Product Information
Registration Status: ActiveSIN14948P
ENTRESTO FILM COATED TABLET 100MG is approved to be sold in Singapore with effective from 2016-02-12. It is marketed by NOVARTIS (SINGAPORE) PTE LTD, with the registration number of SIN14948P.
This product contains Sacubitril 48.6mg, and Valsartan 51.4mg in the form of TABLET, FILM-COATED. It is approved for ORAL use.
This product is manufactured by Novartis Pharma Stein AG in SINGAPORE,NOVARTIS SINGAPORE PHARMACEUTICAL MANUFACTURING PTE. LTD. in SWITZERLAND, andNovartis Farma SpA in ITALY.
It is a Prescription Only Medicine that can only be obtained from a doctor or a dentist, or a pharmacist with a prescription from a Singapore-registered doctor or dentist.
Product Reference
Important Note: For generic product, the SPC/PIL provided may not be brand specific.
{{/items}} {{^items}}Description
Sacubitril is a prodrug neprilysin inhibitor used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It was approved under the FDA's priority review process for use in heart failure on July 7, 2015. Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Inhibition of neprilysin therefore leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II.
Indication
Used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.
Mechanism of Action
Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin.
Pharmacokinetics
- Absorption
- Peak plasma concentrations of sacubitril and it's metabolite, LBQ657 are reached in 0.5 hours and 2 hours respectively. Food does not clinically affect the systemic exposure of sacubitril or LBQ657. The oral bioavailability of sacubitril is >60%. It should be noted that the valsartan found in this combination is more bioavailable than other market available valsartan.
- Distribution
- 103 L
- Metabolism
- Sacubitril is metabolized to LBQ657 by esterases. A low concentration (
- Elimination
Toxicity
The most common adverse reactions (≥5%) are hypotension, hyperkalemia, cough, dizziness, and renal failure.
Active Ingredient/Synonyms
Sacubitril | Sacubitril |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.
Description
Valsartan is an angiotensin-receptor blocker (ARB) that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. Valsartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough. Valsartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of heart failure, systolic dysfunction, myocardial infarction and coronary artery disease.
Indication
May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Losartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors.
Mechanism of Action
Valsartan is an ARB that selectively inhibits the binding of angiotensin II to AT1, which is found in many tissues such as vascular smooth muscle and the adrenal glands. This effectively inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in a decrease in vascular resistance and blood pressure. Valsartan is selective for AT1 and has virtually no affinity for AT2. Inhibition of aldosterone secretion may inhibit sodium and water reabsorption in the kidneys while decreasing potassium excretion. The primary metabolite of valsartan, valeryl 4-hydroxy valsartan, has no pharmacological activity.
Pharmacokinetics
- Absorption
- Absolute bioavailability = 23% with high variability.
- Distribution
- * 17 L (low tissue distribution)
- Metabolism
- Valsartan is excreted largely as unchanged drug (80%) and is minimally metabolized in humans. The primary circulating metabolite, 4-OH-valsartan, is pharmacologically inactive and produced CYP2C9. 4-OH-valsartan accounts for approximately 9% of the circulating dose of valsartan. Although valsartan is metabolized by CYP2C9, CYP-mediated drug-drug interactions between valsartan and other drugs is unlikely.
- Elimination
Clearance
* 2 L/h [IV administration] * 4.5 L/h [heart Failure patients receiving oral administration 40 to 160 mg twice a day]
Active Ingredient/Synonyms
(S)-N-Valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl}-valine | N-(P-(O-1H-Tetrazol-5-ylphenyl)benzyl)-N-valeryl-L-valine | N-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine | Valsartan |
Source of information: Drugbank (External Link). Last updated on: 3rd July 18. *Trade Name used in the content below may not be the same as the HSA-registered product.