Sacubitril

ENTRESTO contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. ENTRESTO inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan.

• ENTRESTO is a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and is indicated: to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.ICD-10: I50.9

• ENTRESTO is contraindicated: in patients with hypersensitivity to any component in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy [see Warnings and Precautions (5.2)] with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor [see Drug Interactions (7.1)] with concomitant use of aliskiren in patients with diabetes [see Drug Interactions (7.1)] Hypersensitivity to any component.contraindicated

The recommended starting dosage for adults is 49 mg/51 mg orally twice daily. The target maintenance dose is 97 mg/103mg orally twice daily. ( 2.2 ) Adjust adult doses every 2 to 4 weeks to the target maintenance dose, as tolerated by the patient. ( 2.2 ) For pediatric patients, see the Full Prescribing Information for recommended dosage, titrations, preparation and administration instructions. ( 2.3 , 2.4 , 2.5 ) Reduce starting dose to half the usually recommended starting dosage for: patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents. ( 2.6 ) patients with severe renal impairment. ( 2.7 ) patients with moderate hepatic impairment. ( 2.8 ) 2.1 General Considerations ENTRESTO is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to ENTRESTO allow a washout period of 36 hours between administration of the two drugs [see Contraindications (4) and Drug Interactions (7.1)] . 2.2 Adult Heart Failure The recommended starting dose of ENTRESTO is 49/51 mg orally twice-daily. Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient. 2.3 Pediatric Heart Failure For the recommended dosage for pediatric patients aged 1 year and older, refer to Table 1 if using the tablets, or Table 2 if using the oral pellets. Take the recommended dose orally twice daily.

Observe for signs and symptoms of angioedema and hypotension. ( 5.2 , 5.3 ) Monitor renal function and potassium in susceptible patients. ( 5.4 , 5.5 ) 5.1 Fetal Toxicity ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus [see Use in Specific Populations (8.1)] . 5.2 Angioedema ENTRESTO may cause angioedema [see Adverse Reactions (6.1)] . If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and take measures necessary to ensure maintenance of a patent airway.

Clinically significant adverse reactions that appear in other sections of the labeling include: Angioedema [see Warnings and Precautions (5.2)] Hypotension [see Warnings and Precautions (5.3)] Impaired Renal Function [see Warnings and Precautions (5.4)] Hyperkalemia [see Warnings and Precautions (5.5)] Adverse reactions occurring greater than or equal to 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 6,622 heart failure patients were treated with ENTRESTO in the PARADIGM-HF (vs. enalapril) and PARAGON-HF (vs. valsartan) clinical trials. Of these, 5,085 were exposed for at least 1 year. Adult Heart Failure In PARADIGM-HF, patients were required to complete sequential enalapril and ENTRESTO run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing ENTRESTO and enalapril. During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%).

Lactation: Breastfeeding not recommended. ( 8.2 ) Severe Hepatic Impairment: Use not recommended. ( 2.8 , 8.6 ) 8.1 Pregnancy Risk Summary ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death ( see Clinical Considerations ). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. In animal reproduction studies, ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits ( see Data ). When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.

Metabolism

Absorption Following oral administration, ENTRESTO dissociates into sacubitril and valsartan. Sacubitril is further metabolized to LBQ657.

Limited data are available with regard to overdosage in human subjects with ENTRESTO. In healthy volunteers, a single dose of ENTRESTO 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of ENTRESTO. Symptomatic treatment should be provided. ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding.

• Jul 7, 2015NDANDA207620Novartis Pharms Corp
• Apr 12, 2024NDANDA218591Novartis
• May 28, 2024ANDAANDA213605Crystal
• May 28, 2024ANDAANDA213676Laurus
• May 28, 2024ANDAANDA213682Alembic
• Jul 9, 2024ANDAANDA213719Zydus Pharms
• Aug 22, 2024ANDAANDA213604Torrent
• Aug 30, 2024ANDAANDA213680Biocon Pharma

1. 1Hypotension11,50210%
2. 2Death9,1258.0%
3. 3Dyspnoea8,9437.8%
4. 4Dizziness8,6657.6%
5. 5Fatigue8,6577.6%
6. 6Cough7,8446.8%
7. 7Wrong Technique In Product Usage Process7,3056.4%
8. 8Weight Decreased5,1914.5%
9. 9Cardiac Failure4,4763.9%
10. 10Malaise4,4433.9%
11. 11Asthenia3,7843.3%
12. 12Weight Increased3,5033.1%
13. 13Blood Pressure Decreased3,1552.8%
14. 14Product Dose Omission Issue2,8312.5%
15. 15Myocardial Infarction2,7702.4%

The 10 most recently updated of 226 ClinicalTrials.gov registrations naming Sacubitril as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

• Angiotensin-Neprilysin Inhibition in Hemodialysis Initiation
  Completed · Phase 2 · Interventional · 45 enrolled · Brigham and Women's Hospital
  NCT05498181updated 2026-06-08
• Sacubitril-Valsartan in Heart Failure With Preserved Ejection Fraction and Secondary Mitral Valve Regurgitation
  Completed · Phase 4 · Interventional · 84 enrolled · Ziekenhuis Oost-Limburg
  NCT05991284updated 2026-06-08
• STEPwise De-escalation and Optimizing Withdrawal of ARNI and SGLT2i in Normalized Heart Failure
  Not yet recruiting · Phase 4 · Interventional · 80 enrolled · Kyungsub Song
  NCT07631156updated 2026-06-05
• ARNI Combined With SGLT2 Inhibitors on Functional Mitral Regurgitation Remodeling
  Completed · Interventional · 180 enrolled · Rehab Werida
  NCT07379788updated 2026-06-02
• Delayed Initiation of ARNI and SGLT2i in Heart Failure With Corrected Aetiology (DELAY-HF), Pilot Study
  Recruiting · Phase 4 · Interventional · 80 enrolled · Kyungsub Song
  NCT07572032updated 2026-06-01
• A Real-world Study of the Effectiveness of Angiotensin Receptor-Neprilysin Inhibitor Therapy in Hypertensive Patients in the United Arab Emirates
  Not yet recruiting · Observational · 500 enrolled · Novartis Pharmaceuticals
  NCT07465666updated 2026-05-22
• The Effect of Sacubitril and Valsartan on Heart Function in Chronic Hemodialysis Patients With HFpEF
  Completed · Phase 4 · Interventional · 52 enrolled · University Clinical Hospital Mostar
  NCT07417215updated 2026-05-20
• Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC
  Completed · Phase 4 · Interventional · 922 enrolled · Novartis Pharmaceuticals
  NCT04023227updated 2026-05-11
• [177Lu]-NeoB in Patients With Advanced Solid Tumors and With [68Ga]-neoB Lesion Uptake
  Completed · Phase 1 · Phase 2 · Interventional · 35 enrolled · Advanced Accelerator Applications
  NCT03872778updated 2026-04-30
• Triple Combination Therapy (ARNI, SGLT2i, MRA) in Advanced HFpEF
  Recruiting · Phase 2 · Interventional · 50 enrolled · National Medical Research Center for Cardiology, Ministry of Health of Russian Federation
  NCT06655480updated 2026-04-24

Frequently asked questions

How does Sacubitril work?

ENTRESTO contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. ENTRESTO inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan.

What is Sacubitril used for?

According to FDA labeling, Sacubitril carries indications including: ENTRESTO is a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and is indicated: to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.

What class of drug is Sacubitril?

Sacubitril is classified as Neprilysin Inhibitors.

What are the brand names for Sacubitril?

Sacubitril is marketed under brand names including Entresto.

What are the contraindications for Sacubitril?

Sacubitril labeling lists contraindications including: ENTRESTO is contraindicated: in patients with hypersensitivity to any component in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy [see Warnings and Precautions (5.2)] with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor [see Drug Interactions (7.1)] with concomitant use of aliskiren in patients with diabetes [see Drug Interactions (7.1)] Hypersensitivity to any component.. Always consult the full prescribing information and a clinician.