UPERIOR 200 TABLET

Indications

• Heart failure with reduced ejection fraction (HFrEF)
• Reduction of cardiovascular death and hospitalization in chronic heart failure patients

Dosage

Adults: The usual recommended dose of sacubitril/valsartan is 49 mg/51 mg taken twice daily. The dose

Mechanism of action

Sacubitril's active metabolite, LBQ657, inhibits neprilysin, a neutral endopeptidase that cleaves natriuretic peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). By inhibiting neprilysin, sacubitril increases the concentrations of these peptides, which leads to vasodilation, natriuresis, and diuresis. Furthermore, when combined with valsartan, it also blocks the action of angiotensin II, resulting in decreased vascular resistance and blood pressure.

Pharmacodynamics

Clinical studies have demonstrated that sacubitril, especially in combination with valsartan, leads to significant increases in natriuresis and urine levels of cGMP. It has been shown to decrease plasma levels of NT-proBNP, aldosterone, and endothelin-1, indicating an overall beneficial effect on heart failure parameters. It has no significant effect on the QTc interval.

Pharmacokinetics

Sacubitril is rapidly converted to its active metabolite LBQ657, which is responsible for its therapeutic effects. It has a half-life of approximately 11 hours. The drug is metabolized primarily by hydrolysis and conjugation, and it is excreted mainly in the urine. The pharmacokinetics may be affected by renal function, necessitating dose adjustments in patients with significant renal impairment.

Contra-indications

• Hypersensitivity to sacubitril, valsartan or any of the excipients
• History of angioedema related to previous treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB)
• Concurrent use of ACE inhibitors
• Severe hepatic impairment
• Pregnancy

Adverse effects

• Hypotension
• Hyperkalemia
• Cough
• Dizziness
• Renal impairment
• Angioedema
• Fatigue

Interactions

• ACE inhibitors
• NSAIDs may reduce the antihypertensive effect
• Potassium-sparing diuretics may increase the risk of hyperkalemia
• Lithium levels may increase

Precautions

• Monitor renal function and potassium levels
• Use with caution in patients with a history of angioedema
• Adjust dose in patients with renal impairment
• Risk of hypotension in volume-depleted patients

Pregnancy

Contraindicated due to potential harm to the fetus.

Breast-feeding

Not recommended, as it is not known if sacubitril is excreted in human milk.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets: 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg (sacubitril/valsartan)

Indications

• Hypertension
• Heart failure
• Reduction of cardiovascular mortality in patients with left ventricular dysfunction following myocardial infarction

Dosage

Children: Refer to the BNF for Children for specific paediatric dosing guidelines.

Adults: Refer to the BNF for specific adult dosing guidelines based on the condition being treated.

Mechanism of action

Valsartan selectively antagonizes the angiotensin II type 1 (AT1) receptor, which mediates the effects of angiotensin II, including vasoconstriction and aldosterone secretion. By blocking this receptor, valsartan promotes vasodilation and decreases blood pressure, leading to improved cardiac output.

Pharmacodynamics

Valsartan's pharmacodynamic effects include a reduction in blood pressure and an improvement in cardiac function in patients with heart failure. The drug's antihypertensive effects can be observed within hours of administration, reaching peak effects typically within 2 to 6 hours. The duration of action can last up to 24 hours, allowing for once-daily dosing.

Pharmacokinetics

Valsartan is well absorbed after oral administration, with a bioavailability of approximately 23%. It is extensively metabolized in the liver, primarily by UDP-glucuronosyltransferase enzymes, and is excreted mainly through the bile and urine. The elimination half-life of valsartan is about 6 hours, but its antihypertensive effects can persist for 24 hours, allowing for once-daily dosing. The pharmacokinetics may be affected by renal impairment, and dose adjustments may be necessary in such patients.

Contra-indications

• Hypersensitivity to valsartan or any of the excipients.
• Severe hepatic impairment.
• Bilateral renal artery stenosis or unilateral stenosis in a solitary kidney.
• Pregnancy.

Adverse effects

• Dizziness.
• Hypotension.
• Hyperkalemia.
• Renal impairment.
• Cough.
• Fatigue.
• Nausea.

Interactions

• Potassium-sparing diuretics may increase the risk of hyperkalemia.
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect.
• Other antihypertensive agents may have additive effects.
• Lithium levels may increase when used with valsartan.

Precautions

• Monitor renal function, especially in patients with renal impairment.
• Use with caution in patients with a history of angioedema.
• Caution in patients with heart failure or aortic stenosis.
• Discontinue if pregnancy is detected.

Pregnancy

Valsartan is contraindicated during pregnancy due to potential harm to the fetus, particularly in the second and third trimesters.

Breast-feeding

It is not known whether valsartan is excreted in human milk. Caution is advised when administering to breastfeeding women.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets (various strengths including 40 mg, 80 mg, and 160 mg).
• Oral solution.

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.

Pharmacodynamics

n a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril + valsartan (Entresto) resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, it significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. In clinical studies, this combination had no effect on QTc interval.