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The PARADIGM-HF study showed that the use of the drug sacubitril/valsartan (a combination of a neprilysin inhibitor and an angiotensin II receptor antagonist) compared with standard therapy with enalapril in patients with mild to moderate NK with reduced LVEF significantly reduces cardiovascular mortality and re-hospitalization rates due to NK decompensation. The biological effect of neprilysin is the cleavage of a number of biologically active peptides, including natriuretic peptides. Accordingly, the use of sacubitril leads to increased renal blood flow, increased glomerular filtration rate and increased natriuresis. Excessive neprilysin activity has been documented in target organs affected by diabetes, including the kidneys.

As part of the PARADIGM-HF study, the dynamics of renal function in all included patients, including those with diabetes, was prospectively assessed over a 44-month period.

A total of 8399 patients were included in the PARADIGM HF study (including 3784 patients with diabetes mellitus). Patients were randomized to sacubitril/valsartan (97 mg/103 mg) or enalapril (10 mg twice daily). It was shown that the rate of decline in renal function in patients without diabetes is 1.1 ml/1.73 m2 per year, in patients with diabetes - 2 ml/1.73 m2 per year (P0.0001). In the entire cohort of patients, sacubitril/valsartan use was associated with a significantly lower rate of loss of renal function (1.3 vs. 1.8 ml/1.73 m2 per year, P0.0001). This protective effect is most pronounced in patients with concomitant diabetes mellitus: the difference in the rate of loss of renal function in patients with diabetes is 0.6 ml/1.73 m2 per year, without diabetes - 0.3 ml/1.73 m2 per year ( p=0.038).

At the same time, the protective properties of sacubitril/valsartan in relation to renal function did not depend on the effectiveness of this drug in relation to the course of CHF, as well as on the level of glycated hemoglobin.

Thus, the use of a neprilysin inhibitor in patients with CHF and complete blockade of the RAAS has an additional protective effect on renal function, including those with concomitant diabetes mellitus.

Based on materials:

Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Packer, Milton et al. The Lancet Diabetes & Endocrinology 2021 Apr 13. pii: S2213-8587(18)30100-1. doi: 10.1016/S2213-8587(18)30100-1.

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(18)30100-1/fulltext

The text was prepared by Ph.D. Shakhmatova O.O.

Uperio

The above information on the use of this drug is presented for informational purposes only and is intended for specialists. For more complete information, please refer to the manufacturer's instructions included in the package. Before starting to use any drug, it is recommended to consult a doctor.

Trade name of the drug : Uperio (Entresto)
International nonproprietary name :

Valsartan + Sacubitril (Valsartanum + Sacubitrilum)

Dosage form: film-coated tablets

Active ingredients: valsartan, sacubitril

Pharmacotherapeutic group: not assigned

Pharmacological properties:

The effect of the drug Uperio is mediated by a new mechanism, namely, the simultaneous suppression of the activity of neprilysin (neutral endopeptidase (NEP)) by the substance LBQ657 (the active metabolite of sacubitril) and blockade of receptors for angiotensin II type 1 (AT1) by valsartan, which is an angiotensin receptor antagonist II (ARA II). The complementary beneficial effects of sacubitril and valsartan on the cardiovascular system and kidneys in patients with heart failure are due to an increase in the number of peptides cleaved by neprilysin (such as natriuretic peptides (NPs)), which is mediated by the action of LBQ657, while valsartan simultaneously suppresses the negative effects of angiotensin II. NPs activate membrane-bound receptors coupled to guanylyl cyclase, which leads to increased concentrations of cyclic guanosine monophosphate (cGMP), causing symptoms of vasodilation, increased natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, suppression of renin and aldosterone release, decreased sympathetic activity, as well as antihypertrophic and antifibrotic effect. 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 release of aldosterone. This prevents persistent activation of the renin-angiotensin-aldosterone system (RAAS), which causes vasoconstriction, sodium and water retention by the kidneys, activation of cell growth and proliferation, as well as subsequent restructuring of the cardiovascular system, aggravating disturbances in its functioning.

Indications for use:

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 sacubitril or valsartan, as well as to other auxiliary components of the drug. Concomitant use with angiotensin-converting enzyme (ACE) inhibitors, as well as a period of 36 hours after discontinuation of ACE inhibitors. A history of angioedema due to previous therapy with ACE inhibitors or ARB II. Concomitant use with aliskiren in patients with diabetes mellitus or in patients with moderate or severe renal impairment (eGFR <60 ml/min/1.73 m2 body surface area). Severe liver dysfunction (Child Pugh class C), biliary cirrhosis and cholestasis. Inresto is not recommended for use in children under 18 years of age due to the lack of data on efficacy and safety. Pregnancy, pregnancy planning and breastfeeding. Simultaneous use with other drugs containing ARA II, because The drug contains valsartan. Caution should be exercised when using Uperio in patients with severely impaired renal function (eGFR <30 ml/min/1.73 m2 body surface area), incl. in patients on hemodialysis or undergoing hemodialysis (eGFR <15 ml/min/1.73 m body surface area) due to the lack of safety data in patients in this category, patients with bilateral renal artery stenosis, with hypovolemia, which may may be caused by diuretic therapy, a low-salt diet, diarrhea or vomiting, as well as in patients taking drugs that can increase serum potassium levels (for example, potassium-sparing diuretics, potassium supplements). Caution should be exercised when using the drug simultaneously with statins and phosphodiesterase type 5 inhibitors. Caution should be exercised when using the drug in patients with a history of angioedema due to the lack of data on the use of the drug in patients in this category. Black patients may be at greater risk of angioedema.

Directions for use and dosage:

The time of taking Uperio does not depend on the time of meals. The target (maximum daily) dose of Uperio is 200 mg (102.8 mg + 97.2 mg) 2 times a day. The recommended starting dose of Uperio is 100 mg (51.4 mg + 48.6 mg) 2 times a day. In patients who have not previously received therapy with ACE inhibitors or ARB II, 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) 2 times a day with a slow increase in dose ( doubling the daily dose once every 3-4 weeks). Depending on tolerability, the dose of Inresto should be doubled every 2-4 weeks until the target (maximum daily) dose of 200 mg (102.8 mg + 97.2 mg) 2 times a day is reached. The use of the drug Uperio is possible no earlier than 36 hours after discontinuation of the ACE inhibitor, since in case of simultaneous use, angioedema may develop. Since Uperio contains ARA II valsartan, it should not be used simultaneously with another drug that contains ARA II. If signs of intolerance to the drug Uperio develop (clinically pronounced decrease in blood pressure, hyperkalemia, impaired renal function), a temporary dose reduction or dose adjustment of concomitantly used medications should be considered.

Side effect:

The identified adverse events (AEs) were consistent with the pharmacological characteristics of the drug Uperio and the concomitant diseases present in the patients. The most common AEs were a marked decrease in blood pressure, hyperkalemia and renal dysfunction caused by dose adjustment of Uperio or discontinuation of therapy. The frequency of AEs did not depend on the gender, age or race of patients. AEs are listed according to the organ system class of the MedDRA Medical Dictionary for Regulatory Activities. Within each systemic organ class, AEs are distributed by frequency of occurrence in order of decreasing importance. The following criteria were used to assess frequency: very often (>1/10); often (from >1/100 to <1/10); uncommon (> 1/1,000 to < 1/100); rare (from > 1/10000 to < 1/1000); very rare (<1/10000), including isolated reports.

Metabolic and nutritional disorders: very often - hyperkalemia; often - hypokalemia.

Nervous system disorders: often - dizziness, headache; infrequently - orthostatic dizziness.

Hearing and labyrinthine disorders: often - vertigo.

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

Disorders of the respiratory system, chest and mediastinal organs: often - cough.

Gastrointestinal disorders: often - diarrhea, nausea.

Disorders of the track and subcutaneous tissues: infrequently - angioedema.

Disorders of the kidneys and urinary tract: very often - impaired renal function; often - renal failure (including acute renal failure).

General disorders and disorders at the injection site: often - increased fatigue, asthenia. If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Interaction with other drugs:

Contraindicated drug interactions ACE inhibitors Uperio is contraindicated for use simultaneously with ACE inhibitors, since suppression of neprilysin simultaneously with the use of an ACE inhibitor may increase the risk of developing angioedema. The use of the drug Uperio is possible no earlier than 36 hours after discontinuation of the ACE inhibitor. The use of an ACE inhibitor is possible no earlier than 36 hours after the last dose of Uperio. Aliskiren. In patients with diabetes mellitus and in patients with impaired renal function (eGFR <60 ml/min/1.73 m2 body surface area), Uperio should not be used concomitantly with aliskiren. Not recommended drug interactions. Angiotensin receptor antagonists. Since one of the active ingredients of the drug is an angiotensin II receptor antagonist, simultaneous use with another drug containing ARA II is not recommended. Drug interactions to consider. HMG-CoA reductase inhibitors (statins). Research data show that sacubitril inhibits the activity of the OATP1B1 and OATP1B3 transporters. Uperio may increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. In patients receiving Uperio simultaneously with atorvastatin, the maximum plasma concentration (Cmax) of atorvastatin and its metabolites increased up to 2 times, and AUC increased up to 1.3 times. For this reason, Uperio should be used concomitantly with statins with caution. Sildenafil. In patients with a marked increase in blood pressure receiving Uperio (until equilibrium concentrations were reached), a single dose of sildenafil enhanced the antihypertensive effect compared with the use of Uperio in monotherapy. For this reason, sildenafil or another phosphodiesterase type 5 inhibitor should be used with caution in patients receiving Uperio. Suspected drug interactions that need to be considered. Potassium. Concomitant use of potassium-sparing diuretics (for example, triamterene and amiloride), mineralocorticoid antagonists (for example, spironolactone and eplerenone), potassium supplements or potassium-containing salt substitutes may cause an increase in potassium and creatinine concentrations in the blood serum. In patients receiving Uperio concomitantly with these drugs, it is recommended to regularly monitor serum potassium levels. Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors). The use of Uperio concomitantly with NSAIDs in patients over the age of 65 years, in patients with hypovolemia (including patients receiving diuretics) and in patients with impaired renal function may increase the risk of deterioration of renal function. In patients receiving Uperio concomitantly with NSAIDs, it is recommended to monitor renal function when prescribing such a treatment regimen and in case of changes in it. Lithium preparations. The possibility of drug interactions between Uperio and lithium preparations has not been 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 observed and, in connection with this, an increase in toxic manifestations. In patients receiving Uperio together with lithium preparations, it is recommended to carefully monitor the lithium content in the blood serum. If a diuretic drug is used additionally, the risk of lithium toxicity may increase. Transport proteins. The active metabolite of sacubitril (LBQ657) and valsartan are substrates of the transporter proteins 0ATP1B1, 0ATP1B3 and OATZ; valsartan is also a substrate of the MRP2 transporter protein. In patients receiving Uperio concomitantly with OATP1B1, OATP1B3, OATZ (e.g., rifampicin and cyclosporine), or MRP2 (e.g., ritonavir) inhibitors, systemic exposure to LBQ657 or valsartan, respectively, may be increased. Caution must be exercised at the beginning and at the time of completion of the combined use of the drug Uperio and this group of drugs. No significant drug interactions. When Uperio was used in combination with furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, metformin, omeprazole, carvedilol, intravenous (IV) nitroglycerin or a combination drug of levonorgestrel and ethinyl estradiol, no clinically significant interactions were identified. Interactions with atenolol, indomethacin, glibenclamide (glyburide) or cimetidine are not expected when used together with Uperio. Interactions with isoenzymes of the cytochrome P450 system. Available studies demonstrate that the likelihood of drug interactions mediated by cytochrome CYP450 isoenzymes is low, since the complex of active substances is metabolized to a small extent with the participation of CYP450 isoenzymes. The complex of active ingredients of the drug Uperio is not an inhibitor or inducer of CYP450 isoenzymes.

Shelf life : 2.5 years

Conditions for dispensing from pharmacies : by prescription

Manufacturer:

Novartis Pharma Stein AG, Switzerland (4650069870081, 4603695005211, 4650069870098, 4603695005228, 4650069870074, 4603695005204).