Sacubitril/Valsartan

Sacubitril/valsartan is a first-in-class angiotensin receptor–neprilysin inhibitor (ARNI). It combines two mechanisms of action in a single molecular salt complex: enhancement of beneficial natriuretic peptide signalling (via neprilysin inhibition) and blockade of the deleterious renin-angiotensin-aldosterone system (via AT1 receptor antagonism). The combination is essential because neprilysin inhibition alone would cause reflex angiotensin II accumulation; pairing with valsartan neutralises that compensatory vasoconstriction.

Mechanism of Action

Sacubitril (neprilysin inhibition arm)

• Sacubitril is a prodrug, rapidly de-ethylated by esterases to the active metabolite LBQ657 (sacubitrilat), which inhibits neprilysin — a neutral endopeptidase (NEP) that normally degrades natriuretic peptides.
• Neprilysin inhibition increases circulating levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These peptides activate guanylate cyclase-coupled receptors to raise intracellular cGMP, producing vasodilation, natriuresis and diuresis, suppression of renin and aldosterone secretion, and inhibition of pathological cardiac remodelling.
• Because neprilysin also degrades angiotensin I, angiotensin II, endothelin-1, bradykinin, and substance P, its inhibition raises some vasoconstrictor and pro-inflammatory peptides — which is why an AT1 blocker is co-administered.

Valsartan (AT1 receptor blockade arm)

• Valsartan selectively binds the angiotensin II type 1 (AT1) receptor with approximately 20,000-fold higher affinity than the AT2 receptor.
• Blocking AT1 prevents angiotensin II-mediated vasoconstriction, aldosterone secretion, ADH release, cardiac stimulation, and renal sodium reabsorption — independent of the source of angiotensin II generation (ACE-dependent or ACE-independent pathways).
• Net effect: lower blood pressure, lower aldosterone, reduced afterload, increased natriuresis, attenuation of ventricular hypertrophy and remodelling.

Why ACE inhibitors are not co-administered: combining sacubitril with an ACE inhibitor markedly increases the risk of angioedema because both ACE and neprilysin contribute to bradykinin degradation. A washout period is therefore mandatory when switching.

Pharmacokinetics

Sacubitril and LBQ657

• Absorption: oral bioavailability of sacubitril >60%; peak plasma concentration of sacubitril at 0.5 h, of LBQ657 at 2 h. Food does not clinically affect exposure.
• Volume of distribution: 103 L for LBQ657.
• Protein binding: 94–97% for both sacubitril and LBQ657.
• Metabolism: sacubitril is rapidly hydrolysed by esterases to LBQ657 — minimal CYP involvement.
• Half-life: sacubitril 1.1–3.6 h; LBQ657 9.9–11.1 h.
• Excretion: 52–68% renal (primarily as LBQ657); 37–48% faecal.

Valsartan (in this fixed-dose combination)

• Absorption: the valsartan in this combination is more bioavailable than standard valsartan formulations; therefore the labelled strengths are not interchangeable with conventional valsartan tablets on a milligram basis.
• Protein binding: ~95%, mainly to albumin.
• Metabolism: minimal; only ~20% recovered as metabolites, principally via CYP2C9 (valeryl-4-hydroxy valsartan).
• Half-life: approximately 6 hours.
• Excretion: predominantly biliary/faecal (~83%); ~13% renal.

Transporters: LBQ657 and valsartan are substrates of OATP1B1 and OATP1B3; clinically relevant interactions occur with potent OATP1B1/3 inhibitors.

• Chronic heart failure with reduced ejection fraction (HFrEF, NYHA Class II–IV) in adults: to reduce the risk of cardiovascular death and hospitalisation for heart failure. Used as a replacement for an ACE inhibitor or ARB in patients tolerating those classes.
• Paediatric heart failure: treatment of symptomatic chronic heart failure with systemic left ventricular systolic dysfunction in paediatric patients aged ≥1 year.

• Hypersensitivity to sacubitril, valsartan, or any of the excipients.
• Concomitant use with ACE inhibitors — must not be administered within 36 hours of switching from an ACE inhibitor, owing to increased angioedema risk.
• History of angioedema related to previous ACE inhibitor or ARB therapy.
• Hereditary or idiopathic angioedema.
• Concomitant use with aliskiren in patients with diabetes mellitus or with renal impairment (eGFR <60 mL/min/1.73 m²).
• Severe hepatic impairment (Child-Pugh C), biliary cirrhosis, and cholestasis.
• Pregnancy (especially second and third trimesters — RAAS inhibitors cause fetal injury and death).

Very common (≥1/10): hyperkalaemia, hypotension, renal impairment.

Common (≥1/100 to <1/10): anaemia, hypokalaemia, hypoglycaemia, dizziness, headache, syncope, vertigo, orthostatic hypotension, cough, diarrhoea, nausea, renal failure (including acute renal failure), fatigue, asthenia.

Uncommon (≥1/1,000 to <1/100): hypersensitivity reactions, hyponatraemia, sleep disorders, postural dizziness, gastritis, pruritus, rash, angioedema (notable for its mechanistic basis; higher incidence in Black patients).

Rare (<1/1,000): hallucinations (auditory and visual), paranoia, myoclonus.

• ACE inhibitors: contraindicated within 36 hours — combined neprilysin and ACE inhibition markedly increases angioedema risk.
• Other ARBs: must not be combined — sacubitril/valsartan already contains an ARB.
• Aliskiren: contraindicated in diabetes or renal impairment.
• Potassium-sparing diuretics (spironolactone, eplerenone, amiloride, triamterene) and potassium supplements: increased risk of hyperkalaemia — monitor potassium.
• NSAIDs (including selective COX-2 inhibitors): increased risk of renal impairment, especially in elderly, volume-depleted, or pre-existing renal impairment patients; may reduce antihypertensive efficacy.
• Lithium: increased serum lithium concentrations and risk of toxicity; monitor levels.
• Statins (atorvastatin, simvastatin) and other OATP1B1/1B3 substrates: LBQ657 can inhibit OATP transporters; clinically meaningful interaction with statins may occur.
• Sildenafil and other PDE5 inhibitors: additive blood-pressure–lowering effects.
• Metformin: exposure may decrease; monitor glycaemic control.
• Concomitant antidiabetics: closer glycaemic monitoring may be required.

Tablets are swallowed whole with water, with or without food. Doses are expressed as the sacubitril/valsartan combined strength (e.g., 24/26 mg = 24 mg sacubitril plus 26 mg valsartan).

Adults

• Starting dose: 49/51 mg twice daily in patients currently on a moderate-to-high dose ACE inhibitor or ARB. 24/26 mg twice daily in ACE/ARB-naïve patients, those on low doses, patients with severe renal impairment, moderate hepatic impairment, or aged ≥75 years.
• Titration: double the dose every 2–4 weeks as tolerated, targeting 97/103 mg twice daily.

Switching from an ACE Inhibitor

ACE inhibitor must be stopped at least 36 hours before initiating sacubitril/valsartan to minimise angioedema risk.

Paediatric Use (≥1 Year)

Weight-band dosing using granules-for-suspension or appropriate tablet strengths; refer to specialist paediatric protocols.

Renal Impairment

• eGFR ≥60: no adjustment.
• eGFR 30–59: no initial adjustment; use the lower starting dose where appropriate.
• eGFR <30 (severe): start at 24/26 mg twice daily; titrate cautiously.
• End-stage renal disease / dialysis: limited data; use with caution.

Hepatic Impairment

• Mild (Child-Pugh A): no adjustment.
• Moderate (Child-Pugh B): start at 24/26 mg twice daily.
• Severe (Child-Pugh C): contraindicated.

Missed Dose

Take as soon as remembered. If close to the next scheduled dose, skip the missed dose; do not double up.

Angioedema

Discontinue immediately if angioedema occurs. Patients with prior ACE inhibitor– or ARB-related angioedema, and patients of Black African descent, are at higher baseline risk.

Hypotension

Correct volume and salt depletion before initiation. Initial symptomatic hypotension is common; recovery is usually rapid with brief dose reduction or temporary withholding.

Renal Function and Potassium

Monitor renal function and serum potassium before initiation, after each dose change, and periodically thereafter. Risk is heightened in elderly patients, those with pre-existing renal impairment, volume depletion, or concomitant nephrotoxic medication.

Pregnancy and Lactation

• Pregnancy: contraindicated. RAAS inhibitors cause fetal renal failure, oligohydramnios, skull hypoplasia, and death — switch to an alternative therapy before conception or as soon as pregnancy is recognised.
• Breastfeeding: not recommended.

Elderly

Start at the lower 24/26 mg dose; titrate cautiously. Increased susceptibility to hypotension and renal effects.

BNP as a Biomarker

Sacubitril inhibits the breakdown of BNP, so BNP is no longer a reliable biomarker for heart failure monitoring in patients taking this combination. NT-proBNP, which is not a neprilysin substrate, remains valid.

Effect on Driving

Dizziness and fatigue have been reported; affected patients should refrain from driving or operating machinery.

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from moisture. Do not transfer to alternative containers.

Typically 3 years for the film-coated tablets. Do not use after the expiry date printed on the packaging.

Prescription required (Rx).