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
Sacubitril and valsartan in fixed combination (sacubitril/valsartan) is used to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic heart failure; benefits are most clear in patients with left ventricular ejection fraction (LVEF) below normal.1
Sacubitril/valsartan in fixed combination is also used for treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction (LVSD) in pediatric patients aged ≥1 year.1 Reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) by sacubitril/valsartan is expected to improve cardiovascular outcomes.1
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 (New York Heart Association [NYHA] class II-IV) chronic heart failure and reduced ejection fraction (LVEF of 40% or less).1, 2, 3, 4, 11, 12
Patients enrolled in the PARADIGM-HF trial were receiving an angiotensin-converting enzyme (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 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 Enrolled patients were 68% white, 18% Asian, and 5% Black, with a mean age of 64 years; 78% were male and the mean LVEF was 29%.1
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, treatment with sacubitril/valsartan compared with that of enalapril showed a reduction in the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure (21.8 versus 26.5%, respectively).1, 2 The event rate for cardiovascular death with sacubitril/valsartan or enalapril was 13.3 or 16.5% , respectively, and for first hospitalization for worsening heart failure was 12.8 or 15.6% , respectively.1, 2 Sacubitril/valsartan also substantially improved overall survival compared to treatment with enalapril (all-cause mortality, 17 versus 19.8%).2
The PARAGON-HF trial was a multicenter, randomized, double-blind study comparing sacubitril/valsartan to valsartan alone in 4796 adult patients with NYHA class II to IV and LVEF ≥45%.1, 1000 Following a single-blind run-in period where patients were first given valsartan followed by sacubitril/valsartan, both given as half the target dose, patients were randomized to treatment with either sacubitril 97 mg/valsartan 103 mg or valsartan 160 mg twice daily.1, 1000 The primary outcome assessed was a composite of total (first and recurrent) hospitalizations for heart failure and death from cardiovascular causes.1000
Enrolled patients were 81% White, 13% Asian, and 2% Black.1 The mean age was 73 years, 52% were female, and 77% were in NYHA class II.1 The event rate for the primary composite endpoint was 12.8 or 14.6% for sacubitril/valsartan or valsartan, respectively.1, 1000 Differences in the primary composite outcomes were primarily driven by change in total hospitalizations with sacubitril/valsartan compared with valsartan.1, 1000
The PIONEER-HF trial, a multicenter, randomized, double-blind trial, evaluated the efficacy of sacubitril/valsartan compared to enalapril in patients hospitalized for acute decompensated heart failure†.1003 Adult patients (N=881) with an LVEF ≤40%, an NT-proBNP concentration ≥1600 pg/mL, or a B-type natriuretic concentration ≥400 pg/mL were randomly assigned to treatment with sacubitril/valsartan or enalapril during hospitalization.1003 A decrease in NT-proBNP concentration from baseline (the primary outcome) occurred in both treatment groups, and was greater with sacubitril/valsartan compared to enalapril (-46.7 or -25.3%, respectively).1003
A second trial, PARAGLIDE-HF, evaluated the use of sacubitril/valsartan compared to valsartan in patients with heart failure, an LVEF >40%, and a recent worsening heart failure event†.1004 Adult patients (N=466) with an elevated NT-proBNP or B-type natriuretic peptide currently hospitalized for or within 30 days of a worsening heart failure event were randomly assigned to treatment with either sacubitril/valsartan or valsartan.1004 Change in NT-proBNP at 4 and 8 weeks (the primary outcome) was greater with sacubitril/valsartan compared to valsartan, with a ratio of change of 0.85.1004
The efficacy of sacubitril/valsartan in the treatment of pediatric patients with heart failure was established principally by the results of the PANORAMA-HF study, a randomized, multicenter, double-blind trial.1, 1001 A total of 375 patients (aged 1 month to ≤18 years) with a LVEF ≤45% or fractional shortening ≤22.5% were randomized to treatment with either sacubitril/valsartan or enalapril; randomization was stratified by age with weight-based dosing.1, 1001 The outcome (whether sacubitril/valsartan was superior to enalapril for treatment of heart failure due to LVSD in pediatric patients) was assessed using a primary global rank endpoint through 52 weeks of treatment.1001 Patients were ranked from worst to best based on 5 categories of clinical heart failure events.1001 The categories were ranked from 1 to 5, with 1 being the worst outcome (death) and 5 being the best outcome (improved).1001
Enrolled patients were a mean of 8.1 years of age and 52% were female; most patients were in NYHA class II.1001 Nearly half of patients were White, approximately 13% were Black, and an estimated 27% were Asian.1001 At week 52, no difference was seen in the global rank endpoint between the 2 treatment groups.1, 1001 For sacubitril/valsartan, 24.1 or 45.5% were classified as Category 4 (unchanged) or 5 (improved), respectively.1001 For enalapril, 30.3 or 41.0% were in Category 4 or 5, respectively.1001 Worsening heart failure (Category 2) was seen in 9.6 or 4.8% with sacubitril/valsartan or enalapril.1001 For sacubitril/valsartan, 10.2% of patients were classified in Category 1 (i.e., death, 1A listing for heart transplant, or need for ventricular assist device or similar support) compared to 16% with enalapril.1001 Estimated least squares mean reduction from baseline in NT-proBNP, an exploratory outcome, was 65 or 62% for sacubitril/valsartan or enalapril, respectively.1, 1001
Current guidelines for the management of heart failure recommend guideline-directed medical therapy with a combination of drug therapies to reduce morbidity and mortality, including ACE inhibitors, sodium-glucose cotransporter 2 inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors (ARNIs), β-blockers, and mineralocorticoid receptor antagonists.700 Diuretics are recommended on an as-needed basis to improve symptoms of congestion and prevent worsening of disease in patients with fluid retention.700 Once guideline-directed medical therapy is optimized, additional therapies may be considered based on patient-specific factors, including ivabradine, vericiguat, digoxin, polyunsaturated fatty acids, and potassium binders.700
In patients with heart failure with reduced ejection fraction (HFrEF) and NYHA class II to III symptoms, use of an ARNI is recommended first-line to reduce morbidity and mortality.700, 701 Angiotensin II receptor antagonists or ACE inhibitors are recommended for such patients only when an ARNI is contraindicated, inaccessible, or poorly tolerated.701 In patients with symptomatic heart failure with mildly reduced ejection fraction (i.e., LVEF 41-49%), angiotensin II receptor antagonists may be considered (particularly in patients with a LVEF on the lower end of the range) to reduce the risk of hospitalizations for heart failure and cardiovascular mortality.700
A statement from the American Heart Association (AHA) on management of chronic heart failure in pediatric patients with congenital heart disease discusses the use of several agents for medical management.1002 Data on use of adult guideline-directed therapies for heart failure in pediatric patients are limited, and adult therapies are sometimes used empirically for pediatric patients with congenital heart disease and reduced ventricular ejection fraction.1002 For pediatric patients with asymptomatic heart failure and in NYHA class I with mildly reduced ventricular function, ACE inhibitors or β-blockers are recommended for left ventricular dysfunction, with digoxin used for single ventricle congenital heart disease.1002 In symptomatic patients in NYHA class II or III and moderately or greater reduced ventricular function, diuretics can be used for fluid overload, with ACE inhibitors, angiotensin II receptor antagonists, or an ARNI, β-blockers, or aldosterone antagonists used for left ventricular dysfunction.1002 For those patients with NYHA class IV heart failure, consideration is also given to ventricular assist devices or cardiac transplant.1002
The fixed combination of sacubitril and valsartan (sacubitril/valsartan) is administered orally as tablets (Entresto®) or capsules containing oral pellets (Entresto Sprinkle®).1 Each fixed-combination tablet of sacubitril/valsartan contains sacubitril 24 mg/valsartan 26 mg, sacubitril 49 mg/valsartan 51 mg, or sacubitril 97 mg/valsartan 103 mg.1 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 Each capsule of fixed-combination sacubitril/valsartan oral pellets contains sacubitril 6 mg/valsartan 6 mg or sacubitril 15 mg/valsartan 16 mg.1 The capsules containing oral pellets should not be swallowed whole, and the oral pellets should not be crushed or chewed.1
Sacubitril/valsartan is administered orally twice daily without regard to food.1 Store sacubitril/valsartan tablets and capsules containing oral pellets at 20-25°C (excursions permitted between 15-30°C) and protect from moisture.1
For pediatric patients weighing 13-40 kg or patients unable to swallow tablets, the manufacturer recommends administering sacubitril/valsartan as oral pellets or as an oral suspension prepared from sacubitril/valsartan tablets.1 For pediatric patients weighing <13 kg, the manufacturer recommends administering sacubitril/valsartan as an oral suspension prepared from sacubitril/valsartan tablets.1
When administering sacubitril/valsartan oral pellets, use the entire contents of the capsule(s) to achieve the desired dose.1 Open the capsule(s) and sprinkle the full contents onto 1-2 teaspoons of soft food.1 Consume the food containing the oral pellets immediately after adding them.1 Discard the empty capsule shells after use; do not swallow the capsule shells.1 Do not administer the oral pellets via nasogastric, gastrostomy, or other enteral tubes, as this may lead to enteral tube obstruction.1
To prepare an oral suspension from sacubitril/valsartan tablets, transfer 8 tablets of sacubitril 49 mg/valsartan 51 mg into a mortar and crush the tablets into a fine powder.1 Add 60 mL of Ora-Plus® into the mortar and triturate gently for 10 minutes; then, add 140 mL of Ora-Sweet® SF into the mortar and triturate gently for another 10 minutes to form a uniform suspension.1 The concentration of the resulting suspension is 4 mg/mL (each mL contains 1.96 mg sacubitril and 2.04 mg of valsartan).1 Transfer the prepared suspension into a clean 200 mL amber-colored polyethylene terephthalate (PET) or glass bottle, place a press-in bottle adapter, and close the bottle with a child-resistant cap.1 The suspension may be stored for up to 15 days at room temperature; do not store above 25°C or in the refrigerator.1 Shake the suspension well before each use.1
Dosage of sacubitril/valsartan in fixed combination is expressed in terms of both sacubitril and valsartan components.1 Recommended mg/kg dosages of sacubitril/valsartan are expressed as the combined amount of both sacubitril and valsartan.1
The recommended initial dosage of sacubitril/valsartan in patients with chronic heart failure switching from therapy with an ACE inhibitor or angiotensin receptor blocker (ARB) is sacubitril 49 mg/valsartan 51 mg twice daily; sacubitril/valsartan therapy should begin after discontinuance of the ARB or 36 hours after discontinuance of the ACE inhibitor.1
In patients not currently taking an ACE inhibitor or ARB and patients switching from low dosages of an ACE inhibitor or ARB, initiate sacubitril/valsartan at half the usual recommended starting dosage.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
The recommended dosage of sacubitril/valsartan in pediatric patients ≥1 year of age with symptomatic heart failure and systemic left ventricular systolic dysfunction who are switching from therapy with an ACE inhibitor or ARB depends on patient weight and the formulation of sacubitril/valsartan used.1 Pediatric patients weighing ≥40 kg may be treated with sacubitril/valsartan oral tablets.1 Pediatric patients weighing 13 to <40 kg should be treated with sacubitril/valsartan oral pellets or an oral suspension prepared from sacubitril/valsartan tablets; pediatric patients weighing <13 kg should be treated with an oral suspension prepared from sacubitril/valsartan tablets.1 Recommended weight-based dosages and titration schedules are summarized in Table 1 (for sacubitril/valsartan tablets) and Table 2 (for sacubitril/valsartan oral pellets).1 The recommended dosage should be taken twice daily, and the dosage should be adjusted every 2 weeks as tolerated by the patient.1
In patients not currently taking an ACE inhibitor or ARB and patients switching from low dosages of these agents, start sacubitril/valsartan at half the recommended dosage and increase the dosage every 2 weeks to follow the recommended dosage escalation thereafter.1
Weight (kg) | Initial Dosage | Second Dosage | Final Dosage |
|---|---|---|---|
<40a | 1.6 mg/kg | 2.3 mg/kg | 3.1 mg/kg |
40 to <50b | 24 mg/26 mg | 49 mg/51 mg | 72 mg/78 mgc |
≥50 | 49 mg/51 mg | 72 mg/78 mgc | 97 mg/103 mg |
aUse of oral pellets or an oral suspension prepared from the tablets is recommended in these patients. Recommended mg/kg dosages are of the combined amount of both sacubitril and valsartan.
bIn pediatric patients weighing 40-50 kg who are not currently taking an ACE inhibitor or ARB or who were previously taking low dosages of these agents, initiate at 0.8 mg/kg twice daily using the oral pellets or an oral suspension prepared from the tablets. After 2 weeks at this lower dosage, increase the dosage following the recommended dosage escalation.
cDoses of 72 mg/78 mg can be achieved using three 24 mg/26 mg tablets.
Weight (kg) | Initial Dosage | Second Dosage | Final Dosage |
|---|---|---|---|
<13a | 1.6 mg/kg | 2.3 mg/kg | 3.1 mg/kg |
13 to <19 | 12 mg/12 mg (two 6 mg/6 mg capsules) | 18 mg/18 mg (three 6 mg/6 mg capsules) | 24 mg/24 mg (four 6 mg/6 mg capsules) |
19 to <26 | 18 mg/18 mg (three 6 mg/6 mg capsules) | 24 mg/24 mg (four 6 mg/6 mg capsules) | 30 mg/32 mg (two 15 mg/16 mg capsules) |
26 to <34 | 24 mg/24 mg (four 6 mg/6mg capsules) | 30 mg/32 mg (two 15 mg/16 mg capsules) | 45 mg/48 mg (three 15 mg/16 mg capsules) |
30 mg/32 mg (two 15 mg/16 mg capsules) | 45 mg/48 mg (three 15 mg/16 mg capsules) | 60 mg/64 mg (four 15 mg/16 mg capsules) |
aUse of an oral suspension prepared from the tablets is recommended in these patients. Recommended mg/kg dosages are of the combined amount of both sacubitril and valsartan.
bFor patients weighing ≥50 kg, see Table 1.
cIn pediatric patients weighing 40-50 kg who are not currently taking an ACE inhibitor or ARB or who were previously taking low dosages of these agents, initiate at 0.8 mg/kg twice daily using the oral pellets or an oral suspension prepared from the tablets. After 2 weeks at this lower dosage, increase the dosage following the recommended dosage escalation.
No adjustment of sacubitril/valsartan dosage is necessary in patients with mild hepatic impairment (Child-Pugh class A).1
In adults and pediatric patients with moderate hepatic impairment (Child-Pugh class B), initiate sacubitril/valsartan at half the usual recommended starting dosage and increase the dosage (following the recommended dosage escalation) thereafter.1 In pediatric patients weighing 40-50 kg with moderate hepatic impairment, the recommended starting dosage of sacubitril/valsartan is 0.8 mg/kg twice daily; the drug should be administered as oral pellets or as an oral suspension prepared from tablets.1
Sacubitril/valsartan is not recommended in patients with severe hepatic impairment (Child-Pugh class C).1
No adjustment of sacubitril/valsartan dosage is necessary in patients with mild or moderate renal impairment.1
In adults and pediatric patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/minute per 1.73 m2), initiate sacubitril/valsartan at half the usual recommended starting dosage and increase the dosage (following the recommended dosage escalation) thereafter.1 In pediatric patients weighing 40-50 kg with severe renal impairment, the recommended starting dosage of sacubitril/valsartan is 0.8 mg/kg twice daily; the drug should be administered as oral pellets or as an oral suspension prepared from tablets.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Fetal/Neonatal Morbidity and Mortality
Drugs that act directly on the renin-angiotensin system (e.g., ACE inhibitors, ARBs) can reduce fetal renal function and increase fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters.1 A boxed warning regarding this risk is included in the sacubitril/valsartan prescribing information.1 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 and there is no appropriate alternative therapy.1 If therapy is continued during pregnancy, advise the patient of the risk to the fetus.1
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 hereditary angioedema or a known history of angioedema related to previous ACE inhibitor or ARB therapy; Black patients and those with a history of angioedema may be at an increased risk of angioedema with sacubitril/valsartan therapy.1
Sacubitril/valsartan lowers blood pressure and may cause symptomatic hypotension.1 Symptomatic hypotension may occur in patients with an activated renin-angiotensin-aldosterone (RAA) system (e.g., patients with volume or salt depletion secondary to high-dose diuretic therapy).1
Correct volume or salt depletion prior to administration of sacubitril/valsartan or start sacubitril/valsartan therapy at a lower dosage.1 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
Because the RAA system appears to contribute substantially to maintenance of glomerular filtration in patients with severe congestive heart failure, 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 ARB (e.g., valsartan).1 Closely monitor serum creatinine during therapy.1 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
Hyperkalemia may occur in patients receiving sacubitril/valsartan, especially in those with severe renal impairment, diabetes mellitus, hypoaldosteronism, or a potassium-rich diet.1 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
Sacubitril/valsartan can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman.1 Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy may lead to oligohydramnios, which in turn can cause reduced fetal renal function (leading to anuria and renal failure), fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), hypotension, and death.1 Reproduction studies in rats and rabbits using sacubitril/valsartan during organogenesis have demonstrated increased embryofetal death and teratogenic effects.1
Sacubitril/valsartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving and there are no appropriate alternatives; in such cases, the woman should be advised of the risk to the fetus.1 Perform serial ultrasound examinations to assess the intra-amniotic environment; fetal testing may also be appropriate, depending on the week of gestation.1 Patients and physicians should be aware that oligohydramnios may not appear until after irreversible injury has occurred.1 If oligohydramnios is observed, consider alternative drug treatment.1
Closely observe neonates with a history of in utero exposure to sacubitril/valsartan for hypotension, oliguria, and hyperkalemia.1 Support blood pressure and renal perfusion if oliguria or hypotension occurs.1 Exchange transfusion or dialysis may be required.1
Sacubitril/valsartan is distributed into milk in rats.1 It is not known whether sacubitril/valsartan is distributed into human milk.1 The effects of sacubitril/valsartan on the breast-fed infant or on milk production are also unknown.1 Because of the potential for serious adverse reactions to sacubitril/valsartan in breast-fed infants, breast-feeding is not recommended during treatment.1
The safety and efficacy of sacubitril/valsartan for the treatment of heart failure in pediatric patients ≥1 year of age was established in a randomized controlled trial of 375 patients 1 month to <18 years of age (PANORAMA-HF).1 The safety profile of sacubitril/valsartan in pediatric patients 1 to <18 years of age was similar to that observed in adult patients.1 Limited safety and efficacy data in patients 1 month to <1 year of age were inadequate to support conclusions on safety and efficacy in this age group.1
In the PARADIGM-HF and PARAGON-HF trials respectively, 49.6 and 82.9% of patients who received sacubitril/valsartan were ≥65 years of a 18.7 and 45.7% were ≥75 years of age.1 No differences in safety or effectiveness were observed between patients ≥65 years of age and younger adult patients.1
No clinically relevant pharmacokinetic differences have been observed in patients 65 years of age and older compared with the overall population.1
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; in patients with moderate hepatic impairment, the manufacturer recommends initiating therapy at half of the usual recommended starting dosage.1, 21, 31
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
Results of a pharmacokinetic study indicate that exposure to LBQ657 (the active metabolite of sacubitril) is increased by approximately 2-fold 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 The manufacturer recommends initiating sacubitril/valsartan at half of the usual recommended starting dosage in patients with severe renal impairment.1
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
Adverse effects occurring in at least 5% of patients receiving sacubitril/valsartan include hypotension, hyperkalemia, cough, dizziness, and renal failure.1
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
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 Sacubitril may increase systemic exposure of OATP1B1 and OATP1B3 substrates (e.g., atorvastatin).1
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 Concomitant therapy with sacubitril/valsartan and an angiotensin II receptor blocker (ARB) should be avoided because the valsartan component of sacubitril/valsartan is an ARB.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
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 Serum potassium concentrations should be monitored periodically during such concomitant use.1
No clinically relevant pharmacokinetic interaction was observed with coadministration of sacubitril/valsartan and amlodipine.1
Concomitant administration of sacubitril/valsartan and atorvastatin did not alter systemic exposure to sacubitril/valsartan to a clinically important degree; however, the AUC and peak plasma concentration of atorvastatin were increased.1, 31
No clinically relevant pharmacokinetic interaction was observed when sacubitril/valsartan was coadministered with carvedilol.1
No clinically relevant pharmacokinetic interaction was observed when sacubitril/valsartan was coadministered with digoxin.1
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
Increased serum lithium concentrations and lithium toxicity have been reported with concomitant use of ARBs and lithium.1 Monitoring of serum lithium concentrations is recommended during such concomitant use.1
No clinically relevant pharmacokinetic interaction was observed with coadministration of sacubitril/valsartan and metformin.1
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
No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and omeprazole. 1
No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and an oral contraceptive containing ethinyl estradiol and levonorgestrel. 1
No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and sildenafil.1 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
No clinically relevant pharmacokinetic interaction was observed with concomitant administration of sacubitril/valsartan and warfarin.1
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 by selectively inhibiting access of angiotensin II to AT1 receptors; it also inhibits angiotensin II-dependent aldosterone release.1
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 A hydroxyl metabolite of valsartan has been identified in plasma at low concentrations (<10%).1 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
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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | Sacubitril 6 mg and Valsartan 6 mg | Entresto® Sprinkle (available as capsules containing pellets) | |
Sacubitril 15 mg and Valsartan 16 mg | Entresto® Sprinkle (available as capsules containing pellets) | |||
Tablets, film-coated | Sacubitril 24 mg and Valsartan 26 mg* | Sacubitril and Valsartan Tablets | ||
Entresto® | ||||
Sacubitril 49 mg and Valsartan 51 mg* | Sacubitril and Valsartan Tablets | |||
Entresto® | Novartis | |||
Sacubitril 97 mg and Valsartan 103 mg* | Sacubitril and Valsartan Tablets | |||
Entresto® | Novartis |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Novartis. Entresto® (sacubitril and valsartan) tablets and pellets for oral use prescribing information. East Hanover, NJ; 2024 Apr.
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