Sarvellio (Tablets) Instructions for Use

Marketing Authorization Holder

Velpharm-M, LLC (Russia)

Manufactured By

Velpharm, LLC (Russia)

Velpharm-M, LLC (Russia)

ATC Code

C09DX04 (Valsartan and Sacubitril)

Active Substances

Valsartan (Rec.INN registered by WHO)

Sacubitril (Rec.INN registered by WHO)

Dosage Forms

	Sarvellio	Film-coated tablets 100 mg (51.4 mg+48.6 mg)
		Film-coated tablets 200 mg (102.8 mg+97.2 mg)

Dosage Form, Packaging, and Composition

Film-coated tablets

	1 tab.
Valsartan and sacubitril hydrated mixture of sodium salts (calculated as the acid form, anhydrous)	113.103 mg (100 mg)
Equivalent to content of
Valsartan	51.4 mg
Sacubitril	48.6 mg

10 pcs. – jars – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs – cardboard packs (10 pcs.) – By prescription
10 pcs. – blister packs (10 pcs.) – cardboard packs (100 pcs.) – By prescription
10 pcs. – blister packs (2 pcs.) – cardboard packs (20 pcs.) – By prescription
10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blister packs (4 pcs.) – cardboard packs (40 pcs.) – By prescription
10 pcs. – blister packs (5 pcs.) – cardboard packs (50 pcs.) – By prescription
10 pcs. – blister packs (6 pcs.) – cardboard packs (60 pcs.) – By prescription
10 pcs. – blister packs (7 pcs.) – cardboard packs (70 pcs.) – By prescription
10 pcs. – blister packs (8 pcs.) – cardboard packs (80 pcs.) – By prescription
10 pcs. – blister packs (9 pcs.) – cardboard packs (90 pcs.) – By prescription
100 pcs. – jars – cardboard packs (100 pcs.) – By prescription
14 pcs. – jars – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs – cardboard packs (14 pcs.) – By prescription
14 pcs. – blister packs (10 pcs.) – cardboard packs (140 pcs.) – By prescription
14 pcs. – blister packs (2 pcs.) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (3 pcs.) – cardboard packs (42 pcs.) – By prescription
14 pcs. – blister packs (4 pcs.) – cardboard packs (56 pcs.) – By prescription
14 pcs. – blister packs (5 pcs.) – cardboard packs (70 pcs.) – By prescription
14 pcs. – blister packs (6 pcs.) – cardboard packs (84 pcs.) – By prescription
14 pcs. – blister packs (7 pcs.) – cardboard packs (98 pcs.) – By prescription
14 pcs. – blister packs (8 pcs.) – cardboard packs (112 pcs.) – By prescription
14 pcs. – blister packs (9 pcs.) – cardboard packs (126 pcs.) – By prescription
20 pcs. – jars – cardboard packs (20 pcs.) – By prescription
28 pcs. – jars – cardboard packs (28 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
40 pcs. – jars – cardboard packs (40 pcs.) – By prescription
42 pcs. – jars – cardboard packs (42 pcs.) – By prescription
50 pcs. – jars – cardboard packs (50 pcs.) – By prescription
56 pcs. – jars – cardboard packs (56 pcs.) – By prescription
60 pcs. – jars – cardboard packs (60 pcs.) – By prescription
7 pcs. – jars – cardboard packs (7 pcs.) – By prescription
7 pcs. – blister packs – cardboard packs (7 pcs.) – By prescription
7 pcs. – blister packs (10 pcs.) – cardboard packs (70 pcs.) – By prescription
7 pcs. – blister packs (2 pcs.) – cardboard packs (14 pcs.) – By prescription
7 pcs. – blister packs (3 pcs.) – cardboard packs (21 pcs.) – By prescription
7 pcs. – blister packs (4 pcs.) – cardboard packs (28 pcs.) – By prescription
7 pcs. – blister packs (5 pcs.) – cardboard packs (35 pcs.) – By prescription
7 pcs. – blister packs (6 pcs.) – cardboard packs (42 pcs.) – By prescription
7 pcs. – blister packs (7 pcs.) – cardboard packs (49 pcs.) – By prescription
7 pcs. – blister packs (8 pcs.) – cardboard packs (56 pcs.) – By prescription
7 pcs. – blister packs (9 pcs.) – cardboard packs (63 pcs.) – By prescription
70 pcs. – jars – cardboard packs (70 pcs.) – By prescription
80 pcs. – jars – cardboard packs (80 pcs.) – By prescription
84 pcs. – jars – cardboard packs (84 pcs.) – By prescription
90 pcs. – jars – cardboard packs (90 pcs.) – By prescription
98 pcs. – jars – cardboard packs (98 pcs.) – By prescription

Film-coated tablets

	1 tab.
Valsartan and sacubitril hydrated mixture of sodium salts (calculated as the acid form, anhydrous)	226.206 mg (200 mg)
Equivalent to content of
Valsartan	102.8 mg
Sacubitril	97.2 mg

Clinical-Pharmacological Group

Angiotensin II receptor antagonist in combination with a neprilysin inhibitor

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin II receptor antagonists, combinations; angiotensin II receptor antagonists, other combinations

Pharmacological Action

A combined medicinal product. Its action is mediated by the simultaneous suppression of neprilysin (neutral endopeptidase, NEP) activity by LBQ657 (the active metabolite of sacubitril) and blockade of angiotensin II type 1 (AT₁) receptors by valsartan, which is an angiotensin II receptor antagonist (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 amount of peptides degraded by neprilysin (such as natriuretic peptides, NP), mediated by the action of LBQ657, while simultaneously suppressing the negative effects of angiotensin II by valsartan.

NPs activate membrane-bound guanylyl cyclase-coupled receptors, leading to an increase in cyclic guanosine monophosphate (cGMP) concentration, which causes symptoms of vasodilation, increased natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, suppression of renin and aldosterone release, reduced sympathetic activity, as well as antihypertrophic and antifibrotic effects. Valsartan, by selectively blocking the AT₁ receptor, suppresses the negative effects of angiotensin II on the cardiovascular system and kidneys, and also blocks angiotensin II-dependent aldosterone release. This prevents persistent activation of the RAAS, which causes vasoconstriction, sodium and water retention by the kidneys, activation of cell growth and proliferation, and subsequent remodeling of the cardiovascular system, which worsens its functional impairment.

In a clinical study, the use of the valsartan/sacubitril combination in patients with chronic heart failure statistically significantly reduced the risk of death from cardiovascular causes or hospitalization due to acute heart failure. The absolute risk reduction for death from cardiovascular causes or hospitalization due to acute heart failure was 4.7%.

Pharmacokinetics

After oral administration, the Sacubitril/Valsartan complex dissociates into sacubitril, which is then metabolized to form the metabolite LBQ657, and valsartan; the plasma concentrations of these substances reach their maximum after 0.5 h, 3 h, and 1.5 h, respectively. The absolute bioavailability of sacubitril and valsartan after oral administration is >60% and 23%, respectively. When taking the sacubitril and valsartan complex twice daily, the C_ss of sacubitril, LBQ657, and valsartan are reached in 3 days. No statistically significant accumulation of sacubitril and valsartan was noted at steady state; meanwhile, the accumulation of LBQ657 exceeded the concentration after a single dose by 1.6 times.

The binding of the Sacubitril/Valsartan complex to plasma proteins is 94-97%. Comparison of plasma and CSF exposures shows that LBQ657 penetrates the BBB to a small extent (0.28%). The apparent V_d of the Sacubitril/Valsartan complex ranges from 107.8 to 157.4 L.

Sacubitril is rapidly converted by enzymes into the metabolite LBQ657, which is then not significantly metabolized. Valsartan is metabolized to a small extent, with only about 20% of the administered dose found as metabolites. A hydroxyl metabolite was detected in plasma in low concentrations (<10%). Since both sacubitril and valsartan are minimally metabolized by cytochrome CYP450 isoenzymes, a change in their pharmacokinetics when used concomitantly with drugs affecting CYP450 isoenzymes seems unlikely.

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

Sacubitril, LBQ657, and valsartan are eliminated from plasma with mean T_1/2 of approximately 1.43 h, 11.48 h, and 9.9 h, respectively.

In the studied dose range of the Sacubitril/Valsartan complex (50-400 mg), the pharmacokinetic parameters of sacubitril, LBQ657, and valsartan change proportionally to the dose.

A correlation was observed between renal function and AUC for LBQ657, but no such correlation was observed for valsartan. In patients with mild to moderate renal impairment (eGFR >30 ml/min/1.73 m² to <60 ml/min/1.73 m²), the AUC of LBQ657 was 2 times greater than in patients with normal renal function. In patients with severe renal impairment (eGFR <30 ml/min/1.73 m²), the AUC for LBQ657 increased by 2.7 times. No dose adjustment of the drug is required in patients with mild to moderate renal impairment. There is insufficient data on use in patients with severe renal impairment; caution is recommended when using the sacubitril and valsartan complex in this category of patients.

LBQ657 and valsartan are highly bound to plasma proteins, so their effective removal from the blood by hemodialysis is unlikely.

In patients with mild and moderate hepatic impairment, the exposure of sacubitril increased by 1.5 and 3.4 times, respectively. The exposure of LBQ657 – by 1.5 and 1.9 times, and valsartan – by 1.2 and 2.1 times (compared to healthy volunteers).

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.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
I50.0	Congestive heart failure

ICD-11 code	Indication
BD10	Congestive heart failure

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

For oral administration.

The target (maximum daily) dose of the complex is 200 mg twice daily. The recommended starting dose is 100 mg twice daily.

In patients who have not previously received therapy with ACE inhibitors or ARAs II, or who have received these drugs in low doses, therapy with the complex should be started at a dose of 50 mg twice daily with a slow dose increase (doubling the daily dose once every 3-4 weeks).

Depending on tolerance, the dose should be doubled every 2-4 weeks until the target (maximum daily) dose of 200 mg twice daily is reached.

Use of this complex is possible no earlier than 36 hours after discontinuation of an ACE inhibitor, because simultaneous use may cause angioedema.

Since the complex contains the ARA II Valsartan, it should not be used simultaneously with another drug containing an ARA II.

Adverse Reactions

Definition of adverse reaction frequency: very common (≥1/10); common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000, <1/1000); very rare (<1/10 000); unknown (cannot be estimated from available data).

Metabolism and nutrition disorders very common – hyperkalemia; common – hypokalemia.

Nervous system disorders common – dizziness, headache; uncommon – orthostatic dizziness.

Ear and labyrinth disorders common – vertigo.

Cardiac and vascular disorders very common – marked decrease in blood pressure; common – syncope, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders common – cough.

Gastrointestinal disorders common – diarrhea, nausea.

Skin and subcutaneous tissue disorders uncommon – angioedema.

Renal and urinary disorders very common – renal function impairment; common – renal failure (including acute renal failure).

General disorders and administration site conditions common – increased fatigue, asthenia.

Contraindications

Simultaneous use with ACE inhibitors, as well as the period 36 hours after discontinuation of ACE inhibitors; history of angioedema during previous therapy with ACE inhibitors or ARAs II; simultaneous use with aliskiren in patients with diabetes mellitus or in patients with moderate or severe renal impairment (eGFR <60 ml/min/1.73 m²); simultaneous use with other drugs containing ARAs II, because the drug contains Valsartan; severe hepatic impairment (Child-Pugh class C), biliary cirrhosis and cholestasis; age under 18 years; pregnancy, pregnancy planning and lactation (breastfeeding); hypersensitivity to sacubitril or to valsartan.

With caution

Severe renal impairment (eGFR <30 ml/min/1.73 m²), including patients on hemodialysis or undergoing hemodialysis (eGFR<15 ml/min/1.73 m²), bilateral renal artery stenosis, hypovolemia (which may be caused by diuretic therapy, low-salt diet, diarrhea or vomiting), during treatment with drugs that can cause hyperkalemia (e.g., potassium-sparing diuretics, potassium preparations); simultaneously with statins, PDE5 inhibitors; history of angioedema; patients of Black race (as they may be more susceptible to the risk of angioedema).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

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

Use in Renal Impairment

Contraindication: concomitant use with aliskiren in patients with moderate or severe renal impairment (GFR<60 ml/min/1.73 m²).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

The likelihood of a pronounced decrease in blood pressure is generally higher in patients with hypovolemia, which may be caused by diuretic therapy, a low-salt diet, diarrhea, or vomiting. Before starting the use of the combination, sodium levels should be corrected and/or circulating blood volume should be replenished.

In case of a clinically significant deterioration in renal function, a dose reduction of the combination should be considered. Caution should be exercised when used in patients with severe renal impairment.

In the event of clinically significant hyperkalemia, measures such as reducing dietary potassium intake or adjusting the dose of concomitant medications should be considered. Regular monitoring of serum potassium is recommended, especially in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism, or a high-potassium diet.

If angioedema occurs, treatment with this combination should be discontinued immediately, and appropriate treatment and patient monitoring should be instituted until all symptoms have completely and permanently resolved. Drugs containing Sacubitril and Valsartan should not be readministered. In cases of confirmed angioedema where the swelling was limited to the face and lips, the condition generally resolved without intervention, although antihistamines helped alleviate symptoms.

Angioedema involving laryngeal edema can be fatal. In cases where swelling extends to the tongue, vocal cords, or larynx, which may lead to airway obstruction, appropriate treatment must be initiated immediately.

Effect on Ability to Drive and Operate Machinery

Due to the potential for dizziness or increased fatigue, caution should be exercised when driving vehicles or operating machinery.

Drug Interactions

The use of drugs containing the Sacubitril+Valsartan combination concomitantly with NSAIDs in patients over 65 years of age, in patients with hypovolemia (including those receiving diuretics), and in patients with renal impairment may increase the risk of worsening renal function.

The possibility of a drug interaction between this combination and lithium preparations has not been studied. Concomitant use of lithium preparations with ACE inhibitors and ARBs has been associated with reversible increases in serum lithium concentrations and a consequent enhancement of toxic manifestations.

In patients receiving a drug containing the Sacubitril+Valsartan combination together with lithium preparations, careful monitoring of serum lithium levels is recommended. If a diuretic drug is additionally used, the risk of lithium toxicity may increase.

The active metabolite of sacubitril (LBQ657) and Valsartan are substrates of the OATP1B1, OATP1B3, and OAT3 transporter proteins; Valsartan is also a substrate of the MRP2 transporter protein. In patients receiving this combination concomitantly with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g., rifampicin and cyclosporine) or MRP2 (e.g., ritonavir), the systemic exposure to LBQ657 or valsartan, respectively, may be increased. Caution is required at the start and at the time of discontinuation of concomitant use of this combination and this group of drugs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.

Medical Disclaimer

Medixlife (Author)

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