Sacubitril/valsartan
Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI). Sacubitril/valsartan is used for Adult chronic heart failure and Paediatric heart failure.
Pronunciation: pronunciation varies by local usage.
- Generic name
- sacubitril and valsartan
- Brand names
- Entresto
- Drug class
- Angiotensin receptor-neprilysin inhibitor (ARNI)
- Form
- Film-coated tablets and granules (granule formulation noted in the EU source; exact available strengths and forms are country-specific and not fully enumerated in the supplied notes)
- Route
- Oral
- Legal status
- Prescription-only medicine
Availability and supply rules vary by country
Trade names by country: United States
Australia: · Full directory
What sacubitril and valsartan is and how it works
Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI). Sacubitril is a prodrug whose active metabolite LBQ657 inhibits neprilysin, raising natriuretic peptides; valsartan blocks the angiotensin II AT1 receptor and angiotensin II-dependent aldosterone release. It is used to treat heart failure. (3) (4)
It is a prescription heart-failure medicine, not a general blood-pressure medicine. Benefits in adults have been most clearly evident with left ventricular ejection fraction below normal. It must not be taken with an ACE inhibitor, and switching between the two requires a 36-hour gap because of angioedema risk. It acts on the renin-angiotensin system and carries a boxed fetal-toxicity warning, so pregnancy must be reported to the prescriber promptly.
Mechanism of action: how sacubitril and valsartan works
Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI). Sacubitril is a prodrug whose active metabolite LBQ657 inhibits neprilysin, raising natriuretic peptides; valsartan blocks the angiotensin II AT1 receptor and angiotensin II-dependent aldosterone release. Peak concentrations of sacubitril, LBQ657, and valsartan occur at 0.5, 2, and 1.5 hours, respectively. Steady state is reached in 3 days with twice-daily dosing. The valsartan in this product is more bioavailable than in other valsartan tablets (26/51/103 mg equivalent to 40/80/160 mg). Food has no clinically significant effect. The medicine is unlikely to be removed by haemodialysis due to high protein binding. (3) (4)
What is Sacubitril and valsartan used for?
Adult chronic heart failure
Adults: to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure (US wording), with benefits most clearly evident with LVEF below normal. The EU wording is: treatment of symptomatic chronic heart failure with reduced ejection fraction in adults. Indication wording differs between the US and EU labels. (3) (4)
Paediatric heart failure
Children and adolescents aged one year and older: treatment of symptomatic heart failure with left ventricular systolic dysfunction (US wording: systemic left ventricular systolic dysfunction). The safety and efficacy of sacubitril/valsartan in children aged below 1 year have not been established and no posology recommendation can be made. (3) (4)
Before taking sacubitril and valsartan
Do not take / not appropriate for
- Do not take sacubitril/valsartan together with an ACE inhibitor. A 36-hour gap is required between the last dose of an ACE inhibitor and starting sacubitril/valsartan, and between the last dose of sacubitril/valsartan and starting an ACE inhibitor, because of the increased risk of angioedema. A clinician must direct this switch. (all patients) (3) (4)
- Do not take sacubitril/valsartan after a hypersensitivity reaction to sacubitril, valsartan, or any component of the product. (all products) (3) (4)
- Do not take sacubitril/valsartan if there is a known history of angioedema related to previous ACE inhibitor or ARB therapy, or if there is hereditary or idiopathic angioedema. (all patients) (3) (4)
- Do not take sacubitril/valsartan with aliskiren-containing medicines if there is diabetes mellitus, or if there is renal impairment with eGFR below 60 ml/min/1.73 m2. (patients with diabetes or renal impairment) (3) (4)
- In the EU labelling, sacubitril/valsartan is contraindicated in severe hepatic impairment, biliary cirrhosis, and cholestasis (Child-Pugh C), and in the second and third trimesters of pregnancy. Tell the prescriber about liver problems or pregnancy so eligibility can be assessed. (EU labelling) (4)
Tell your clinician about
- Any pregnancy, suspected pregnancy, or plans for pregnancy, and whether breastfeeding; sacubitril/valsartan is not recommended during breastfeeding, and the boxed warning concerns fetal toxicity.
- Any previous angioedema, including any swelling related to a previous ACE inhibitor or ARB, or hereditary or idiopathic angioedema.
- Every medicine being taken, especially ACE inhibitors, other ARBs, aliskiren, potassium-sparing diuretics, mineralocorticoid antagonists (such as spironolactone or eplerenone), potassium supplements or potassium-containing salt substitutes, NSAIDs, lithium, statins, PDE5 inhibitors such as sildenafil, furosemide, metformin, rifampicin, ciclosporin, tenofovir, cidofovir, or ritonavir.
- Kidney problems, liver problems, or a history of renal artery stenosis; renal function and potassium are monitored before and during treatment.
- Current blood pressure and any history of low blood pressure, dizziness, fainting, or volume depletion from diuretics, dietary salt restriction, diarrhoea, or vomiting.
- Recent or current high potassium levels, diabetes, hypoaldosteronism, or a high-potassium diet.
- Any new hallucinations, paranoia, or sleep problems, since psychiatric events have been associated with this medicine.
- Whether dizziness or fatigue could affect driving or operating machines.
Sacubitril and valsartan dosage and how to take it
- Sacubitril/valsartan is taken by mouth twice daily. The tablets must be swallowed with a glass of water; splitting or crushing the tablets is not recommended.
- It may be taken with or without food; food has no clinically significant effect.
- If a dose is missed, take the next dose at the scheduled time (EU wording). Do not change the dose, interval, or product without the prescriber's direction.
- Do not take it with an ACE inhibitor or another ARB, and do not start or restart an ACE inhibitor without a 36-hour gap as directed by the prescriber.
- Do not initiate treatment if serum potassium is above 5.4 mmol/l in adults or above 5.3 mmol/l in children, or if systolic blood pressure is below 100 mmHg in adults or below the 5th percentile for age in children; a clinician must assess and manage this.
- In the EU labelling, film-coated tablets are not suitable for children weighing less than 40 kg; granules are available for these patients.
Procedures and treatment changes
Tell the treating team before surgery, procedures, or any medicine change. Do not alter treatment without the responsible clinician. (3) (2) (4)
Missed dose
If a dose is missed, the patient should take the next dose at the scheduled time (EU wording). Contact the prescribing clinic for guidance; do not take an extra dose or alter the next dose or interval without prescriber advice.
Overdose
Limited data are available on overdose in humans. Hypotension is the most likely symptom because of the blood-pressure-lowering effects, and symptomatic treatment should be provided. The medicine is unlikely to be removed by haemodialysis because of high protein binding. Patient action: call emergency services or poison control (US label patient instruction). (3) (4)
Sacubitril and valsartan side effects
The most commonly reported adverse reactions in adults were hypotension (17.6%), hyperkalaemia (11.6%) and renal impairment (10.1%). Angioedema was reported in 0.5% of patients in the PARADIGM-HF study, with a higher incidence in Black patients (2.4%). The safety profile in paediatric studies was similar to that in adults.
Hypotension (very common)
What to notice: Low blood pressure, dizziness, light-headedness, or fainting, especially in patients aged 65 years or older, patients with kidney disease, or patients with low systolic blood pressure. In PARADIGM-HF, hypotension was reported in 17.6% of sacubitril/valsartan-treated patients and clinically relevant low systolic blood pressure (<90 mmHg and a fall of more than 20 mmHg from baseline) in 4.76%.
What to do: Blood pressure should be monitored routinely during initiation and dose titration. If hypotension occurs, the prescriber may adjust other medicines, temporarily down-titrate, or discontinue. Seek medical advice rather than changing the dose yourself. (3) (4)
Hyperkalaemia (very common) and hypokalaemia (common)
What to notice: Raised or low blood potassium. In PARADIGM-HF, hyperkalaemia and serum potassium above 5.4 mmol/l were reported in 11.6% and 19.7% of sacubitril/valsartan-treated patients, respectively. Monitoring of serum potassium is recommended, especially with renal impairment, diabetes, hypoaldosteronism, a high-potassium diet, or mineralocorticoid antagonists.
What to do: Tell the treatment team; potassium monitoring is part of routine care. If hyperkalaemia is clinically significant, adjustment of other medicines, temporary down-titration, or discontinuation may be recommended, and discontinuation should be considered if serum potassium is above 5.4 mmol/l. (3) (4)
Renal impairment (very common) and renal failure (common)
What to notice: Worsening kidney function, which may be further increased by dehydration or by NSAID use. In PARADIGM-HF, renal impairment was reported in 10.1% of sacubitril/valsartan-treated patients.
What to do: Renal function is assessed before and during treatment. Down-titration should be considered in patients who develop a clinically significant decrease in renal function; discuss with the treatment team. (3) (4)
Cough, dizziness, vertigo, headache, syncope, orthostatic hypotension, diarrhoea, nausea, gastritis, fatigue, asthenia, anaemia, hypoglycaemia
What to notice: These were common adverse reactions in adults ranked by system organ class. Dizziness and fatigue may occasionally occur and sacubitril/valsartan has a minor influence on the ability to drive and use machines.
What to do: Discuss persistent or troublesome symptoms with the prescribing team rather than stopping treatment yourself. (4)
Angioedema
What to notice: Swelling, including swelling of the face, lips, tongue, glottis, or larynx. Angioedema associated with laryngeal oedema may be fatal. Angioedema was reported in 0.5% of sacubitril/valsartan-treated patients in PARADIGM-HF, and the incidence was higher in Black patients (2.4%).
What to do: Seek emergency medical attention promptly. If angioedema occurs, the medicine must be immediately discontinued and appropriate therapy and monitoring provided until complete and sustained resolution; it must not be re-administered. Let the clinician you see advise on whether to continue or stop. (3) (4)
Intestinal angioedema
What to notice: Abdominal pain, nausea, vomiting, and diarrhoea, reported with angiotensin II receptor antagonists including valsartan. Symptoms resolved after discontinuation of angiotensin II receptor antagonists.
What to do: Seek prompt medical assessment. If intestinal angioedema is diagnosed, sacubitril/valsartan should be discontinued and monitoring initiated until complete resolution of symptoms. (4)
Psychiatric events
What to notice: Hallucinations (including auditory and visual), paranoia, and sleep disorders in the context of psychotic events have been associated with sacubitril/valsartan use.
What to do: Contact the prescriber; discontinuation of treatment should be considered, with the decision made by the clinician. (4)
Serious warnings
Fetal toxicity (boxed warning) — emergency
Symptoms: Drugs acting directly on the renin-angiotensin system, including sacubitril/valsartan, can cause injury and death to the developing fetus. Exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Action: Pregnancy should be reported to the prescriber as soon as it is detected; the US boxed warning directs stopping as soon as possible when pregnancy is detected. Let the clinician manage whether and how to stop. In the EU labelling, use is not recommended during the first trimester and is contraindicated during the second and third trimesters. (3) (4)
Angioedema — emergency
Symptoms: Swelling of the face, lips, tongue, glottis, or larynx that may cause airway obstruction. Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, appropriate therapy such as adrenaline solution 1 mg/1 ml (0.3-0.5 ml) and/or measures to ensure a patent airway should be promptly administered. Black patients have an increased susceptibility. Patients with a prior history of angioedema were not studied and may be at higher risk.
Action: Seek emergency medical attention promptly. If angioedema occurs, sacubitril/valsartan should be immediately discontinued and appropriate therapy and monitoring provided until complete and sustained resolution; it must not be re-administered. (3) (4)
Hypotension — urgent
Symptoms: Symptomatic low blood pressure, especially in patients aged 65 years or older, patients with renal disease, and patients with low systolic blood pressure (<112 mmHg). Symptomatic hypotension is more likely if the patient has been volume-depleted by diuretic therapy, dietary salt restriction, diarrhoea, or vomiting. Treatment should not be initiated unless systolic blood pressure is at least 100 mmHg in adults or at least the 5th percentile for age in children.
Action: Blood pressure should be monitored routinely when initiating or titrating. If hypotension occurs, temporary down-titration or discontinuation is recommended, along with adjustment of diuretics and other antihypertensives and correction of other causes such as hypovolaemia. Seek medical advice; do not adjust the dose yourself. (3) (4)
Hyperkalaemia — urgent
Symptoms: Raised serum potassium, which may occur with this medicine, and low potassium has also been reported. Risk factors include renal impairment, diabetes mellitus, hypoaldosteronism, a high-potassium diet, and mineralocorticoid antagonists. Treatment should not be initiated if serum potassium is above 5.4 mmol/l in adults or above 5.3 mmol/l in children.
Action: Monitoring of serum potassium is recommended. If clinically significant hyperkalaemia occurs, adjustment of other medicines, or temporary down-titration or discontinuation, is recommended, and discontinuation should be considered if serum potassium is above 5.4 mmol/l. This decision must be made by the clinician. (3) (4)
Impaired or worsening renal function — urgent
Symptoms: Decreased kidney function, which may be increased by dehydration or by concomitant NSAID use. Patients with mild and moderate renal impairment are more at risk of developing hypotension, and there is very limited clinical experience in patients with severe renal impairment (eGFR below 30 ml/min/1.73 m2). There is no experience in patients with end-stage renal disease.
Action: Renal function is monitored before and during treatment. Down-titration should be considered in patients who develop a clinically significant decrease in renal function. Use is not recommended in end-stage renal disease. Seek clinician advice on any dose decision. (3) (4)
Interactions
| Medicine or test | Effect | Action |
|---|---|---|
| ACE inhibitors | Concomitant use is contraindicated because the combined inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan must not be started until 36 hours after the last dose of an ACE inhibitor, and an ACE inhibitor must not be started until 36 hours after the last dose of sacubitril/valsartan. | Do not take these together. The switch must be directed by the prescriber with the required 36-hour gap. (3) (4) |
| Other ARBs | Sacubitril/valsartan contains valsartan and should not be co-administered with another ARB-containing medicine. | Tell the prescriber and pharmacist about all current medicines so that duplicate ARB therapy is avoided. (4) |
| Aliskiren | Concomitant use with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (eGFR below 60 ml/min/1.73 m2). The combination with direct renin inhibitors such as aliskiren is not recommended and is potentially associated with a higher frequency of hypotension, hyperkalaemia, and decreased renal function including acute renal failure. | Give the specialist and pharmacist a complete medicine list before starting any aliskiren-containing product. (3) (4) |
| Potassium-sparing diuretics, mineralocorticoid antagonists, potassium supplements, potassium-containing salt substitutes, and other agents such as heparin | Concomitant use may lead to increases in serum potassium and serum creatinine. Monitoring of serum potassium is recommended when sacubitril/valsartan is co-administered with these agents. | Tell the prescriber about these products; potassium monitoring is part of the management plan. (3) (4) |
| NSAIDs, including selective COX-2 inhibitors | In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use may lead to an increased risk of worsening renal function. | Monitoring of renal function is recommended when initiating or modifying treatment in patients taking NSAIDs concomitantly. (3) (4) |
| Lithium | Reversible increases in serum lithium concentrations and toxicity have been reported with lithium and ACE inhibitors or angiotensin II receptor antagonists including sacubitril/valsartan. The combination is not recommended. If a diuretic is also used, the risk of lithium toxicity may increase further. | If the combination is necessary, careful monitoring of serum lithium levels is recommended; this must be managed by the prescriber. (3) (4) |
| OATP1B1 and OATP1B3 substrates, e.g. statins | Sacubitril inhibits OATP1B1 and OATP1B3 transporters in vitro and may increase the systemic exposure of substrates such as statins. Co-administration increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. No clinically relevant interaction was observed with simvastatin. | Caution should be exercised when co-administering sacubitril/valsartan with statins. (4) |
| PDE5 inhibitors including sildenafil | Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction than sacubitril/valsartan alone. | Caution should be exercised when sildenafil or another PDE5 inhibitor is initiated in patients treated with sacubitril/valsartan. (4) |
| OATP1B1, OATP1B3, OAT1, OAT3, and MRP2 inhibitors (e.g. rifampicin, ciclosporin, tenofovir, cidofovir, ritonavir) | LBQ657 and valsartan are OATP1B1, OATP1B3, OAT1, and OAT3 substrates; valsartan is also an MRP2 substrate. Co-administration with inhibitors of these transporters may increase the systemic exposure of LBQ657 or valsartan. | Appropriate care should be exercised when initiating or ending concomitant treatment with such medicines. (4) |
| Furosemide | Co-administration had no effect on the pharmacokinetics of sacubitril/valsartan but reduced the Cmax and AUC of furosemide by 50% and 28%, respectively. Urinary sodium excretion was reduced within 4 hours and 24 hours after co-administration, although urine volume did not change relevantly. | Discuss any diuretic changes with the prescriber. (4) |
| Nitrates, e.g. nitroglycerine | No interaction was observed with intravenously administered nitroglycerin with regard to blood-pressure reduction; co-administration was associated with a treatment difference of 5 bpm in heart rate compared with nitroglycerine alone. A similar effect may occur with sublingual, oral, or transdermal nitrates. | In general no dose adjustment is required. (4) |
| Metformin | Co-administration reduced both the Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. | When initiating sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be evaluated. (4) |
| No significant interaction reported: digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol, levonorgestrel/ethinyl estradiol | No clinically meaningful interaction was observed when sacubitril/valsartan was co-administered with these medicines. | Still provide a complete medicine list to the prescriber and pharmacist. (4) |
Special populations
Children and adolescents
Sacubitril/valsartan is indicated in children and adolescents aged one year or older for symptomatic chronic heart failure with left ventricular systolic dysfunction. Dosing is weight-based and set by the prescriber, with dose increases every 2-4 weeks to the target dose as tolerated. In the EU labelling, film-coated tablets are not suitable for children weighing less than 40 kg; granules are available for these patients. The safety and efficacy in children aged below 1 year have not been established and no posology recommendation can be made. In the PANORAMA-HF study the safety profile was similar to that in adults, with limited safety data in patients aged 1 month to less than 1 year and in paediatric patients with moderate hepatic impairment or moderate to severe renal impairment. (3) (4)
Pregnancy and breastfeeding
Drugs acting on the renin-angiotensin system can injure or kill the developing baby; pregnancy should be reported as soon as it is detected and the US boxed warning directs stopping as soon as possible. In the EU labelling, use is not recommended during the first trimester and is contraindicated during the second and third trimesters. Patients planning pregnancy should be changed to alternative treatments with an established safety profile in pregnancy, as decided by the prescriber. Sacubitril and its active metabolite LBQ657 are excreted in human milk in very low amounts (estimated relative infant dose 0.01% for sacubitril and 0.46% for LBQ657 at 24 mg/26 mg twice daily), and valsartan was below the limit of detection; there is insufficient information on effects in newborns and infants, and sacubitril/valsartan is not recommended in women who are breastfeeding. (3) (4)
Elderly patients
The dose should be in line with the renal function of the elderly patient. Symptomatic hypotension has been reported especially in patients aged 65 years or older. (4)
Renal impairment
No dose adjustment is 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), and half of the starting dose is recommended with caution in severe renal impairment (eGFR below 30 ml/min/1.73 m2) because of very limited clinical experience. There is no experience in end-stage renal disease and use is not recommended. Patients with mild and moderate renal impairment are more at risk of developing hypotension. In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended, increased following the recommended titration every 2-4 weeks. (3) (4)
Hepatic impairment
No dose adjustment is required in mild hepatic impairment (Child-Pugh A). There is limited clinical experience in moderate hepatic impairment (Child-Pugh B) or with AST/ALT values more than twice the upper limit of normal; caution is recommended and half of the starting dose is recommended. In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended, increased following the recommended titration every 2-4 weeks. Sacubitril/valsartan is contraindicated in severe hepatic impairment, biliary cirrhosis, and cholestasis (Child-Pugh C) in the EU labelling. The US addendum lists moderate liver impairment as a situation for starting at half dose (24/26 mg twice daily). (3) (4)
Patients with renal artery stenosis
Sacubitril/valsartan may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Caution is required and monitoring of renal function is recommended. (4)
Patients with NYHA class IV heart failure
Caution should be exercised when initiating sacubitril/valsartan in patients with NYHA functional classification IV because of limited clinical experience in this population. (4)
Monitoring
Before starting
- Assess renal function: evaluation of patients with heart failure should always include assessment of renal function.
- Check serum potassium; treatment should not be initiated if serum potassium is above 5.4 mmol/l in adults or above 5.3 mmol/l in children.
- Check systolic blood pressure; treatment should not be initiated unless systolic blood pressure is at least 100 mmHg in adults or at least the 5th percentile for age in children.
- Review every medicine, especially ACE inhibitors, other ARBs, aliskiren, potassium-raising agents, NSAIDs, lithium, statins, PDE5 inhibitors, and transporter inhibitors.
- Assess pregnancy status and breastfeeding plans; consider alternative treatments with an established safety profile in pregnancy if pregnancy is planned.
- Correct sodium and/or volume depletion before starting, weighing this against the risk of volume overload.
- Assess for prior angioedema, renal artery stenosis, NYHA class IV, and hepatic impairment.
During treatment
- Monitor blood pressure routinely when initiating therapy and during dose titration; if hypotension occurs, temporary down-titration or discontinuation is recommended, along with adjustment of diuretics and other antihypertensives and treatment of other causes of hypotension.
- Monitor serum potassium, especially in patients with renal impairment, diabetes mellitus, hypoaldosteronism, a high-potassium diet, or mineralocorticoid antagonist use. If serum potassium is above 5.4 mmol/l, discontinuation should be considered.
- Monitor renal function; down-titration should be considered in patients who develop a clinically significant decrease in renal function, and renal function monitoring is recommended when initiating or modifying treatment in patients taking NSAIDs.
- Monitor for angioedema; if it occurs, sacubitril/valsartan should be immediately discontinued with appropriate therapy and monitoring until complete and sustained resolution, and it must not be re-administered.
- Monitor for intestinal angioedema (abdominal pain, nausea, vomiting, diarrhoea) and discontinue with monitoring until complete resolution if diagnosed.
- Monitor for psychiatric events such as hallucinations, paranoia, and sleep disorders; discontinuation should be considered if these occur.
- Dose should be doubled at 2-4 weeks to the target dose as tolerated, or a slower titration used in certain situations; decisions are made by the prescriber.
- Note that BNP is not a suitable biomarker of heart failure in patients treated with sacubitril/valsartan because it is a neprilysin substrate.
Storage
Follow the exact product label and keep medicines away from children.
Professional information
Clinician-facing context only. Use the current local indication, dosing table, product information, and heart-failure guideline. US and EU label wording and some contraindications differ and must be applied as stated for the relevant region.
United States
Indication: Adult heart failure
Dose summary: Start 49 mg/51 mg twice daily; double after 2-4 weeks to the target 97 mg/103 mg twice daily as tolerated. Start at half dose (24/26 mg twice daily) if not currently on an ACE inhibitor or ARB or on a low dose, with severe kidney impairment, or with moderate liver impairment.
Renal context: Severe kidney impairment is listed as a situation for starting at half dose (24/26 mg twice daily). Full renal dose-adjustment detail beyond this is not given in the supplied US notes. (3)
United States
Indication: Paediatric heart failure (1 year and older)
Dose summary: Weight-based dosing set by the prescriber.
Renal context: Not specified in the supplied US notes beyond the prescriber setting the dose. (3)
European Union / United Kingdom
Indication: Adult heart failure
Dose summary: Recommended starting dose is one tablet of 49 mg/51 mg twice daily, except in the situations described below. The dose should be doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated. 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 and slow dose titration (doubling every 3-4 weeks) are recommended. A starting dose of 24 mg/26 mg twice daily should be considered for patients with systolic blood pressure at least 100 to 110 mmHg. If patients experience tolerability issues (systolic blood pressure 95 mmHg or below, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicines, temporary down-titration, or discontinuation is recommended. Treatment should not be initiated in patients with serum potassium above 5.4 mmol/l or systolic blood pressure below 100 mmHg.
Renal context: No dose adjustment 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). Use with caution and half of the starting dose is recommended in severe renal impairment (eGFR below 30 ml/min/1.73 m2) due to very limited clinical experience. No experience in end-stage renal disease; use is not recommended. (4)
European Union / United Kingdom
Indication: Paediatric heart failure (1 year and older)
Dose summary: Dose is taken orally twice daily and increased every 2-4 weeks to the target dose as tolerated. Recommended dose titration by weight: patients less than 40 kg - half starting dose 0.8 mg/kg, starting dose 1.6 mg/kg, intermediate dose 2.3 mg/kg, target dose 3.1 mg/kg (all twice daily, as combined sacubitril and valsartan, given using granules). Patients at least 40 kg and less than 50 kg - starting dose 24 mg/26 mg, intermediate dose 49 mg/51 mg, target dose 72 mg/78 mg. Patients at least 50 kg - starting dose 24 mg/26 mg, intermediate dose 49 mg/51 mg, target dose 72 mg/78 mg, then 97 mg/103 mg as the highest listed target. Half the starting dose (0.8 mg/kg for those under 40 kg) is recommended in patients who have not been taking an ACE inhibitor or ARB or have been on low doses, patients with eGFR below 60 ml/min/1.73 m2, and patients with moderate hepatic impairment. For paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended, increased following the recommended titration every 2-4 weeks. Treatment should not be initiated in patients with serum potassium above 5.3 mmol/l or systolic blood pressure below the 5th percentile for age. Film-coated tablets are not suitable for children weighing less than 40 kg; granules are available.
Renal context: Half the starting dose is recommended in patients with eGFR below 60 ml/min/1.73 m2. For paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended, increased following the recommended titration every 2-4 weeks. (4)
Hepatic guidance
No dose adjustment is required in mild hepatic impairment (Child-Pugh A). Limited clinical experience exists in moderate hepatic impairment (Child-Pugh B) or with AST/ALT more than twice the upper limit of normal; caution is recommended and half of the starting dose is recommended. Sacubitril/valsartan is contraindicated in severe hepatic impairment, biliary cirrhosis, and cholestasis (Child-Pugh C) in the EU labelling. Use current local product information and specialist judgement; this page does not provide impairment-specific dosing beyond what the sources state.
Overdose note
Limited data are available on overdose in humans. A single dose of 583 mg sacubitril/617 mg valsartan and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) were studied in healthy adult volunteers and were well tolerated. Hypotension is the most likely symptom due to the blood-pressure-lowering effects; symptomatic treatment should be provided. The medicine is unlikely to be removed by haemodialysis due to high protein binding. (3) (4)
Frequently asked questions
Can I take sacubitril/valsartan with my ACE inhibitor?
No. Taking it with an ACE inhibitor is contraindicated because of the increased risk of angioedema. A 36-hour gap is required between stopping an ACE inhibitor and starting sacubitril/valsartan, and between stopping sacubitril/valsartan and starting an ACE inhibitor. The switch must be directed by the prescriber. (3) (4)
Why does sacubitril/valsartan have a boxed warning?
The boxed warning concerns fetal toxicity: drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. Pregnancy should be reported to the prescriber as soon as it is detected; the US boxed warning directs stopping as soon as possible, and in the EU labelling use is not recommended in the first trimester and contraindicated in the second and third trimesters. (3) (4)
Can I breastfeed while taking sacubitril/valsartan?
It is not recommended during breastfeeding. Sacubitril and its active metabolite LBQ657 are excreted in human milk in very low amounts (estimated relative infant dose 0.01% for sacubitril and 0.46% for LBQ657 at 24 mg/26 mg twice daily), and valsartan was below the limit of detection, but there is insufficient information on effects in newborns and infants. Discuss infant feeding with the prescriber. (3) (4)
Can I switch from my current valsartan tablets to the same number on sacubitril/valsartan?
No. The valsartan in this product is more bioavailable than the valsartan in other marketed tablet formulations (26/51/103 mg in this product is equivalent to 40/80/160 mg in other valsartan tablets). Any switch must be made by the prescriber using the correct product and dosing. (3) (4)
What should I do if I miss a dose?
In the EU labelling, if a dose is missed the patient should take the next dose at the scheduled time. Do not take an extra dose or change the interval; contact the prescribing clinic for guidance. (4)
What is the mechanism of action of sacubitril and valsartan?
Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI). Sacubitril is a prodrug whose active metabolite LBQ657 inhibits neprilysin, raising natriuretic peptides; valsartan blocks the angiotensin II AT1 receptor and angiotensin II-dependent aldosterone release. Peak concentrations of sacubitril, LBQ657, and valsartan occur at 0.5, 2, and 1.5 hours, respectively. Steady state is reached in 3 days with twice-daily dosing. The valsartan in this product is more bioavailable than in other valsartan tablets (26/51/103 mg equivalent to 40/80/160 mg). Food has no clinically significant effect. The medicine is unlikely to be removed by haemodialysis due to high protein binding. (3) (4)
References
- ENTRESTO (sacubitril and valsartan) — prescribing informationDailyMed, U.S. National Library of Medicine (Novartis; SPL effective 2026-07-06) · United States · dated 2026-07-06 · accessed 2026-10-09 · source 1
- Sacubitril and Valsartan: MedlinePlus Drug InformationMedlinePlus, U.S. National Library of Medicine · United States · accessed 2026-10-09 · source 2
- Entresto (sacubitril/valsartan) prescribing information — dose addendumDailyMed, U.S. National Library of Medicine (openFDA drug label API, same SPL set id) · United States · dated 2026-07-06 · accessed 2026-10-12 · source 3
- Entresto (sacubitril/valsartan) — EPAR product information, Summary of Product CharacteristicsEuropean Medicines Agency · European Union / United Kingdom labelling wording · accessed 2026-10-17 · source 4
Brand names by country
Single-ingredient sacubitril and valsartan names are shown separately by country. Product availability, strengths, and supply rules can change; combination products are not included here.
Priority countries
United States
- Entrestotablet, film coated, pellet · 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg · novartis pharmaceuticals corporationregulator source