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Angiotensin receptor-neprilysin inhibitor (ARNI) Pregnancy: Not recommended during the first trimester of pregnancy and contraindicated during the second and third trimesters (SPC section 4.6). ARB exposure in the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia); stop immediately when pregnancy is diagnosed and, if exposure occurred from the second trimester, ultrasound check of foetal renal function and skull is recommended. Not recommended in women who are breast-feeding.

Sacubitril with valsartan

Brand names: Entresto

Used in: Heart Failure

Sacubitril with valsartan is an oral angiotensin-receptor neprilysin inhibitor used to treat symptomatic chronic heart failure with reduced ejection fraction, typically in place of an ACE inhibitor or angiotensin-receptor blocker.

Auto-extracted from the source labelling — not yet independently clinician-verified. These values were distilled from the UK SPC (or the US label where noted) but have not had a clinician sign-off. Confirm against the current SmPC before prescribing.

Adult dose

Dose: One tablet of 49 mg/51 mg (sacubitril/valsartan) twice daily as the recommended starting dose in adult heart failure; double at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated
Route: Oral
Frequency: Twice daily
Max: 97 mg/103 mg twice daily (target dose - the highest step in the SPC titration schedule; section 4.2 states no separate maximum dose)
Indication per SPC: adult heart failure. A starting dose of 24 mg/26 mg twice daily with slow titration (doubling every 3-4 weeks) is recommended in patients not currently taking an ACE inhibitor or an ARB, or taking low doses of these; a starting dose of 24 mg/26 mg twice daily should also be considered for patients with SBP 100 to 110 mmHg. Must not be co-administered with an ACE inhibitor or an ARB, and must not be started for at least 36 hours after discontinuing ACE inhibitor therapy (angioedema risk). Do not initiate if serum potassium is greater than 5.4 mmol/l or SBP is less than 100 mmHg. If tolerability issues occur (SBP 95 mmHg or below, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjust concomitant medicinal products and consider temporary down-titration or discontinuation. The valsartan contained in this product is more bioavailable than the valsartan in other marketed tablet formulations - doses are not interchangeable. If a dose is missed, take the next dose at the scheduled time. Elderly: the dose should be in line with the renal function of the patient. Hepatic impairment: no adjustment in mild (Child-Pugh A); use with caution and half the starting dose in moderate (Child-Pugh B) or where AST/ALT are more than twice the upper limit of normal; contraindicated in severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C). Source: Entresto 24 mg/26 mg film-coated tablets SPC (eMC product 7751), section 4.2. Section 4.5 was not included in the fetched bundle - the interaction entries below are drawn from the section 4.2/4.3/4.4 text only; clinician to review the full section 4.5.

Paediatric dose

Dose: 1.6 mg/kg
Route: Oral (granules - film-coated tablets are not suitable for children weighing less than 40 kg)
Frequency: Twice daily (starting dose for patients under 40 kg); increase every 2-4 weeks as tolerated - intermediate 2.3 mg/kg twice daily, target 3.1 mg/kg twice daily
Max: Target dose 3.1 mg/kg twice daily in paediatric patients less than 40 kg; 72 mg/78 mg twice daily (at least 40 kg, less than 50 kg); 97 mg/103 mg twice daily (at least 50 kg)
Paediatric heart failure, eMC section 4.2 Table 1. All doses are given twice daily; the mg/kg figures refer to the COMBINED amount of sacubitril and valsartan and are to be given using granules. Less than 40 kg: half starting dose 0.8 mg/kg, starting dose 1.6 mg/kg, intermediate 2.3 mg/kg, target 3.1 mg/kg. At least 40 kg and less than 50 kg: half starting dose 0.8 mg/kg (granules), starting dose 24 mg/26 mg, intermediate 49 mg/51 mg, target 72 mg/78 mg. At least 50 kg: half starting dose 24 mg/26 mg, starting dose 49 mg/51 mg, intermediate 72 mg/78 mg, target 97 mg/103 mg. Half the starting dose is recommended in patients not previously taking an ACE inhibitor or an ARB or taking low doses of these, in renal impairment (eGFR less than 60 ml/min/1.73 m2) and in moderate hepatic impairment; where half the starting dose is used, adjust every 3-4 weeks. SPC worked example: a 25 kg patient not previously on an ACE inhibitor starts at half the standard starting dose = 20 mg (25 kg x 0.8 mg/kg) twice daily as granules, which after rounding to the closest number of full capsules corresponds to 2 capsules of 6 mg/6 mg twice daily. Do not initiate if serum potassium is greater than 5.3 mmol/l or if SBP is below the 5th percentile for the age of the patient. If tolerability issues occur (SBP below the 5th percentile for age, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjust concomitant medicinal products and consider temporary down-titration or discontinuation. Safety and efficacy in children aged below 1 year have not been established and no recommendation on a posology can be made. Verify all paediatric doses against a children's formulary and local policy before prescribing.

Dose adjustments

Renal

No dose adjustment required in mild renal impairment (eGFR 60-90 ml/min/1.73 m2). Half of the starting dose should be considered in moderate renal impairment (eGFR 30-60 ml/min/1.73 m2). In severe renal impairment (eGFR less than 30 ml/min/1.73 m2) clinical experience is very limited: use with caution and half of the starting dose is recommended. No experience in end-stage renal disease - use is not recommended. In paediatric patients weighing 40 kg to less than 50 kg a starting dose of 0.8 mg/kg twice daily (granules) is recommended, then increased following the recommended dose titration every 2-4 weeks.

Dose auto-extracted from UK Summary of Product Characteristics (SPC) via the eMC — not yet clinician-verified. Always confirm against the product SmPC and your local formulary before prescribing.

Paediatric weight-based calculator

Paediatric heart failure, eMC section 4.2 Table 1. All doses are given twice daily; the mg/kg figures refer to the COMBINED amount of sacubitril and valsartan and are to be given using granules. Less than 40 kg: half starting dose 0.8 mg/kg, starting dose 1.6 mg/kg, intermediate 2.3 mg/kg, target 3.1 mg/kg. At least 40 kg and less than 50 kg: half starting dose 0.8 mg/kg (granules), starting dose 24 mg/26 mg, intermediate 49 mg/51 mg, target 72 mg/78 mg. At least 50 kg: half starting dose 24 mg/26 mg, starting dose 49 mg/51 mg, intermediate 72 mg/78 mg, target 97 mg/103 mg. Half the starting dose is recommended in patients not previously taking an ACE inhibitor or an ARB or taking low doses of these, in renal impairment (eGFR less than 60 ml/min/1.73 m2) and in moderate hepatic impairment; where half the starting dose is used, adjust every 3-4 weeks. SPC worked example: a 25 kg patient not previously on an ACE inhibitor starts at half the standard starting dose = 20 mg (25 kg x 0.8 mg/kg) twice daily as granules, which after rounding to the closest number of full capsules corresponds to 2 capsules of 6 mg/6 mg twice daily. Do not initiate if serum potassium is greater than 5.3 mmol/l or if SBP is below the 5th percentile for the age of the patient. If tolerability issues occur (SBP below the 5th percentile for age, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjust concomitant medicinal products and consider temporary down-titration or discontinuation. Safety and efficacy in children aged below 1 year have not been established and no recommendation on a posology can be made. Verify all paediatric doses against a children's formulary and local policy before prescribing.

Verify in a children's formulary

Contraindications

  • Hypersensitivity to the active substances or to any of the excipients
  • Concomitant use with ACE inhibitors - must not be administered until 36 hours after discontinuing ACE inhibitor therapy
  • Known history of angioedema related to previous ACE inhibitor or ARB therapy
  • Hereditary or idiopathic angioedema
  • Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR less than 60 ml/min/1.73 m2)
  • Severe hepatic impairment, biliary cirrhosis and cholestasis (Child-Pugh C)
  • Second and third trimesters of pregnancy

Side effects

  • Hypotension - very common (17.6% in adults); orthostatic hypotension common
  • Hyperkalaemia - very common (11.6% in adults); hypokalaemia and hypoglycaemia common
  • Renal impairment - very common (10.1% in adults); renal failure / acute renal failure common
  • Dizziness, headache, syncope, vertigo, cough, diarrhoea, nausea, gastritis, anaemia, fatigue and asthenia - common
  • Angioedema - uncommon (0.5% in PARADIGM-HF vs 0.2% with enalapril; higher incidence in Black patients, 2.4%); intestinal angioedema very rare

Interactions

  • ACE inhibitors - combination contraindicated (increased risk of angioedema); do not initiate until 36 hours after the last ACE inhibitor dose, and do not restart an ACE inhibitor until 36 hours after the last sacubitril/valsartan dose (sections 4.3/4.4)
  • Other ARB-containing medicinal products - must not be co-administered, as this product already contains valsartan (section 4.4)
  • Aliskiren / direct renin inhibitors - combination not recommended; contraindicated in patients with diabetes mellitus or renal impairment (eGFR less than 60 ml/min/1.73 m2) (sections 4.3/4.4)
  • Diuretics and other antihypertensives - dose adjustment should be considered if hypotension occurs; symptomatic hypotension is more likely if the patient is volume-depleted by diuretic therapy, dietary salt restriction, diarrhoea or vomiting (section 4.4)
  • NOTE: section 4.5 was not included in the fetched bundle - entries above are drawn from sections 4.2/4.3/4.4. Clinician to review the full interactions section.

Clinical monograph

How it works

Sacubitril is metabolised to a neprilysin inhibitor that increases beneficial natriuretic peptides promoting natriuresis and vasodilatation, while valsartan blocks the angiotensin-II type-1 receptor; the combined effect reduces preload, afterload and harmful neurohormonal activation.

Prescribing in practice

  • Never co-administer with an ACE inhibitor and allow a washout of at least 36 hours when switching from one, because concurrent neprilysin and ACE inhibition substantially increases the risk of angioedema.
  • Avoid in pregnancy and in patients with a history of ACE-inhibitor- or angiotensin-receptor-blocker-related angioedema, and use with caution in significant renal or hepatic impairment.
  • It can cause hypotension, hyperkalaemia and renal impairment, so monitor closely particularly during initiation and up-titration.

Monitoring

Monitor blood pressure, renal function and serum potassium at baseline and after each dose change, with closer review in renal impairment or volume depletion.

Counselling the patient

  • Seek urgent help for any swelling of the face, lips, tongue or throat.
  • Do not take this with an ACE-inhibitor medicine and observe the gap when switching.
  • Report dizziness, which may indicate low blood pressure, and tell your doctor if you become pregnant.

Evidence & guidelines

The PARADIGM-HF trial showed sacubitril-valsartan reduced cardiovascular death and heart-failure hospitalisation compared with enalapril, and it is recommended by NICE for heart failure with reduced ejection fraction.

Reference: NICE TA388; ESC HF 2021; Drug verified in RxNorm (NLM); confirm dosing against the manufacturer SPC (eMC). Verify against your local formulary and current prescribing references before prescribing. The structured dose values shown have been reviewed by a clinician. Monograph status: clinician-reviewed (2026-07-04).

Related

Curated clinical cross-links plus same-class fallbacks.

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