Huperio, 100 mg 56 pcs.

Pharmacotherapeutic group: not assigned.

The ATX code: C09DX04.

Pharmacological properties

Mechanism of action

The action of Huperio is mediated by a novel mechanism, namely the simultaneous inhibition of neprilysin activity (neutral endopeptidase (NEP)) by sacubitrilate (the active metabolite of sacubitril) and blockade of angiotensin II type 1 receptors (AT₁) with valsartan, which is an angiotensin II receptor antagonist (ARA II).

Sacubitrilat increases neprilysin-degradable peptides (such as natriuretic peptides (NUPs)), which, while suppressing the negative effects of angiotensin II with valsartan, result in the complementary beneficial effects of sacubitril and valsartan on cardiovascular and renal health in patients with heart failure. NUPs activate membrane-bound guanylyl cyclase-conjugated receptors resulting in increased 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, decreased sympathetic activity, and antihypertrophic and antifibrotic effects.

Valsartan, by selectively blocking the AT₁ receptor, suppresses the negative effects of angiotensin II on the cardiovascular system and the kidneys and also blocks angiotensin II-dependent aldosterone release. This prevents persistent activation of the renin-angiotensin-aldosterone system (RAAS), which causes vasoconstriction, renal sodium and water retention, activation of cell growth and proliferation, and subsequent maladaptive cardiovascular remodeling.

Pharmacodynamics

The pharmacodynamic effects of the sacubitril and valsartan complex of the drug 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 simultaneous inhibition of neprilysin and RAAS blockade.

. 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 sacubitril and valsartan complex resulted in a statistically significant short-term increase in natriuresis, increased urinary cGMP concentration and decreased plasma concentrations of mid-regional atrial natriuretic peptide precursor (MR-proANP) and N-terminal fragment of brain natriuretic peptide precursor (NT-proBNP) (compared with valsartan). In a 21-day study in patients with reduced left ventricular PV, use of sacubitril and valsartan caused statistically significant increases in urinary atrial natriuretic peptide (ANP) and cGMP and plasma cGMP concentrations, as well as decreases in plasma NT-proBNP, aldosterone and endothelin-1 concentrations (compared with baseline).

In addition, use of the sacubitril and valsartan complex blocks the AT₁ receptor, as indicated by increased plasma renin activity and concentrations. In another study, the complex of sacubitril and valsartan caused a more pronounced decrease in plasma NT-proBNP concentrations and a greater increase in urinary concentrations of brain natriuretic peptide (BNP) and cGMP than did enalapril. While BNP is a substrate of neprilysin, NT-proBNP is not, so NT-proBNP, unlike BNP, can be used as a biomarker in monitoring patients with heart failure receiving sacubitril and valsartan complex.

In a study detailing the QTc interval in healthy male volunteers, the use of sacubitril and valsartan complex once at doses of 400 mg and 1200 mg had no effect on myocardial repolarization.

Neprilysin is one of several enzymes involved in amyloid-β (Aβ) metabolism of brain and cerebrospinal fluid (CSF). In healthy volunteers, the Aβ 1-38 concentrations in the CSF were increased with the use of sacubitril and valsartan at a dose of 400 mg once daily for 2 weeks, while the Aβ 1-40 and 1-42 concentrations in the CSF were unchanged. The clinical significance of this finding is unknown.

In a clinical trial, use of the sacubitril and valsartan complex in patients with chronic heart failure statistically significantly reduced the risk of death due to cardiovascular disease or 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 disease or hospitalization due to heart failure was 4.7% (3.1% for risk of death due to cardiovascular disease and 2.8% for primary hospitalization due to heart failure).

The relative risk reduction compared with enalapril was 20%. The effect was noted early in the use of the drug and persisted throughout the study period. Both active ingredients of the drug contributed to the development of the effect. The incidence of sudden death, which accounted for 45% of all cardiovascular deaths, was reduced by 20% in the study drug group compared to the enalapril group (hazard ratio (HR) 0.80, p=0.0082).

The incidence of myocardial insufficiency, which caused 26% of cardiovascular deaths, decreased 21% in the study drug group compared with enalapril (HR 0.79, p=0.0338).

Pharmacokinetics

absorption

. After oral administration, the complex of sacubitril and valsartan breaks down into sacubitril, which is then metabolized to form the metabolite sacubitrilate, and valsartan; plasma concentrations of the above substances peak after 0.5 h, 2 h and 1.5 h, respectively. Absolute bioavailability of sacubitril and valsartan after oral administration is ≥60% and 23%, respectively. Valsartan in Imperio has higher bioavailability compared to other tablet forms.

When taking the complex of sacubitril and valsartan twice daily, equilibrium concentrations of sacubitril, sacubitrilate and valsartan are reached after 3 days. No statistically significant accumulation of sacubitril and valsartan at equilibrium is noted; at the same time, accumulation of sacubitrilat exceeds the concentration with a single application by a factor of 1.6. Administration of sacubitril and valsartan complex simultaneously with meals had no clinically significant effect on systemic exposure to sacubitril, sacubitrilate, and valsartan. Reduced valsartan exposure when taking sacubitril and valsartan complex concomitantly with meals was not accompanied by a clinically significant reduction in therapeutic effect. The timing of administration of sacubitril and valsartan complex is independent of the timing of meals.

Distribution

The sacubitril and valsartan complex is significantly bound to plasma proteins (94% to 97%). A comparison of exposures in plasma and CSF shows that sacubitrilat penetrates the blood-brain barrier to a small extent (0.28%). The apparent volume of distribution of the complex ranges from 75 to 103 liters.

Metabolism

Sacubitril is rapidly converted by enzymes to sacubitrilate, which is not significantly metabolized further. Valsartan is slightly metabolized, with only about 20% of the administered dose found as metabolites. A hydroxyl metabolite was detected in low concentrations (<10%) in blood plasma. Since both sacubitril and valsartan are minimally metabolized with cytochrome CYP450 isoenzymes, a change in their pharmacokinetics is unlikely in the case of concomitant use of drugs affecting CYP450 isoenzymes.

Elimation

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

Sacubitril, sacubitrilate, and valsartan are excreted from plasma with mean elimination half-lives (T_1/2) of approximately 1.43 h, 11.48 h, and 9.90 h, respectively.

Linearity/nonlinearity

In the studied dose range of sacubitril and valsartan complex (50-400 mg), the pharmacokinetic parameters of sacubitril, sacubitrilate, and valsartan vary in proportion to dose.

Pharmacokinetics in special clinical cases

Patients older than 65 years

. Exposures to sacubitrilate and valsartan are 42% and 30% higher, respectively, in patients in this category than in younger patients. These differences are not associated with clinically significant effects, so no dose adjustments are required.

Patients younger than 18 years

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

Patients with impaired renal function

A correlation between renal function and area under the concentration-time curve (AUC) was observed for sacubitrilat, no such correlation was observed for valsartan. In patients with impaired renal function of mild (calculated glomerular filtration rate (rGFR) 89-60 ml/min/1.73 m²) and moderate severity (59-30 ml/min/1.73 m²).

The AUC of sacubitrilate was 2 times higher than in patients with normal renal function. In patients with mild to moderate renal dysfunction no dose adjustment of the drug is required.

In patients with severe renal dysfunction (rSFR <30 ml/min/1.73 m²) AUC of Sacubitrilate was 2.7 times increased, the recommended starting dose of this medicine is 50 mg 2 times per day in this category of patients. Caution should be exercised when using the drug in patients with severe renal dysfunction due to limited relevant data.

There are no data on the use of the drug in patients on hemodialysis. However, both sacubitrilate and valsartan are significantly bound to plasma proteins, so their effective removal from the blood by hemodialysis is unlikely.

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment, exposure to sacubitril increased 1.5 and 3.4-fold, respectively. Exposure to sacubitrilat was 1.5 and 1.9 times, and to valsartan 1.2 and 2.1 times (compared with healthy volunteers). No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh class A), including patients with biliary obstruction.

In patients with moderate hepatic impairment (Child-Pugh Class B), the recommended starting dose of the drug is 50 mg twice daily.

In the absence of data, use in patients with severe hepatic impairment is not recommended.

Ethnicity

The pharmacokinetics of sacubitril and valsartan complex (sacubitril, sacubitrilate, and valsartan) are not significantly different in patients of different racial and ethnic groups.

Gender

The pharmacokinetics of sacubitril and valsartan complex (sacubitril, sacubitrilate, and valsartan) are not significantly different in men and women.

Indications

Active ingredient

Composition

1 film-coated tablet, 100 mg (51.4 mg + 48.6 mg) contains:

Active ingredient:

Sacubitril and valsartan sodium salt hydrate complex, 113.103 mg (converted to 100 mg anhydrous acid form, equivalent to 48.6 mg of sacubitril and 51.4 mg of valsartan);

Auxiliary substances: Microcrystalline cellulose, hyprolose, crosspovidone, magnesium stearate, talc, colloidal silica; coating: 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).

How to take, the dosage

The timing of taking Juperio is independent of the time of eating.

The target (maximum daily) dose of Huperio is 200 mg (102.8 mg + 97.2 mg) 2 times daily. The recommended starting dose of Huperio is 100 mg (51.4 mg + 48.6 mg) 2 times daily. Depending on tolerance, the dose of Juperio should be doubled every 2-4 weeks up to the target (maximum daily) dose of 200 mg (102.8 mg + 97.2 mg) 2 times per day.

In patients who have not previously received MAP or ARA II therapy or who received these drugs in low doses, therapy with Huperio should be started in a dose of 50 mg (25.7 mg + 24.3 mg) 2 times daily with slow dose escalation (doubling the daily dose once every 3 to 4 weeks).

The use of Huperio may not be earlier than 36 hours after discontinuation of the SSRIs because angioedema may develop if used concomitantly.

Because Imperio contains ARA II valsartan, it should not be used concomitantly with any other drug that contains ARA II.

If signs of impaired tolerability of Huperio develop (clinically significant decrease in BP, hyperkalemia, impaired renal function), temporary dose reduction or dose adjustment of concomitant medications should be considered.

Patients in special categories

Patients with impaired renal function

In patients with renal dysfunction of mild (rSF 60-90 ml/min/1.73 m2) or moderate severity (rSF 30-60 ml/min/1.73 m2) no adjustment of the drug dose is required (see See Pharmacological properties).

In patients with severe renal impairment (rSFR <30 ml/min/1.73 m2), the recommended starting dose of the drug is 50 mg 2 times daily.

With regard to the limited data, caution is recommended when using Huperio in this patient population.

Patients with hepatic impairment

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

In patients with moderate hepatic impairment (Child-Pugh Class B), the recommended starting dose of the drug is 50 mg twice daily.

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

Application in children and adolescents under 18 years of age

There are no data on the safety and effectiveness of Huperio in children and adolescents.

Application in patients over 65 years of age

Dose adjustment is not necessary in patients over 65 years of age.

Interaction

Contraindicated drug interactions

AcE inhibitors

. Hyperio is contraindicated concomitantly with ACEs because inhibition of neprilysin concomitantly with ACEs may increase the risk of angioedema. The use of Imperio is possible not earlier than 36 hours after discontinuation of ACEIs. The use of ACEIs is possible no sooner than 36 hours after the last dose of Imperio.

Aliskiren

The concomitant use of Huperio with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or with impaired renal function (rSFR <60 ml/min/1.73 m2 and is not recommended in other patients.

Unrecommended drug interactions

Angiotensin receptor antagonists

Because one of the active substances of the drug is ARA II, concomitant use with another drug containing ARA II is not recommended.

Drug interactions to consider

HMG-CoA reductase inhibitors (statins

Research data show that sacubitril suppresses OATP1B1 and OATP1B3 transporter activity. Huperio may increase systemic exposure to OATP1B1 and OATP1B3 substrates such as statins. In patients who received Juperio concomitantly with atorvastatin, the maximum plasma concentration (Cmax) of atorvastatin and its metabolites was increased up to 2 times, and AUC – up to 1.3 times. Caution should be exercised when concomitant use of statins with Huperio. No clinically significant drug interactions have been observed when concomitant use of Hyperio with simvastatin.

Sildenafil

In patients with significant BP elevation receiving Huperio (before reaching equilibrium concentration), single use of sildenafil enhanced the antihypertensive effect compared to the use of Huperio in monotherapy. For this reason, sildenafil or another type 5 phosphodiesterase inhibitor should be used with caution in patients receiving Huperio.

Predicted drug interactions to consider

Kalium

Concomitant use of potassium-saving diuretics (e.g., triamterene and amiloride), mineralocorticoid antagonists (e.g., spironolactone and eplerenone), potassium products or potassium-containing table salt substitutes may cause increased serum potassium and creatinine concentrations. In patients receiving Juperio concomitantly with these drugs, it is recommended to monitor serum potassium levels regularly.

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

. The use of Huperio concomitantly with NSAIDs in patients over 65 years of age, in patients with hypovolemia (including patients treated with diuretics) and in patients with impaired renal function may increase the risk of impaired renal function. In patients receiving Juperio concomitantly with NSAIDs, it is recommended to monitor renal function when using a similar treatment regimen and if it is changed.

Lithium preparations

The possibility of drug interaction between Hyperio and lithium preparations has not been studied. Concomitant use of lithium preparations with ACEs and ARA II has resulted in a reversible increase in serum lithium levels and an increase in toxic effects associated with this.

In patients receiving Hyperio concomitantly with lithium preparations, it is recommended that serum lithium levels be closely monitored. The risk of lithium toxicity may increase if additional diuretic medication is used.

Carrier proteins

The active metabolite of sacubitril (sacubitrilate) and valsartan are substrates of the carrier proteins OATP1B1, OATP1B3 and OAT3; valsartan is also a substrate of the MRP2 transporter protein. Patients receiving Huperio concomitantly with OATP1B1, OATP1B3, OAT3 inhibitors (eg, rifampicin and cyclosporine) or MPR2 (eg, ritonavir) may have increased systemic exposure to sacubitrilate or valsartan, respectively. Caution is required at initiation and completion of concomitant use of Huperio and this group of drugs.

No significant drug interactions

. No clinically significant drug interactions have been identified when Huperio is used in combination with furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, metformin, omeprazole, carvedilol, IV nitroglycerin (IV) or a combination of levonorgestrel and ethinylestradiol. No interactions with atenolol, indomethacin, glibenclamide (glyburide) or cimetidine are expected when used concomitantly with Huperio.

Interactions with cytochrome P450 system isoenzymes

. The available studies demonstrate that the likelihood of drug interactions mediated by CYP450 cytochrome isoenzymes is low because the complex of active substances is metabolized to a small extent with the participation of CYP450 isoenzymes. The active substance complex of Huperio is not an inhibitor or inducer of CYP450 isoenzymes.

Special Instructions

Significant decrease in BP

There have been cases of clinically significant arterial hypotension in patients treated with Huperio. If arterial hypotension occurs, consideration should be given to adjusting the dose of diuretics, concomitant hypotensive agents, and addressing the causes of arterial hypotension (e.g., hypovolemia). If, despite these measures, hypotension persists, the dose of Huperio should be reduced or the drug should be temporarily withdrawn. Definitive 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, low-salt diet, diarrhea or vomiting. Correction of the sodium content in the body and/or replenishment of the BOD should be performed before starting the use of Huperio.

Kidney function disorders

As any other drug acting on the RAAS, Huperio may cause impairment of renal function. In a comparative safety and efficacy study (compared with enalapril), clinically significant impairment of renal function was rare, and Huperio was withdrawn less frequently (0.65%) than enalapril (1.28%) for such impairment. In cases of clinically significant impairment of renal function, a reduction in the dose of Huperio should be considered. Caution should be exercised when using Huperio in patients with severe renal dysfunction.

Hyperkalemia

As any other drug acting on the RAAS, Huperio may increase the risk of hyperkalemia. In a comparative safety and efficacy study (compared with enalapril), clinically significant hyperkalemia was rare; hyperkalemia was withdrawn due to hyperkalemia in 0.26% of patients and enalapril in 0.35% of patients. Drugs that may increase serum potassium levels (e.g., potassium-saving diuretics, potassium preparations) should be used with caution concomitantly with Huperio. In case of clinically significant hyperkalemia, measures such as reducing potassium intake with food 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 dysfunction, diabetes mellitus, hypoaldosteronism, or a diet high in potassium.

Angeoneurotic edema

In cases of angioedema have been reported with Huperio. If angioedema occurs, Imperio should be discontinued immediately and appropriate treatment should be initiated with patient monitoring until complete and persistent resolution of all symptoms. Reapplication of Huperio should not be repeated. In cases of confirmed angioedema, in which the swelling was limited to the face and lips, the condition usually resolved without intervention, although use of antihistamines did ameliorate the symptoms.

Synopsis

Contraindications

Side effects

In the safety study, the duration of therapy with the drug in patients with chronic heart failure was up to 4.3 years and the average duration of therapy was 24 months.

The discontinuation of therapy due to the development of adverse events (AEs) was required in 10.71% of patients treated with Huperio and in 12.20% of patients treated with the comparison drug. The events most frequently associated with dose adjustments or discontinuation of therapy were: arterial hypotension, hyperkalemia, and renal dysfunction. The detected adverse drug reactions (ADRs) were consistent with the pharmacological characteristics of Huperio and the comorbidities of the patients.

The incidence of adverse reactions (ARs) was independent of gender, age or race.

The NRs are listed according to the system-organ class of the MedDRA Regulatory Medical Dictionary. Within each system-organ class, NERs are categorized by frequency of occurrence in decreasing order of importance. The following criteria were used to assess frequency: Very common (≥1/10); common (≥1/100 to <1/10); infrequent (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), including individual reports; frequency unknown – because information about these NERs is obtained in the post-registration period from spontaneous reports and reports in the literature, it is not always possible to accurately estimate the frequency and causal relationship to the drug, “frequency unknown” is indicated for these reactions).

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

Disorders of metabolism and nutrition:very common – hyperkalemia; common – hypokalemia.

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

Hearing and labyrinth disorders:often – vertigo.

Vascular disorders:very often – arterial hypotension; often – syncope, orthostatic hypotension.

Disorders of the respiratory system, thoracic and mediastinal organs: often – cough.

Gastrointestinal tract disorders:often – diarrhea, nausea.

Skin and subcutaneous tissue disorders: infrequently – angioedema.

Renal and urinary tract disorders: very often – renal dysfunction; often – renal failure (including 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 instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

There are insufficient data on overdose with Huperio in humans. A single dose of 1200 mg and multiple doses of 900 mg in healthy volunteers were well tolerated.

The most likely symptom of overdose is arterial hypotension due to the antihypertensive effect of the drug. Symptomatic treatment is recommended.

The removal of active ingredients during hemodialysis is unlikely because a significant portion of them are bound to plasma proteins.

Pregnancy use

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

Patients of preserved reproductive potential should be advised of the possible effects of the drug during pregnancy and the need to use reliable contraception during treatment with the drug and for one week after the last dose.

Pregnancy

Like other drugs directly acting on the RAAS, Huperio should not be used during pregnancy. The action of Huperio is mediated by angiotensin II receptor blockade, so a risk to the fetus cannot be excluded. Pregnant women who have taken valsartan have had cases of spontaneous miscarriage, low water flow, and renal dysfunction in the newborn. If the patient becomes pregnant during treatment with the drug, she should stop taking it and inform her physician.

Breastfeeding

It is not known whether Huperio penetrates into human breast milk. Because preclinical studies have noted excretion of sacubitril and valsartan with the milk of lactating rats, the use of Huperio is not recommended during breastfeeding. The decision to discontinue breastfeeding or to discontinue treatment with Huperio and to continue breastfeeding should be made taking into account the importance of its use to the mother.

Fertility

There are no data on the effect of Huperio on fertility in men and women. No reduction in fertility has been noted in studies of Huperio in animals.