iron oxide black 0.005 mg, macrogene 4000 0.003 mg, talc 0.003 mg).
    Description:

    Tablets 50 mg (25.7 mg + 24.3 mg)

    Oval biconvex tablets, covered with a film shell of white with a purple hue of color with a facet, without any risks. On one side is engraved "LZ", on the other side - "NVR". On the cross section, the nucleus is white or almost white in color.

    Tablets 100 mg (51.4 mg + 48.6 mg)

    Oval biconvex tablets covered with a film coat of pale yellow color with a bevel, without risks. On one side is engraved "Ll", on the other side - "NVR". On the cross section, the nucleus is white or almost white in color.

    Tablets 200 mg (102.8 mg + 97.2 mg)

    Oval biconvex tablets, covered with a film coating of light pink color with a facet, without any risks. On one side is engraved "Lll", on the other side - "NVR". On the cross section, the nucleus is white or almost white in color.

    Pharmacotherapeutic group:Not assigned
    ATX: & nbsp

    C.09.C.A.03   Valsartan

    Pharmacodynamics:

    Mechanism of action

    The action of the drug Yuperio is mediated by a new mechanism, namely: simultaneous suppression of the activity of neprilysin (neutral endopeptidase (NEP)) with the substance LBQ657 (active metabolite of sakubitrile) and blockade of receptors for angiotensin II type 1 (AT1) valsartan, which is an antagonist of angiotensin II receptors (APA II).Complementary beneficial effects sakubitrila and valsartan on the cardiovascular system and the kidney in patients with heart failure due to the increased number of peptides cleavable neprilysin (such as natriuretic peptides (NP)), which is mediated by the action LBQ657, simultaneous suppression of valsartan negative effects angioatenzina II. NP activated membrane-bound receptors coupled with guanylyl cyclase, which leads to increased concentrations of cyclic guanosine monophosphate (cGMP) inducing vasodilation symptoms increase natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin release and aldosterone, decreased sympathetic activity, and antigipertroficheskoe and antifibrotic action. Valsartan, selectively blocking AT1receptor inhibits the negative effects of angiotensin II on the cardiovascular system and kidneys, as well as blocking the angiotensin II-dependent release of aldosterone. This prevents persistent activation of the renin-angiotensin-aldosterone system (RAAS), which causes vasoconstriction,retention of sodium and water by the kidneys, activation of growth and cell proliferation, as well as the subsequent restructuring of the cardiovascular system, aggravating the disturbances in its functioning.

    Pharmacodynamics

    Pharmacodynamic effects of sakubitril and valsartan included in the preparation were evaluated after its single and repeated use 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, consisting in the simultaneous suppression of non-lysis and blockade of the RAAS. In a seven-day study in patients with a reduced ejection fraction (EF) of the left ventricle, in which valsartan used as a control, the use of sakubitrile and valsartan resulted in a statistically significant short-term increase in natriuresis, an increase in cGMP concentration in the urine, and a decrease in the concentration of the atrial natriuretic peptide (MR-proANP) and the N-terminal fragment of the brain natriuretic peptide (NT-proBNP) (in comparison with valsartan). In a 21-day study in patients with reduced left ventricular ejection, the use of sakubitrile andvalsartan caused a statistically significant increase in the concentration of atrial natriuretic peptide (ANP) and cGMP and urinary cGMP concentration in the blood plasma, and reduced plasma NT-proBNP concentrations of aldosterone and endothelin-1 (compared to baseline). In addition, the use of sakubitrile and valsartan blocks the AT1 receptor, as indicated by an increase in activity and renin concentration in the blood plasma. In another study sakubitrila complex of valsartan and caused a greater reduction in NT-proBNP concentrations in plasma and a significant increase in the concentration of brain natriuretic peptide (BNP) and urinary cGMP than enalapril. While BNP is a non-lysine substrate, NT-proBNP is not. Therefore, NT-proBNP, unlike BNP, can be used as a biomarker in monitoring patients with heart failure receiving a complex of sakubitrile and valsartan.

    In a study with a detailed study of QTc interval in healthy male volunteers and the use of the complex of valsartan sakubitrila singly in doses of 400 mg and 1200 mg had no effect on cardiac repolarization.

    Neprylysin is one of several enzymes involved in the metabolism of amyloid-β (Aβ) of the brain and cerebrospinal fluid (CSF). Against the background of the use of a complex of sakubitryla and valsartan in a dose of 400 mg once a day for 2 weeks in healthy volunteers, the concentration of Aβ l-38 in CSF increased; the concentration Aβ 1-40 and 1-42 in CSF did not change in any way. The clinical significance of this fact is unknown.

    In a clinical study, the use of the complex of sakubitrile and valsartan in patients with chronic heart failure statistically significantly reduced the risk of death due to cardiovascular pathology or hospitalization due to acute heart failure (21.8% in the study drug group versus 26.5% in the group enalapril). Absolute reduction in the risk of death due to cardiovascular pathology or hospitalization due to acute heart failure was 4.7% (3.1% for the risk of death due to cardiovascular disease and 2.8% for primary hospitalization due to acute cardiac failure insufficiency). The relative risk reduction compared with enalapril was 20%.The effect was noted in the early stages of the use of the drug and persisted throughout the study period. The development of the effect was promoted by both active components of the preparation. The rate of sudden deaths, which accounted for 45% of all deaths due to cardiovascular disease, decreased by 20% in the study drug group compared to the enalapril group (hazard ratio, HR 0.80, p = 0.0082 ). The incidence of contractile heart failure, which was the cause of death in 26% of cases due to cardiovascular disease, decreased by 21% in the study drug group compared to that in the enalapril group (HR 0.79, p = 0, 0338).
    Pharmacokinetics:

    Suction

    After ingestion, the complex of sacubitryl and valsartan decomposes into saccitrile, which is then metabolized to form the metabolite LBQ657, and valsartan; the concentrations of these substances in the blood plasma reach a maximum after 0.5 hours, 3 hours and 1.5 hours, respectively. Absolute bioavailability of saccitribil and valsartan after oral administration is ≥60% and 23% respectively.

    In the case of receiving the complex of sakubitril and valsartan, the equilibrium concentrations of sacubitryl, LBQ657 and valsartan are reached twice a day after 3 days. There is no statistically significant accumulation of sakubitrile and valsartan in the equilibrium state; At the same time, the accumulation of LBQ657 exceeds the concentration by a single application of 1.6 times. The use of the complex of sakubitrile and valsartan at the same time as food intake had no clinically significant effect on systemic exposure to saccitrile, LBQ657, and valsartan. Reducing the exposure of valsartan in the case of a combination of sakubitrile and valsartan at the same time as food intake is not accompanied by a clinically significant decrease in the therapeutic effect. The use of the complex of sakubitril and valsartan does not depend on the time of eating.

    Distribution

    The complex of sakubitrile and valsartan is largely associated with blood plasma proteins (94% - 97%). Comparison of exposures in blood plasma and CSF shows that LBQ657 penetrates to a small extent through the blood-brain barrier (0.28%). The apparent volume of distribution of the complex of sakubitrile and valsartan is from 107.8 to 157.4 liters.

    Metabolism

    Sacubitryl under the action of enzymes quickly turns into a metabolite LBQ657, which further is not significantly metabolized. Valsartan is metabolized to an insignificant degree, in the form of metabolites only about 20% of the administered dose is detected. In blood plasma at low concentrations (<10%) was found hydroxyl metabolite. Since both sacubitryl 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, affecting isozymes CYP450, is submitted unlikely.

    Excretion

    After oral administration, 52-68% of saccitrile (mainly in the form of LBQ657) and ~ 13% of valsartan and its metabolites are excreted by the kidneys; 37-48% of saccitrile (mainly in the form of LBQ657) and 86% of valsartan and its metabolites are excreted through the intestine.

    Sacubitryl, LBQ657 and valsartan are derived from blood plasma with average half-life (T½) of about 1.43 hours, 11.48 hours and 9.90 hours, respectively.

    Linearity / nonlinearity

    In the studied range of doses of the complex of sakubitril and valsartan (50-400 mg), the pharmacokinetic parameters of sacubitryl, LBQ657 and valsartan vary in proportion to the dose.

    Pharmacokinetics in special clinical cases

    Patients over 65 years of age

    Exposures of LBQ657 and valsartan in this category of patients are higher by 42% and 30%, respectively, than in patients of younger age. Such differences are not associated with clinically significant effects, so adjust the dose of the drug is not required.

    Patients under the age of 18 years

    The complex of sakubitril and valsartan in this category of patients was not studied.

    Patients with impaired renal function

    For LBQ657, there was a correlation between renal function and the area under the concentration-time curve (AUC), no correlation was observed for valsartan. In patients with impaired renal function of mild to moderate severity (calculated glomerular filtration rate (rSKF)> 30 ml / min /1.73 m2 Psurface area of ​​the body to <60 ml / min / 1.73 m2 body surface area) AUC for LBQ657 was 2 times higher than in patients with normal renal function. In patients with impaired renal function of severe severity (rSKF <30 ml / min /1.73 m2 Psurface area) AUC for LBQ657 increased by 2.7 times. In patients with impaired renal function of mild to moderate severity, dosage adjustment is not required. Data on the use in patients with impaired renal function of severe severity is not enough,When using the complex of sakubitril and valsartan in this category of patients, it is recommended to be cautious.

    There are no data on the use of the complex of sakubitrile and valsartan in patients on hemodialysis. However, LBQ657, and valsartan are largely associated with blood plasma proteins, so their effective removal from the blood during hemodialysis is unlikely.

    Patients with hepatic impairment

    In patients with impaired hepatic function of mild to moderate degrees of severity, exposure of sacubitryl increased by 1.5 and 3.4 times, respectively. Exposition LBQ657 - in 1,5 and 1,9 times, and valsartan - in 1,2 and 2,1 times (in comparison with healthy volunteers). In patients with impaired liver function of mild to moderate severity (class A and B according to the Child-Pugh classification), including patients with biliary tract obstruction, the dose of the sakubitrile and valsartan complex is not required to be corrected. The study of the use of the complex of sakubitrile and valsartan in patients with violations of liver function of severe severity was not carried out, the drug is not recommended for this category of patients.

    Ethnicity

    The pharmacokinetics of the complex of sakubitrile and valsartan in patients from different racial and ethnic groups do not differ significantly.

    Floor

    Pharmacokinetics of the complex of sakubitril and valsartan (sacubitryl, LBQ657 and valsartan) in men and women does not differ significantly.

    Indications:

    Chronic heart failure (NYHA class II-IV) in patients with systolic dysfunction to reduce the risk of cardiovascular mortality and hospitalization for heart failure.

    Contraindications:

    • Hypersensitivity to saccitrile or to valsartan, as well as to other auxiliary components of the drug.
    • Simultaneous use with angiotensin-converting enzyme (ACE) inhibitors, as well as a period of 36 hours after the abolition of ACE inhibitors.
    • Presence of an angioedema in the anamnesis on the background of previous therapy with ACE inhibitors or ARA II.
    • Simultaneous use with aliskiren in patients with diabetes mellitus or patients with moderate or severe renal dysfunction (rSCF <60 mL / min /1.73 m2 Psurface area of ​​the body).
    • Violation of the liver function of a serious degree (class C according to Child Pugh classification), biliary cirrhosis and cholestasis.
    • Intresto drug is not recommended for use in children under the age of 18 years due to lack of efficacy and safety data.
    • Pregnancy, pregnancy planning and the period of breastfeeding.
    • Simultaneous use with other drugs containing ARA II, because the composition of the drug is valsartan.

    Carefully:

    Caution must be exercised when using the drug Yuperio in patients with severe renal impairment (eGFR <30 mL / min / 1.73 m2 surface area of ​​the body), incl. in patients on hemodialysis or undergoing hemodialysis (eGFR <15 ml / min /1.73 m2 Ploschadi body surface area) in the absence of data on the safety of patients in this category, patients with bilateral renal artery stenosis, hypovolaemic which may be caused by diuretic therapy, a low-salt diet, diarrhea or vomiting, as well as in patients taking drugs that can increase the content of potassium in the blood serum (eg, potassium-sparing diuretics, potassium preparations).

    Care should be taken when using the drug with statins, phosphodiesterase type 5 inhibitors.

    Caution should be used when using the drug in patients with angioedema in history because of the lack of data on the use of the drug in patients in this category.

    Patients of the Negroid race may be more at risk of angioedema.
    If you have one of the listed diseases, before taking the drug necessarily consult a doctor.

    Pregnancy and lactation:

    Women with preserved reproductive function during treatment with the drug Yuperio and within a week after its last application should use reliable methods of contraception.

    Like other drugs that directly affect RAAS, the drug should not be used during pregnancy. The action of the drug Yuperio is mediated by the blockade of the angiotensin II receptors, therefore, the risk to the fetus can not be ruled out. Pregnant women who took valsartan, there were cases of spontaneous abortion, lack of water, and renal dysfunction in newborns. If against the background of the use of the drug Juperio has become pregnant, the drug should be canceled as soon as possible.

    Since the isolation of sakubitril and valsartan with milk from lactating animals is noted in experimental studies, it is not recommended to use the drug Yuperio during the period of breastfeeding. The decision to refuse breastfeeding or to cancel the drug Yuperio and continue breastfeeding should be taken in consideration of the importance of its use for the mother.

    Data on the effect of the drug Juperio on the fertility of men and women do not. In the studies of the drug Yuperio, there was no decrease in fertility in animals.
    Dosing and Administration:

    The time of taking the drug is not dependent on the time of food intake.

    Target (maximum daily) dose of the drug Yuperio is 200 mg (102.8 mg + 97.2 mg) 2 times a day. The recommended initial dose of the drug Yupero is 100 mg (51.4 mg + 48.6 mg) twice daily.

    In patients who have not previously received therapy with ACE inhibitors or ARA II, or who received these drugs in low doses, initiate drug therapy Yupero followed by a dose of 50 mg (25.7 mg + 24.3 mg) 2 times a day with a slow increase in dose (doubling the daily dose once every 3-4 weeks).

    Depending on the tolerability of the dose of the drug Yupero should be increased twice every 2-4 weeks until the target (maximum daily) dose of 200 mg (102.8 mg + 97.2 mg) twice daily.

    Application of the drug Yupero probably not earlier than 36 hours after the withdrawal of the ACE inhibitor, since in the case of concomitant use, angioedema may occur.

    Since the composition of the drug Yupero includes ARA II valsartan, it should not be used simultaneously with another drug, which includes ARA II.

    If patients have problems with drug tolerance Yupero (clinically pronounced decrease in blood pressure, hyperkalemia, renal dysfunction), a temporary dose reduction or dose adjustment of concomitant medications should be considered.

    Patients of special categories
    Patients with impaired renal function

    In patients with impaired renal function of lung (rSFP 60-90 ml / min / 1.73m2 Phorse body surface) or moderate severity (rSKF 30-60 ml / min / 1.73 m2 body surface area) the dose of the drug is not required to be corrected. Data on the use of the drug Yupero in patients with impaired renal function of severe severity (rSKF <30 ml / min / 1.73 m2 body surface area) is not enough, so when using the drug Yupero caution is recommended in this category of patients.

    Patients with impaired hepatic function

    In patients with impaired liver function of mild or moderate severity (class A and B according to the Child-Pugh classification), the dose of the drug Yupero do not need to adjust. A drug Yupero It is not recommended for use in patients with severe impairment of liver function (Child-Pugh class C).

    Use in children and adolescents under the age of 18 years

    Data on the safety and efficacy of the drug Yupero children and adolescents do not.

    Use in patients over 65 years of age

    In patients older than 65 years, dose adjustment is not required.

    Side effects:

    The revealed undesirable phenomena (AE) corresponded to the pharmacological characteristics of the drug Yupero and concomitant diseases that are present in patients. The most common AEs were a marked decrease in blood pressure, hyperkalemia and renal dysfunction caused by dose adjustment Yupero or discontinuation of therapy.

    The frequency of AE was independent of the sex, age or race of the patients.

    NIs are listed in accordance with the system-organ class of the medical vocabulary for the regulatory activity of MedDRA. Within each system-organ Class AEs are distributed according to the frequency of occurrence in order of decreasing importance. The following criteria were used to estimate the frequency: very often (≥1/10); often (from ≥1/100 to <1/10); infrequently ≥ / 1,000 to <1/100); rarely (from ≥1/10000 to <1/1000); very rarely (<1/10000), including individual messages.

    Disorders from the metabolism and nutrition: very often hyperkalemia; often - hypokalemia.

    Impaired nervous system: often - dizziness, headache; infrequently - orthostatic dizziness.

    Hearing disorders and labyrinthine disturbances: often - vertigo.

    Vascular disorders: very often - a marked decrease in blood pressure; often - a syncope, orthostatic hypotension.

    Disturbances from the respiratory system, chest and mediastinal organs: often - a cough.

    Disorders from the gastrointestinal tract: often diarrhea, nausea.

    Disturbances from the skin and subcutaneous tissues: infrequently - angioedema.

    Disorders from the kidneys and urinary tract: very often - renal dysfunction; often - kidney failure (incl.acute renal failure).

    General disorders and disorders at the site of administration: often - increased fatigue, asthenia.

    If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.
    Overdose:

    Data on drug overdose Yupero a person is not enough. A single application of the drug at a dose of 1200 mg and repeated at a dose of 900 mg in healthy volunteers was accompanied by good tolerability.

    The most likely symptom of overdose is a marked decrease in blood pressure, due to the antihypertensive effect of the active substances. In this case, symptomatic treatment is recommended.

    In case of an accidental overdose, you should induce vomiting (if the drug was taken recently) or to wash the stomach. If there is a marked decrease in blood pressure as a therapy, intravenous administration of a 0.9% solution of sodium chloride is necessary, the patient should be placed, lifting his legs, for a period of time necessary for therapy, to take active measures to maintain the activity of the cardiovascular system,including regular monitoring of the heart and respiratory system, the volume of circulating blood (BCC) and the amount of urine released.

    Removal of active substances during hemodialysis is unlikely, since much of it is associated with blood plasma proteins.

    Interaction:

    Contraindicated drug interactions

    ACE Inhibitors

    A drug Yupero is contraindicated for use concomitantly with ACE inhibitors, since the inhibition of non-lipase simultaneously with the use of an ACE inhibitor may increase the risk of developing angioedema. Application of the drug Yupero possibly not earlier than 36 hours after the withdrawal of the ACE inhibitor. The use of an ACE inhibitor is possible not earlier than 36 hours after the last administration of the drug Yupero.

    Aliskiren

    In patients with diabetes mellitus and in patients with impaired renal function (rSCF <60 mL / min /1.73 m2 Psurface area of ​​the body) Yupero Do not use simultaneously with aliskiren.

    Not recommended drug interactions

    Angiotensin receptor antagonists

    Since one of the active substances of the drug is a receptor antagonistangiotensin II, simultaneous use with another drug containing ARA II is not recommended.

    Drug interactions that need to be considered

    Inhibitors of HMG-CoA reductase (statins)

    The data of the studies show that sacubilitrile inhibits the activity of the vectors OATP1B1 and OATP1B3. A drug Yupero can increase the systemic exposure of such substrates as OATP1B1 and OATP1B3, as statins. Patients who received the drug Yupero simultaneously with atorvastatin, the maximum concentration in the blood plasma (Cmax) atorvastatin and its metabolites increased up to 2 times, a AUC - up to 1,3 times. For this reason, the drug Yupero simultaneously with statins should be used with caution.

    Sildenafil

    In patients with a marked increase in blood pressure, receiving the drug Yupero (before achieving an equilibrium concentration), a single application of sildenafil increased antihypertensive effect compared with the use of the drug Yupero in monotherapy. For this reason, patients receiving Yupero, apply sildenafil or another type 5 phosphodiesterase inhibitor should be used with caution.

    Presumptive drug interactions that need to be considered

    Potassium

    Simultaneous use of potassium-sparing diuretics (for example, triamterene and amiloride), mineralocorticoid antagonists (eg spironolactone and eplerenone), potassium or potassium-containing substitutes for table salt can cause an increase in potassium and serum creatinine concentrations. Patients receiving the drug Yupero simultaneously with these drugs, it is recommended to regularly monitor the potassium content in the blood serum.

    Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)

    Application of the drug Yupero concurrent with NSAIDs in patients over the age of 65, patients with hypovolemia (including patients receiving diuretics) and those with impaired renal function may increase the risk of impaired renal function. Patients receiving the drug Yupero simultaneously with NSAIDs, with the appointment of a similar treatment regimen and in case of its change it is recommended to monitor the kidney function.

    Lithium preparations

    The possibility of drug interaction between the drug Yupero and lithium preparations were not studied. With the simultaneous use of lithium preparations with ACE inhibitors and ARA II, a reversible increase in the concentration of lithium in the blood serum was noted and, in this connection, the intensification of toxic manifestations.

    Patients receiving the drug Yupero together with lithium preparations, it is recommended to carefully monitor the lithium content in serum. In case of additional use of a diuretic drug, the risk of toxic effects of lithium may increase.

    Protein-carriers

    The active metabolite of sacubitribil (LBQ657) and valsartan are substrates of the carrier proteins OATP1B1, OATP1B3 and OAT3; valsartan is also a carrier protein substrate of MRP2. Patients receiving the drug Yupero at the same time with inhibitors of OATP1B1, OATP1B3, OAT3 (for example, rifampicin and cyclosporin) or MPR2 (eg, ritonavir), the systemic exposure of LBQ657 or valsartan may be increased, respectively. At the beginning and at the end of the joint application of the drug Yupero and this group of drugs need to be careful.

    Absence of significant drug interactions

    In the case of drug use Yupero in combination with furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, metformin, omeprazole, carvedilol, nitroglycerin intravenously (iv), or a combined drug levonorgestrel and ethinylestradiol, no clinically relevant interactions have been identified. Interactions with atenolol, indomethacin, glibenclamide (glyburide) or cimetidine in combination with the drug Yupero not expected.

    Interactions with cytochrome P450 system isoenzymes

    The available studies demonstrate that the probability of drug interactions mediated by cytochrome CYP450 isoenzymes is low, since the complex of active substances is slightly metabolized with the participation of CYP450 isoenzymes. Complex of active substances of the preparation Yupero is not an inhibitor or inducer of CYP450 isoenzymes.

    Special instructions:

    Marked decrease in blood pressure

    Patients who received the drug Yupero, there were cases of clinically pronounced arterial hypotension.If there is a pronounced decrease in blood pressure, consideration should be given to correcting the dose of diuretics, associated hypotensive drugs, and also to eliminate the causes of marked decrease in blood pressure (eg, hypovolemia). If, despite these measures, a pronounced decrease in blood pressure persists, the dose of the drug Yupero should be reduced or the drug should be temporarily discontinued. The final withdrawal of the drug is usually not required. The likelihood of a marked decrease in blood pressure is usually higher in patients with hypovolemia, which may be caused by diuretic therapy, low salt diet, diarrhea, or vomiting. Before starting the preparation Yupero should correct the sodium content in the body and / or make up the BCC.

    Renal impairment

    Like any other drug acting on RAAS, the drug Yupero can cause impairment of kidney function. In a comparative study of safety and efficacy (in comparison with enalapril) clinically significant disorders of kidney function were rarely observed, and the drug Yupero in connection with such violations were abolished less often (0.65%) than enalapril (1.28%).In the case of clinically significant impairment of renal function, consideration should be given to reducing the dose of the drug Yupero. When using the drug Yupero Care should be taken in patients with severe renal dysfunction.

    Hyperkalemia

    Like any other drug acting on RAAS, the drug Yupero may increase the risk of hyperkalemia. In a comparative study of safety and efficacy (compared with enalapril), clinically significant hyperkalemia was rarely observed; a drug Yupero in connection with hyperkalemia was abolished in 0.26% of patients, and enalapril - in 0.35% of patients. Drugs that can increase the potassium content in the blood serum (eg, potassium-sparing diuretics, potassium preparations) concomitantly with the drug Yupero should be used with caution. In the case of clinically significant hyperkalemia, measures such as reducing potassium intake with food or adjusting the dose of concomitant medications should be considered. It is recommended to regularly monitor the potassium content in the blood serum, especially in patients with risk factors such as severe renal dysfunction, diabetes mellitus,hypoaldosteronism or a diet high in potassium.

    Angioedema

    Against the background of the drug Yupero there were cases of angioedema development. When an angioedema develops, the drug Yupero should be immediately abolished and appropriate treatment and monitoring of the patient should be made before a complete and permanent resolution of all the symptoms that have arisen. Re-administer the drug Yupero do not do it. In cases of confirmed angioedema, in which the edema only spread to the face and lips, this condition was generally resolved without intervention, although the use of antihistamines helped alleviate the symptoms.

    Angioedema, accompanied by swelling of the larynx, can lead to death. In cases where the swelling spreads to the tongue, the vocal cords or the larynx, which can lead to airway obstruction, it is necessary to immediately begin proper treatment, for example subcutaneous injection of a 1: 1000 epinephrine (epinephrine) solution (0.3-0.5 ml) , and / or take appropriate measures to ensure patency of the respiratory tract.

    Patients with an anamnesis who have angioedema, caused by the use of an ACE inhibitor or ARA II, the drug Yupero should not be used. Patients of the Negroid race may be more at risk of angioedema.

    Patients with renal artery stenosis

    Like other drugs acting on RAAS, the drug Yupero can cause an increase in the concentration of urea and creatinine in the blood serum in patients with unilateral or bilateral stenosis of the renal arteries. In patients with renal artery stenosis, the drug should be used with caution, regularly monitoring the kidney function.

    Effect on the ability to drive transp. cf. and fur:

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

    Form release / dosage:

    Film-coated tablets, 50 mg (25.7 mg + 24.3 mg); 100 mg (51.4 mg + 48.6 mg); 200 mg (102.8 mg + 97.2 mg).

    Packaging:

    Film-coated tablets, 50 mg (25.7 mg + 24.3 mg)

    For 14 tablets in a blister of PVC / PVDC and aluminum foil. 2 blisters together with instructions for use in a cardboard box.

    Tablets coated with a film coating, 100 mg (51.4 mg + 48.6 mg)

    For 14 tablets in a blister of PVC / PVDC and aluminum foil. For 2 or 4 blisters together with instructions for use in a cardboard box.

    Tablets coated with a film coating, 200 mg (102.8 mg + 97.2 mg)

    For 14 tablets in a blister of PVC / PVDC and aluminum foil. For 2 or 4 blisters together with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    30 months.

    The drug should not be used after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003532
    Date of registration:25.03.2016 / 13.10.2016
    Expiration Date:25.03.2021
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp22.08.16
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