New Drug Introduction: Entresto™ / sacubitril & valsartan
Pharmacology
Manufacturer
Approval date
Indications
Contraindications
Black Box Warnings
Warnings &
Precautions
Pregnancy/Lactation
Pharmacokinetics –
sacubitril
Pharmacokinetics –
valsartan
Drug interactions –
Precipitant/Object
Adverse Effects
(Entresto) [enalapril]
Monitoring Efficacy
Dosing – initial
Dosing – target
Dosing – Max
Renal Adjustment
Hepatic Adjustment
Sacubitril is a prodrug metabolized to the active drug, LBQ657, which
inhibits neprilysin, a neutral endopeptidase, which increases levels of
natriuretic peptides. Valsartan blocks the angiotensin II type-1 receptor.
Novartis Pharmaceuticals Corporation
July 7 2015
Indicated to reduce the risk of cardiovascular death and hospitalization for
heart failure in patients with chronic heart failure (NYHA Class II-IV) and
reduced ejection fraction
 Hypersensitivity to any component
 History of angioedema related to previous ACE-I or ARB therapy
 Concomitant use with ACE inhibitors
 Concomitant use with aliskiren in patients with diabetes
Fetal Toxicity
 Observe for signs and symptoms of angioedema and hypotension
 Monitor renal function and potassium in susceptible patients
 Pregnancy – Discontinue as soon as pregnancy is detected
 Lactation – not recommended
A – time to peak, plasma: 0.5 hrs; time to peak of metabolite: 2 hrs
D – Protein binding – 94-97%; Vd: 103 L
M – Metabolized by esterases to active metabolite. Major metabolite is not
metabolized.
E – T1/2 sacubitril: 1.4 hrs; T1/2 metabolite: 11.5 hrs
A – bioavailability higher than other formulations
26 mg ~ 40 mg
51 mg ~ 80 mg
103 mg ~ 160 mg
 OATP1B1 and OATP1B3 substrates
 ACE-I – increased risk of angioedema
 Aliskiren – dual RAAS blockade
 Potassium-sparing diuretics, ACE-I – increased risk of hyperkalemia
 Lithium – increased Lithium concentrations
 NSAID – decreased renal function
Hypotension (18) [12]
Hyperkalemia (12) [14]
Dizziness (6) [5]
Impaired renal function (6) [5]
Cough (9) [13]
Angioedema (0.5%) [0.2%]
Blood pressure, S/Sx of Heart Failure
If previous ACE-I or ARB – 49/51 mg bid
If no ACE-I or ARB – 24/26 mg bid
Titrate after 2-4 weeks to 97/103 mg as tolerated by patient
97/103 mg bid
Mild-to-moderate – no dose adjustment
Severe – 24/26 mg bid starting dose; titrate as patient tolerates
Mild – no adjustment
Moderate (Child-Pugh B classification) – 24/26 mg bid; titrate as tolerated
Severe impairment – not recommended
Cost: Source: NY Times – Accessed 08/21/15
Dose(s)
Brand – Generic
49/51 mg
Entresto™ – sacubitril & valsartan
$ (year)
~$4,500
Summary
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Entresto™, sacubitril/valsartan, is a novel combination agent that lowers blood pressure and
reduces the risk of cardiovascular death and hospitalization by inhibiting neprilysin and
angiotensin II type-1 receptor, indicated for patients with chronic heart failure (NYHA Class II-IV)
and reduced ejection fraction.
Black box warning for fetal toxicity.
Avoid use in combination with an ACE-I or in patients with a history of angioedema.
Interactions include OATP substrates (lithium), RAAS agents, NSAIDs, and ACE-I.
Blood pressure should be monitored, as hypotension is the most common side effect of
sacubitril/valsartan.
References:
1. Entresto™ [sacubitril and valsartan] package insert. Novartis Pharmaceutical Corporation. July
2015.
2. McMurray, J, et al. PARADIGM-HF Study. New England Journal of Medicine.
2014;371;11:993-1004.
3. Pollack, A. The New York Times Website. F.D.A. Approves Heart Drug Entresto Said to Cut
Death Risk by 20%. http://www.nytimes.com/2015/07/08/business/international/fda-approvesheart-drug-entresto-after-promising-trial-results.html. Published July 7, 2015. Accessed August
21, 2015.
Date Prepared: August 24, 2015
Editor:
Peter G. Koval, Pharm.D., BCPS
Author:
Leslie Perry, Pharm.D. Candidate, UNC Eshelman School of Pharmacy