AHFS Class:

• Angiotensin II Receptor Antagonists/Neprolysin Inhibitors 24:32.12

Generic Name(s):

• Sacubitril and Valsartan

• Sacubitril

• Valsartan

Sacubitril and valsartan (sacubitril/valsartan) is a fixed combination of sacubitril (a neprilysin [neutral endopeptidase] inhibitor) and valsartan (an angiotensin II type 1 [AT₁] receptor antagonist [i.e., angiotensin II receptor blocker, ARB]); such drug combinations have been referred to as angiotensin receptor-neprilysin inhibitors (ARNIs).1,2,4,7,8

Heart Failure

Sacubitril and valsartan in fixed combination (sacubitril/valsartan) is used to reduce the risk of cardiovascular death and hospitalization for patients with chronic heart failure (New York Heart Association [NYHA] class II-IV) and reduced ejection fraction.1,2,4 Sacubitril/valsartan is usually administered in conjunction with other heart failure therapies (e.g., β-adrenergic blocking agent [β-blocker], aldosterone antagonist, diuretic) as a substitute for therapy with an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin II receptor antagonist.1,2,4,700 Current evidence indicates that sacubitril/valsartan results in improved outcomes compared with enalapril based on reductions in cardiovascular death and heart failure hospitalization in patients with chronic heart failure and reduced ejection fraction receiving optimal heart failure therapy.1,2,3,4,700

Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524,700,701,703 Sacubitril/valsartan achieves dual neurohormonal modulation of the renin-angiotensin-aldosterone (RAA) system and neprilysin enzyme;4,21,23,28 the beneficial effects of RAA inhibition by valsartan are augmented by enhanced natriuretic peptide activity due to sacubitril.3,4 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.524,700

Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (i.e., American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality.524 In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the RAA system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.700 While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization and that such ARNI therapy is cost-effective.2,700,704 ACCF, AHA, and HFSA recommend that patients with NYHA class II or III chronic symptomatic heart failure with reduced LVEF who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.700 However, in patients in whom an ARNI is not appropriate, ACCF, AHA, and HFSA strongly advise continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction.700 In patients in whom therapy with an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.700 For additional information on the use of angiotensin II receptor antagonists in the management of heart failure, see Uses: Heart Failure, in Valsartan 24:32.08 and in Candesartan 24:32.08.

Efficacy and safety of sacubitril/valsartan in the management of heart failure have been established principally by the results of a randomized, double-blind trial (PARADIGM-HF) comparing the long-term efficacy and safety of sacubitril/valsartan with that of enalapril in addition to standard-of-care therapy in 8442 patients with symptomatic (NYHA class II-IV) chronic heart failure and reduced ejection fraction (LVEF of 40% or less).1,2,3,4,11,12 In this trial, sacubitril/valsartan was superior to enalapril in reducing the risk of death and hospitalization for heart failure in patients who were receiving these drugs in addition to the best available medical therapy; the benefit of sacubitril/valsartan was similar for both death and hospitalization and was consistent across subgroups.1,2,3,700 Benefits of sacubitril/valsartan were observed in comparison with optimal therapy with enalapril; the mean dosage of enalapril was similar to the well-established target dosages shown to reduce mortality in patients with chronic heart failure and reduced ejection fraction.2,4,9,10,11

Patients enrolled in the PARADIGM-HF trial were receiving an ACE inhibitor or angiotensin II receptor antagonist at a dosage equivalent to at least 10 mg of enalapril daily for at least 4 weeks prior to trial screening in addition to maximally tolerated dosages of β-blockers.1,2 Most patients also received diuretics and mineralocorticoid receptor antagonists and had mild to moderate heart failure symptoms.2,11 Patients with a systolic blood pressure of less than 100 mm Hg at the time of screening were excluded from the trial.1,2 All enrolled patients discontinued their existing ACE inhibitor or angiotensin II receptor antagonist therapy and entered sequential single-blind run-in periods during which they received enalapril 10 mg twice daily (a dosage that has previously been shown to reduce mortality),2,4,9,10,11,524 followed by sacubitril 49 mg/valsartan 51 mg twice daily, increasing to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily.1,2,4,11 To minimize the potential for angioedema caused by overlapping ACE and neprilysin inhibition, enalapril was withheld a day before initiating sacubitril/valsartan, and sacubitril/valsartan was withheld a day before initiating randomized therapy.2,11 The most common reason for patients failing to successfully complete the enalapril and sacubitril/valsartan run-in period was an adverse event, often related to renal dysfunction, hyperkalemia, or hypotension.2,29 Patients who successfully completed the sequential run-in periods were randomized to receive either sacubitril 97 mg/valsartan 103 mg twice daily or enalapril 10 mg twice daily in addition to standard-of-care therapy.1,2,11 The primary end point was a composite of death from cardiovascular causes or first hospitalization for heart failure.1,2

The PARADIGM-HF trial was terminated prematurely following the revelation of a substantially lower rate of the primary composite outcome of cardiovascular death or heart failure hospitalization in the sacubitril/valsartan treatment group at a prespecified interim analysis.2,4,8,21 After a median follow-up duration of 27 months, sacubitril/valsartan reduced the primary end point by approximately 20% compared with enalapril.1,2,700 The treatment effect of sacubitril/valsartan compared with that of enalapril reflected a reduction in both cardiovascular death (20% reduction; event rate 13.3 or 16.5%, respectively) and first hospitalization for worsening heart failure (21% reduction; event rate 12.8 or 15.6%, respectively).1,2 Therapy with sacubitril/valsartan reduced the likelihood of a first hospitalization as well as of multiple hospitalizations.11 Sacubitril/valsartan therapy also improved measures of nonfatal clinical deterioration, including the need for intensification of outpatient treatment, frequency of emergency department visits for worsening heart failure, the requirement for intensive care or IV inotropic support during hospitalization, and the incidence of progression to heart failure mechanical device implantation or cardiac transplantation.4,11 Sacubitril/valsartan also substantially improved overall survival evidenced by a 16% reduction in all-cause mortality, which was attributable principally to a lower incidence of cardiovascular mortality.1,2,3 Symptomatic hypotension occurred more frequently with sacubitril/valsartan therapy than with enalapril (14 or 9.2%, respectively) but was not associated with an increased rate of discontinuance of therapy due to hypotension-related adverse effects.2,15 There were numerically more cases of angioedema with sacubitril/valsartan than with enalapril therapy but the difference was not statistically significant.2,4,15 While it has been stated that the final adverse event rate for sacubitril/valsartan may not reflect clinical practice because of exclusion of patients with intolerance to the drug during the initial run-in period,4 the overall number of patients who were excluded during this period was small and was higher in the enalapril treatment group; therefore, it is considered unlikely that the implementation of a run-in period in this trial substantially affected the observed safety profile of sacubitril/valsartan.2,15

General

Each fixed-combination tablet of sacubitril and valsartan (sacubitril/valsartan [Entresto^®]) contains sacubitril 24 mg/valsartan 26 mg, sacubitril 49 mg/valsartan 51 mg, or sacubitril 97 mg/valsartan 103 mg.1

Bioavailability of the valsartan component of sacubitril/valsartan tablets is 40-60% higher than that of valsartan in other commercially available tablet formulations;7,17,32 the valsartan dose of 26, 51, or 103 mg in the fixed combination of sacubitril/valsartan is equivalent to valsartan doses of 40, 80, or 160 mg, respectively, in other commercially available valsartan tablets.1,13

When switching from an angiotensin-converting enzyme (ACE) inhibitor to sacubitril/valsartan, ACE inhibitor treatment should be stopped 36 hours prior to initiation of sacubitril/valsartan therapy.1,21 (See Contraindications under Cautions.) Therapy with an angiotensin II receptor antagonist also should be discontinued before initiation of sacubitril/valsartan therapy.1 (See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)

Administration

Sacubitril/valsartan is administered orally twice daily without regard to food.1

Dosage

Heart Failure

Dosage of sacubitril/valsartan in fixed combination is expressed in terms of both sacubitril and valsartan components.1

Initial Dosage

The recommended initial dosage of sacubitril/valsartan in patients with chronic heart failure switching from therapy with an ACE inhibitor or angiotensin II receptor antagonist is sacubitril 49 mg/valsartan 51 mg twice daily; sacubitril/valsartan therapy should begin after discontinuance of the angiotensin II receptor antagonist or 36 hours after discontinuance of the ACE inhibitor.1,15,21,700 (See Cautions: Contraindications.)

The recommended initial dosage of sacubitril/valsartan in patients switching from low dosages of an ACE inhibitor (i.e., in a clinical trial, “low dosage” was considered to be enalapril 10 mg daily or less or an equivalent dosage of another ACE inhibitor) or angiotensin II receptor antagonist (i.e., in a clinical trial, “low dosage” was considered to be valsartan 160 mg daily or less or an equivalent dosage of another angiotensin II receptor antagonist) is sacubitril 24 mg/valsartan 26 mg twice daily.1,15,21,32 Sacubitril/valsartan therapy in such patients should begin after discontinuance of the angiotensin II receptor antagonist or 36 hours after discontinuance of the ACE inhibitor.1,15,21,700 (See Cautions: Contraindications.)

The recommended initial dosage of sacubitril/valsartan in patients not currently taking an ACE inhibitor or an angiotensin II receptor antagonist is sacubitril 24 mg/valsartan 26 mg twice daily.1,15,21

Maintenance Dosage

The dosage of sacubitril/valsartan should be doubled every 2-4 weeks, as tolerated, to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily.1,15,21

Special Populations

Hepatic Impairment

No adjustment of sacubitril/valsartan dosage is necessary in patients with mild hepatic impairment (Child-Pugh class A).1 An initial dosage of sacubitril 24 mg/valsartan 26 mg twice daily is recommended for patients with moderate hepatic impairment (Child-Pugh class B).1 The dosage of sacubitril/valsartan should be doubled every 2-4 weeks, as tolerated, to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily.1 Sacubitril/valsartan is not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

No adjustment of sacubitril/valsartan dosage is necessary in patients with mild or moderate renal impairment.1 An initial dosage of sacubitril 24 mg/valsartan 26 mg twice daily is recommended for patients with severe renal impairment (estimated glomerular filtration rate [GFR] less than 30 mL/minute per 1.73 m²).1 The dosage of sacubitril/valsartan should be doubled every 2-4 weeks, as tolerated, to a target maintenance dosage of sacubitril 97 mg/valsartan 103 mg twice daily.1 Safety and efficacy have not been established in patients undergoing dialysis.31 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Volume- and/or Salt-Depleted Patients

Patients with volume and/or salt depletion should have these imbalances corrected prior to the initiation of sacubitril/valsartan therapy; alternatively, sacubitril/valsartan may be initiated at a lower dosage.1

Contraindications

Known hypersensitivity to sacubitril, valsartan, or any ingredient in the formulation.1

History of angioedema related to prior treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist.1,21

Concomitant use of ACE inhibitors.1 Sacubitril/valsartan should not be administered within 36 hours of switching from or to an ACE inhibitor.1,700

Concomitant use of aliskiren in patients with diabetes mellitus.1

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists) can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters.1,14,33,34,35,36,37,38,39,40,41,42,43,44 The fixed combination of sacubitril and valsartan (sacubitril/valsartan) should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving.1,31 For additional information on the risk of such drugs (i.e., angiotensin II antagonists and ACE inhibitors) during pregnancy, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.

Sensitivity Reactions

Angioedema may occur with sacubitril/valsartan therapy, and if associated with laryngeal edema, may be fatal.1 In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition generally resolves without treatment; however, antihistamines may provide symptomatic relief.1 Swelling of the tongue, glottis, or larynx may cause airway obstruction, and appropriate therapy (e.g., epinephrine, maintenance of patent airway) should be initiated.1 Sacubitril/valsartan should not be used in patients with a known history of angioedema related to previous ACE inhibitor or angiotensin II receptor antagonist therapy1,21 (see Cautions: Contraindications); black patients and those with a prior history of angioedema may be at an increased risk of angioedema with sacubitril/valsartan therapy.1,29

Other Warnings/Precautions

Precautions Related to Use of Fixed Combinations

When the fixed combination of sacubitril/valsartan is used, the cautions, precautions, contraindications, and drug interactions associated with sacubitril and valsartan must be considered. 1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug.1 (For cautionary information specific to valsartan, see Cautions in Valsartan 24:32.08.)

Cardiovascular Effects

Sacubitril/valsartan lowers blood pressure and may cause symptomatic hypotension.1,2,4 Symptomatic hypotension may occur in patients with an activated renin-angiotensin-aldosterone (RAA) system (e.g., patients with volume or salt depletion secondary to salt restriction or high-dose diuretic therapy).1,14 (See Volume- and/or Salt-Depleted Patients under Dosage and Administration: Special Populations.)

If hypotension occurs, dosage adjustments of diuretics or concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia) should be considered.1 If hypotension persists despite such measures, the dosage of sacubitril/valsartan should be reduced or the drug temporarily discontinued.1 Permanent discontinuance of therapy is usually not required.1

Renal Effects

Because the RAA system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly (e.g., leading to oliguria, progressive azotemia, and rarely acute renal failure and death) in these patients during therapy with an ACE inhibitor or an angiotensin II receptor antagonist (e.g., valsartan).1,14,29 Dosage reduction or interruption of sacubitril/valsartan therapy may be required in patients who develop a clinically important decrease in renal function.1 As with all drugs that affect the RAA system, sacubitril/valsartan may increase blood urea and serum creatinine concentrations in patients with bilateral or unilateral renal artery stenosis; renal function should be monitored.1,14 (See Cautions: Renal Effects, in Enalaprilat/Enalapril 24:32.04.)

Hyperkalemia

Hyperkalemia may occur in patients receiving sacubitril/valsartan, especially in those with severe renal impairment, diabetes mellitus, hypoaldosteronism, or a potassium-rich diet.1,2 Serum potassium should be monitored periodically and elevated values treated appropriately.1 Dosage reduction or interruption of sacubitril/valsartan therapy may be required in some instances of hyperkalemia.1

Specific Populations

Pregnancy

Sacubitril/valsartan can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman.1 Sacubitril/valsartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving; in such cases, the woman should be advised of the risk to the fetus.1 (See Advice to Patients.) Reproduction studies in rats and rabbits using sacubitril/valsartan during organogenesis have demonstrated increased embryofetal death and teratogenic effects.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Sacubitril/valsartan is distributed into milk in rats.1 It is not known whether sacubitril/valsartan is distributed into human milk.1 Because of the potential for serious adverse reactions to sacubitril/valsartan in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy of sacubitril/valsartan in pediatric patients have not been established.1,21

Geriatric Use

No clinically relevant pharmacokinetic differences have been observed in patients 65 years of age and older compared with the overall population.1,21

Hepatic Impairment

Results of a pharmacokinetic study indicate that sacubitril/valsartan exposure is increased in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).31 Dosage adjustments are not necessary for patients with mild hepatic impairment; a lower initial dosage is recommended in patients with moderate hepatic impairment.1,21,31 (See Hepatic Impairment under Dosage and Administration: Special Populations.)

Sacubitril/valsartan is not recommended in patients with severe hepatic impairment (Child-Pugh class C); safety and efficacy have not been established in this population.1

Renal Impairment

Results of a pharmacokinetic study indicate that exposure to LBQ657 (the active metabolite of sacubitril) is increased by approximately twofold in patients with mild or moderate renal impairment (creatinine clearance 30-80 mL/minute) and 2.7-fold in patients with severe renal impairment (creatinine clearance less than 30 mL/minute). 31 Exposure to sacubitril and valsartan was not substantially altered in patients with renal impairment.31

In the PARADIGM-HF trial, there was no increase in adverse events associated with the increased exposure to LBQ657 in patients with mild or moderate renal impairment;31 dosage adjustments are not necessary in these patients.1,31

Sacubitril/valsartan should be used with caution in patients with severe renal impairment.1 (See Renal Effects and also see Hyperkalemia under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) In patients with severe renal impairment, no change to the target maintenance dosage is recommended; however, a lower initial dosage of sacubitril/valsartan should be used in these patients.1,31 (See Renal Impairment under Dosage and Administration: Special Populations.) A lower initial dosage and slower titration to the target maintenance dosage may reduce potential tolerability issues.31

Safety and efficacy have not been established in patients undergoing dialysis.31 Sacubitril/valsartan is unlikely to be removed by hemodialysis due to high protein binding.1,31

Common Adverse Effects

Adverse effects occurring in at least 5% of patients with heart failure receiving sacubitril/valsartan in the double-blind phase of the PARADIGM-HF trial included hypotension,1,2 cough,1,2 dizziness,1 and renal failure or acute renal failure.1 Laboratory abnormalities occurring in at least 5% of patients receiving sacubitril/valsartan in the double-blind phase of the PARADIGM-HF trial included decreases in hemoglobin and hematocrit exceeding 20%,1 increases in serum creatinine concentration exceeding 50%,1,2 and serum potassium concentrations exceeding 5.5 mEq/L.1,2

Drugs Affecting Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) enzyme-mediated metabolism of sacubitril and valsartan (sacubitril/valsartan) is minimal; therefore, drugs that affect activity of CYP enzymes are not expected to affect the pharmacokinetics of sacubitril/valsartan.1,21,31

Drugs Affected by Hepatic Transport Systems

In vitro data suggest that sacubitril inhibits organic anion transporter protein (OATP) 1B1 and OATP1B3 (hepatic uptake transporters).1,30,31 Sacubitril may increase systemic exposure of OATP1B1 and OATP1B3 substrates (e.g., atorvastatin).1,31

Drugs that Block the Renin-Angiotensin System

Concomitant therapy with sacubitril/valsartan and an angiotensin-converting enzyme (ACE) inhibitor is contraindicated because of the increased risk of angioedema.1,13,17 Concomitant therapy with sacubitril/valsartan and an angiotensin II receptor antagonist should be avoided because the valsartan component of sacubitril/valsartan is an angiotensin II receptor antagonist.1 Concomitant therapy with sacubitril/valsartan and aliskiren, a direct renin inhibitor, is contraindicated in patients with diabetes mellitus; in addition, such concomitant therapy should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m²).1,56 (See Cautions in Aliskiren Hemifumarate 24:32.40.)

Drugs or Foods that Increase Serum Potassium Concentration

Concomitant use of potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes with valsartan may result in an increased risk of hyperkalemia.1,14 Serum potassium concentrations should be monitored periodically during such concomitant use.1

Amlodipine

No clinically relevant pharmacokinetic interaction was observed with coadministration of sacubitril/valsartan and amlodipine.1,21,31

Atorvastatin

Concomitant administration of sacubitril/valsartan and atorvastatin did not alter systemic exposure to sacubitril/valsartan to a clinically important degree; however, the area under the concentration-time curve (AUC) and peak plasma concentration of atorvastatin were increased.1,31

Cardiac Drugs

No clinically relevant pharmacokinetic interactions were observed when sacubitril/valsartan was coadministered with carvedilol or digoxin.1,21,31

Diuretics

Volume depletion may potentiate symptomatic hypotension in patients receiving concomitant therapy with diuretics and sacubitril/valsartan.1 No clinically relevant pharmacokinetic interactions were observed when sacubitril/valsartan was coadministered with hydrochlorothiazide or furosemide.1,21,31

Lithium

Increased serum lithium concentrations and lithium toxicity have been reported with concomitant use of angiotensin II receptor antagonists and lithium.1 Monitoring of serum lithium concentrations is recommended during such concomitant use.1

Metformin

No clinically relevant pharmacokinetic interaction was observed with coadministration of sacubitril/valsartan and metformin.1,21,31

Nonsteroidal Anti-inflammatory Agents

Deterioration of renal function, including possible acute renal failure, may occur when sacubitril/valsartan is used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors, in geriatric patients, patients with volume depletion (including those receiving concomitant diuretic therapy), or patients with renal impairment.1 These effects are usually reversible; renal function should be monitored periodically in such patients receiving concomitant therapy with sacubitril/valsartan and an NSAIA.1

Omeprazole

No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and omeprazole. 1,21,31

Oral Contraceptives

No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and an oral contraceptive containing ethinyl estradiol and levonorgestrel. 1,21,31

Sildenafil

No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and sildenafil.1,31 Coadministration of a 50-mg single dose of sildenafil with sacubitril/valsartan at steady state (sacubitril 194 mg/valsartan 206 mg once daily for 5 days) in patients with hypertension was associated with additive reductions in blood pressure (approximately 5 or 4 mm Hg for systolic or diastolic blood pressure, respectively) compared with administration of sacubitril/valsartan alone.1,31 Patients should be advised about potential adverse effects due to blood pressure-lowering effects with concomitant use of sacubitril/valsartan and sildenafil.31

Warfarin

No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and warfarin.1,21,31

Description

Sacubitril and valsartan (sacubitril/valsartan) is a combination of a neprilysin inhibitor (sacubitril) and an angiotensin II type 1 (AT₁) receptor antagonist (valsartan).1,2,4,7,8 The dual mechanism of sacubitril/valsartan suppresses harmful compensatory mechanisms of heart failure that are mediated by the renin-angiotensin-aldosterone (RAA) system, while simultaneously enhancing the beneficial adaptive mechanisms of natriuretic peptides by inhibiting their degradation.18

The natriuretic peptide system consists of 3 major peptides (atrial natriuretic peptide [ANP], B-type natriuretic peptide [BNP], and C-type natriuretic peptide [CNP]), which are involved in maintaining normal hemodynamics and plasma volume.4,18,21,23,25,27 Natriuretic peptides stimulate natriuresis and diuresis, promote vasodilation, and oppose acute effects of volume overload by inhibiting the RAA system and the sympathetic nervous system.3,28 Natriuretic peptides also have been shown to attenuate the development of cardiac hypertrophy and fibrosis and enhance endothelial function.3,18,19,21,28 The effects of natriuretic peptides are mediated through guanylyl cyclase receptors.21,26,28 Activation of these receptors increases intracellular cyclic guanosine monophosphate (cGMP), which is ultimately responsible for the physiologic effects of natriuretic peptides.21,25,26,28,32

Natriuretic peptides are predominantly catabolized via enzymatic cleavage by the membrane-bound, zinc-dependent enzyme neprilysin (also known as neutral endopeptidase or membrane-metallo-endopeptidase).19,22,25,27 Other substrates of neprilysin include enkephalins, oxytocin, gastrin, angiotensin I and II, endothelin-1, substance P, and bradykinin.19,21,25 Degradation of these substrates is inhibited by sacubitril, which results in increased concentrations of natriuretic peptides and enhances their beneficial counterregulatory effects in heart failure patients.3,21 Sole inhibition of neprilysin results in increased ANP, BNP, and cGMP concentrations but at the expense of increased potent vasoconstrictors (angiotensin II and endothelin-1), which partly counteracts the benefits of increased natriuretic peptides.4,21,24,25 Augmentation of natriuretic peptide effects through neprilysin inhibition requires concomitant suppression of angiotensin II to yield a beneficial effect.4,25 Valsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects, by selectively inhibiting access of angiotensin II to AT₁ receptors within many tissues, including vascular smooth muscle and the adrenal gland. 7,14 For additional information on the pharmacology of angiotensin II receptor antagonists, see Description in Irbesartan 24:32.08 and Valsartan 24:32.08

Following oral administration, sacubitril/valsartan dissociates into sacubitril and valsartan.1 The absolute oral bioavailability of sacubitril is at least 60%, and the bioavailability of valsartan from sacubitril/valsartan is 40-60% higher than that of valsartan administered as a single agent.1,7,17,31,32 Sacubitril is a prodrug; its neprilysin-inhibitory activity is dependent upon conversion to the active metabolite (LBQ657) by deethylation via plasma esterases.1,4,17,32 LBQ657 is not further metabolized to a substantial extent and valsartan is minimally metabolized; approximately 20% of the dose of valsartan is recovered as metabolites.1,14 The primary metabolite of valsartan, accounting for less than 10% of the dose, is a hydroxyl metabolite formed by metabolism via the cytochrome P-450 (CYP) isoenzyme 2C9.1,14 Administration of sacubitril/valsartan with food has no clinically important effect on the systemic exposure of sacubitril, LBQ657, or valsartan.1,21 The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5, 2 , and 1.5 hours, respectively.1 Sacubitril, LBQ657, and valsartan are 94-97% bound to plasma proteins.1 The average elimination half-lives of sacubitril, LBQ657, and valsartan are 1.4, 11.5, and 9.9 hours, respectively.1 Sacubitril (mainly as LBQ657) is excreted in urine (52-68%) and feces (37-48%).1 Valsartan and its metabolites are excreted in urine (approximately 13%) and feces (86%).1

Advice to Patients

Importance of advising patients to read the manufacturer's patient information.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of advising women of childbearing age about the potential risks to the fetus if sacubitril/valsartan is used during pregnancy.1 All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Risk of angioedema.1 Importance of advising patients to discontinue use of any angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor antagonist before taking sacubitril/valsartan.1 Importance of advising patients to allow a 36-hour wash-out period if switching from or to an ACE inhibitor.1 (See Cautions: Contraindications and also see Sensitivity Reactions under Cautions: Warnings/Precautions.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium), as well as any concomitant diseases.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Novartis. Entresto^® (sacubitril and valsartan) tablets prescribing information. East Hanover, NJ; 2015 Aug.

2. McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med . 2014; 371:993-1004. [PubMed 25176015]

3. Jessup M. Neprilysin inhibition--a novel therapy for heart failure. N Engl J Med . 2014; 371:1062-4. [PubMed 25176014]

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