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Sacubitril; Valsartan
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General Dosing Information
24 mg sacubitril/26 mg valsartan PO twice daily, initially. Double the dose after 2 to 4 weeks to the highest dosage level tolerated. Max: 97 mg sacubitril/103 mg valsartan PO twice daily.[59904] [68064] Guidelines recommend the use of an angiotensin receptor neprilysin inhibitor (ARNI) to reduce morbidity and mortality in persons with reduced ejection fraction heart failure (HFrEF) and NYHA class II to III symptoms.[68064] An ARNI may be considered to reduce hospitalizations in select persons with preserved ejection fraction heart failure (HFpEF), particularly those with lower left ventricular ejection fractions. Sacubitril; valsartan is preferred and provides modest additional benefit compared to valsartan in persons with HFpEF.[68064] [70401]
49 mg sacubitril/51 mg valsartan PO twice daily, initially. Double the dose after 2 to 4 weeks to the highest dosage level tolerated. Max: 97 mg sacubitril/103 mg valsartan PO twice daily.[59904] [68064] Guidelines recommend the use of an angiotensin receptor neprilysin inhibitor (ARNI) to reduce morbidity and mortality in persons with reduced ejection fraction heart failure (HFrEF) and NYHA class II to III symptoms.[68064] An ARNI may be considered to reduce hospitalizations in select persons with preserved ejection fraction heart failure (HFpEF), particularly those with lower left ventricular ejection fractions. Sacubitril; valsartan is preferred and provides modest additional benefit compared to valsartan in persons with HFpEF.[68064] [70401]
24 mg sacubitril/26 mg valsartan PO twice daily, initially. Increase the dose every 2 weeks as tolerated to 49 mg sacubitril/51 mg valsartan PO twice daily, 72 mg sacubitril/78 mg valsartan PO twice daily, and then 97 mg sacubitril/103 mg valsartan PO twice daily.[59904]
0.8 mg/kg/dose PO twice daily, initially. Increase the dose every 2 weeks as tolerated to 24 mg sacubitril/26 mg valsartan PO twice daily, 49 mg sacubitril/51 mg valsartan PO twice daily, and then 72 mg sacubitril/78 mg valsartan PO twice daily.[59904]
0.8 mg/kg/dose PO twice daily, initially. Increase the dose every 2 weeks as tolerated to 1.6 mg/kg/dose PO twice daily, 2.3 mg/kg/dose PO twice daily, and then 3.1 mg/kg/dose PO twice daily.[59904]
49 mg sacubitril/51 mg valsartan PO twice daily, initially. Increase the dose every 2 weeks as tolerated to 72 mg sacubitril/78 mg valsartan PO twice daily and then 97 mg sacubitril/103 mg valsartan PO twice daily.[59904]
24 mg sacubitril/26 mg valsartan PO twice daily, initially. Increase the dose every 2 weeks as tolerated to 49 mg sacubitril/51 mg valsartan PO twice daily and then 72 mg sacubitril/78 mg valsartan PO twice daily.[59904]
1.6 mg/kg/dose PO twice daily, initially. Increase the dose every 2 weeks as tolerated to 2.3 mg/kg/dose PO twice daily and then 3.1 mg/kg/dose PO twice daily.[59904]
sacubitril 194 mg/day PO; valsartan 206 mg/day PO.
sacubitril 194 mg/day PO; valsartan 206 mg/day PO.
weighing 50 kg or more: sacubitril 194 mg/day PO; valsartan 206 mg/day PO.
weighing 40 to 49 kg: sacubitril 144 mg/day PO; valsartan 156 mg/day PO.
weighing less than 40 kg: 6.2 mg/kg/day PO (combined amount of sacubitril and valsartan).
weighing 50 kg or more: sacubitril 194 mg/day PO; valsartan 206 mg/day PO.
weighing 40 to 49 kg: sacubitril 144 mg/day PO; valsartan 156 mg/day PO.
weighing less than 40 kg: 6.2 mg/kg/day PO (combined amount of sacubitril and valsartan).
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Mild hepatic impairment: No dosage adjustment needed.
Moderate hepatic impairment (Child-Pugh Class B): Initiate at half the usual recommended dose; thereafter, follow the recommended dose escalation. In pediatric patients weighing 40 to 49 kg, initiate at 0.8 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily.
Severe hepatic impairment: Use not recommended.[59904]
eGFR 30 mL/minute/1.73 m2 or more: No dosage adjustment needed.
eGFR less than 30 mL/minute/1.73 m2: Initiate at half the usual recommended dose; thereafter, follow the recommended dose escalation. In pediatric patients weighing 40 to 49 kg, initiate at 0.8 mg/kg/dose (combined amount of sacubitril and valsartan) PO twice daily.[59904]
Hemodialysis
Sacubitril; valsartan is unlikely to be removed by hemodialysis due to high protein binding.[59904]
† Off-label indication
Sacubitril; valsartan is a combination product containing sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker. Sacubitril; valsartan is indicated in adults to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. The benefits of sacubitril; valsartan therapy in adult patients with chronic heart failure are most evident in those patients with left ventricular ejection fraction (LVEF) below normal. In the PARADIGM-HF trial, sacubitril; valsartan was superior to enalapril in reducing the rate of cardiovascular death and hospitalizations related to heart failure in adults with symptomatic chronic heart failure (NYHA class II to IV) and systolic dysfunction (LVEF of 40% or less). Most patients were also receiving standard heart failure treatments including beta-blockers, diuretics, and mineralocorticoid antagonists.[59939] In the PARAGON-HF trials, the rate of the primary composite outcome (first and recurrent heart failure hospitalizations and cardiovascular death) was lower in the sacubitril; valsartan group at 12.8 events per 100 patient years compared to the valsartan group at 14.6 events per 100 patient years (RR = 0.87 (0.75, 1.01), p = 0.06). The PARAGON-HF trial enrolled adult patients with symptomatic heart failure with LVEF of 45% or higher and structural heart disease (either left atrial enlargement or left ventricular hypertrophy). Most patients were also receiving a beta-blockers and diuretics.[66422] In an analysis of both the PARADIGM-HF and PARAGON-HF studies, greater risk reductions were observed with patients with LVEF below normal treated with sacubitril; valsartan.[59904] In pediatric patients 1 year and older, sacubitril; valsartan is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction. Results from PANORAMA-HF trial showed a reduction from baseline in NT-proBNP of 44% in sacubitril; valsartan-treated patients compared to 33% in enalapril-treated patients. While not statistically significant, the reductions were similar or larger than what were seen in adult patients. This effect on NT-proBNP was considered a reasonable basis to infer improved cardiovascular outcomes in the pediatric populations, as similar outcomes were seen in the PARADIGM-HF study. Sacubitril; valsartan is contraindicated with concomitant use of an ACE inhibitor; allow a 36-hour washout period between administration of the 2 drugs. The most common adverse effects reported include hypotension, hyperkalemia, cough, dizziness, and renal failure.[59904]
For storage information, see the specific product information within the How Supplied section.
Preparation of 4 mg/mL (1.96 mg sacubitril; 2.04 mg valsartan/mL) oral suspension
Angioedema has been reported with the use of sacubitril; valsartan. During clinical trials, angioedema was reported in 0.5% of patients treated with sacubitril; valsartan compared to 0.2% of those treated with enalapril. The incidence of angioedema was higher in Black patients (2.4%) receiving sacubitril; valsartan compared to non-Black patients (0.4%).[69374] If angioedema occurs, immediately discontinue sacubitril; valsartan therapy, provide appropriate therapy, and monitor for airway compromise. Do not readminister sacubitril; valsartan to patients who have experienced angioedema with its use. In cases where swelling was confined to the face and lips, the condition generally resolved without treatment; however, antihistamines have been used for symptom relief. Laryngeal edema may be fatal. If there is involvement of the tongue, glottis, or larynx, administer appropriate therapy (e.g., epinephrine) to ensure airway patency. Anaphylactoid reactions, pruritus, and rash have been reported during postmarketing use of sacubitril; valsartan.[59904]
Drugs which affect the renin-angiotensin system have been associated with fetal and neonatal abnormalities when administered to pregnant patients. Adverse fetal and neonatal effects have included hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, oligohydramnios, and death. Oligohydramnios has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Due to the potential for teratogenesis, every effort should be made to discontinue sacubitril; valsartan and consider alternative therapy during pregnancy.[59904]
Hypotension has been reported with the use of sacubitril; valsartan. During controlled clinical trials, hypotension was reported in 18% of patients treated with sacubitril; valsartan and in 12% of those receiving enalapril. Hypotension was reported as serious in 1.5% of patients in both treatment arms. Orthostatic hypotension was reported in 2.1% of patients receiving sacubitril; valsartan and 1.1% of patients in the enalapril group. Falls were reported in 1.9% of those receiving sacubitril; valsartan compared to 1.3% of those receiving enalapril. Dizziness was reported in 6% of patients in the sacubitril; valsartan group and 5% in the enalapril group. Volume and salt depletion should be corrected prior to initiating therapy. If hypotension is anticipated, initiating therapy at a lower dose may be necessary. If hypotension occurs during therapy, ensure hypovolemia has not occurred and consider dose adjustments of diuretics and other concomitant antihypertensive drugs. If hypotension persists despite such measures, reduce the dosage or temporarily discontinue sacubitril; valsartan; permanent discontinuation of therapy is usually not required.[59904]
Decrease in renal function has been reported with the use of sacubitril; valsartan. During the PARADIGM-HF clinical trial, renal failure (unspecified) was reported in 5% of patients in both the sacubitril; valsartan and enalapril groups. Increases in serum creatinine of more than 50% were observed in 1.4% of patients in the enalapril run-in period and 2.2% of patients in the sacubitril; valsartan run-in period. During the double-blind period, increases in serum creatinine of more than 50% were reported in approximately 16% of both treatment groups. In the PARAGON-HF trial, increases in serum creatinine of more than 50% were reported in approximately 17% of sacubitril; valsartan patients and 21% of valsartan patients. Oliguria, progressive azotemia, and, rarely, acute renal failure and death have been associated in patients receiving angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure). If a clinically significant decrease in renal function develops, closely monitor serum creatinine and decrease the dose or interrupt sacubitril; valsartan therapy. In addition, serum creatinine and blood urea concentrations may increase in patients with bilateral or unilateral renal artery stenosis.[59904]
Hyperkalemia was reported in 12% of patients treated with sacubitril; valsartan and 14% of patients treated with enalapril during controlled trials. Potassium concentrations more than 5.5 mEq/L were reported in approximately 4% of patients in both the enalapril and sacubitril; valsartan run-in periods. During the double-blind period in the PARADIGM-HF trial, approximately 16% of both treatment groups reported potassium concentrations more than 5.5 mEq/L. During the double-blind period in the PARAGON-HF trial, approximately 18% of sacubitril; valsartan patients and 20% of valsartan patients reported potassium concentrations more than 5.5 mEq/L. Monitor serum potassium periodically and treat appropriately. Dosage reduction or interruption of therapy may be required.[59904]
During controlled clinical trials, cough was reported in 9% of patients receiving sacubitril; valsartan compared to 13% of those in the enalapril group.[59904]
Rhabdomyolysis has been reported with the postmarketing use of sacubitril; valsartan. During clinical trials, evidence of possible muscle harm was noted.[63529]
Sacubitril; valsartan is contraindicated in patients with a history of ACE-inhibitor induced angioedema and in those with angiotensin II receptor blocker (ARB) therapy induced angioedema. Sacubitril; valsartan should not be used in patients with hereditary angioedema. Angioedema was reported during clinical trials of sacubitril; valsartan. Black patients and patients with a prior history of angioedema may be at increased risk of angioedema with sacubitril; valsartan.[59904]
Use sacubitril; valsartan with caution in patients with hypovolemia and in patients who exhibit signs of hypotension. Sacubitril; valsartan lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system including patients who are volume or salt depleted (e.g., those treated with diuretics) are at an increased risk of developing hypotension. Correct volume or salt depletion prior to initiating of therapy or start sacubitril; valsartan at a lower dose.[59904]
Sacubitril; valsartan may decrease renal function in patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure). Treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and reduce the dose or interrupt sacubitril; valsartan in patients who develop a clinically significant decrease in renal function. Similar to other drugs that affect the renin-angiotensin-aldosterone system, sacubitril; valsartan may increase blood urea and serum creatinine concentrations in patients with bilateral or unilateral renal artery stenosis. Monitor renal function in patients with renal artery stenosis.[59904]
Sacubitril; valsartan therapy may result in hyperkalemia and should be used cautiously in patients with risk factors for hyperkalemia, such as severe renal impairment, diabetes mellitus, hypoaldosteronism, or a high potassium diet. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia. Dosage reduction or interruption of sacubitril; valsartan therapy may be required.[59904]
Administration of sacubitril; valsartan is not recommended in patients with severe hepatic disease (Child-Pugh class C), as no studies have been conducted in these patients. Dose adjustments are recommended in patients with moderate hepatic impairment (Child-Pugh class B); no dose adjustment is required when administering sacubitril; valsartan to patients with mild hepatic impairment (Child-Pugh class A).[59904]
When pregnancy is detected, discontinue sacubitril; valsartan as soon as possible and consider alternative therapy. If sacubitril; valsartan must be used during pregnancy, advise pregnant patients of the potential risk of fetal harm. When used during the second and third trimesters of pregnancy, drugs that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) can cause reduced fetal renal function and increased fetal and neonatal morbidity and death. Use of drugs that affect the renin-angiotensin system during pregnancy can cause fetal death or injury such as hypotension, neonatal skull hypoplasia, reversible or irreversible renal failure and death. Anhydramnios and oligohydramnios have also been reported. Development of oligohydramnios may be associated with decreased fetal renal function leading to anuria and renal failure and results in fetal limb contractures, craniofacial deformation, hypotension, hypoplastic lung development, and death.[59904] An observational cohort study evaluating the outcomes of angiotensin receptor blockers (ARBs) use during the first trimester of pregnancy found an increased rate of major birth defects compared to non-hypertensive pregnancies, 5.4% and 3%, respectively; the difference did not reach statistical significance. The authors noted that there was a higher risk of major birth defects with ARB therapy beyond 6 weeks of gestation compared to discontinuation of ARBs before week 6, 7.3% and 2.8%, respectively. The rates of prematurity and reduced birth weight were also increased in the ARB group. There were no statistically significant differences in the rates of major birth defects, spontaneous abortions, or preterm births between women with chronic hypertension treated with an ARB versus methyldopa.[64367] Once pregnancy is detected, perform ultrasound examination if sacubitril; valsartan exposure occurs beyond the first trimester. In rare cases, when another antihypertensive agent cannot be used to treat a pregnant patient, perform serial ultrasound examinations to assess the intraamniotic environment. If oligohydramnios occurs, discontinue sacubitril; valsartan unless it is life-saving to the mother. It should be noted that oligohydramnios may not appear until after the fetus has sustained an irreversible injury. Closely observe newborns with histories of in utero exposure to sacubitril; valsartan for hypotension, oliguria, and hyperkalemia. If oliguria occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. The effect of sacubitril; valsartan on labor and delivery has not been evaluated.[59904]
Breast-feeding is not recommended during treatment with sacubitril; valsartan. There are no data on the presence of sacubitril or valsartan in human milk, the effects on the breastfed child, or the effects on milk production.[59904] Alternative therapies may be considered. Due to low concentrations in breast milk, guidelines generally consider the ACE inhibitors captopril and enalapril to be compatible with breast-feeding unless high doses are required.[63903] [68837] In addition, benazepril and quinapril are excreted in low quantities into breast milk and have been suggested as options during breast-feeding.[65551] [68835] [68836] If a patient is switched from sacubitril; valsartan to one of the alternative ACE inhibitors, allow a 36-hour washout period prior to starting the ACE inhibitor.[59904] Consider the benefits of breast-feeding, the risk of potential drug exposure to the breastfed child, and the risk of an untreated or inadequately treated condition.
Sacubitril is a neprilysin inhibitor, and valsartan antagonizes angiotensin II at the AT1 receptor subtype. Neprilysin degrades endogenous vasoactive peptides, including natriuretic peptide, bradykinin, and adrenomedullin. Inhibition of neprilysin results in increased concentrations of these proteins and their activities, resulting in vasodilation, natriuresis, diuresis, and inhibition of pathologic growth and fibrosis. Inhibition of neprilysin occurs via the active metabolite of sacubitril, LBQ657. Angiotensin II is a potent vasoconstrictor and also stimulates the production and release of aldosterone.[59939][59940] The cardiovascular and renal effects of sacubitril; valsartan in patients with heart failure are due to increased concentrations of peptides that are degraded by neprilysin and the simultaneous inhibition of angiotensin II and angiotensin II-dependent aldosterone release by valsartan.[59904]
Revision Date: 03/28/2024, 01:48:00 AMSacubitril; valsartan is administered orally. Sacubitril and valsartan are highly bound to plasma proteins (more than 94%). Sacubitril is converted to its active metabolite, LBQ657, by plasma esterases and not further metabolized. Valsartan is minimally metabolized; approximately 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified at low concentrations (less than 10%) in plasma. LBQ657 crosses the blood brain barrier to a minimal extent (0.28%). The average volume of distribution of sacubitril and valsartan is 103 and 75 L, respectively. After oral administration, 52% to 68% of sacubitril (primarily as metabolite) and approximately 13% of valsartan and its metabolites are excreted in urine. The remaining drug and metabolites are excreted in feces. Sacubitril, LBQ657, and valsartan exhibit a mean elimination half-life of approximately 1.4, 11.5, and 9.9 hours, respectively.[59904]
In a 21-day study of patients with heart failure and reduced ejection fraction, sacubitril; valsartan administration resulted in significantly increased urine atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) and plasma cGMP, and decreased plasma N-terminal pro b-type natriuretic peptide (NT-proBNP), aldosterone, and endothelin-1. Sacubitril; valsartan blocked the AT1-receptor resulting in increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, sacubitril; valsartan decreased NT-proBNP, increased BNP, and increased urine cGMP compared to enalapril. In the PARAMOUNT study that enrolled patients with heart failure with left ventricular ejection fraction (LVEF) of 45% or higher, sacubitril; valsartan (97 mg; 103 mg twice daily) decreased NT-proBNP by 17% compared to an 8% decrease with valsartan (160 mg twice daily) after 12 weeks of therapy. In the PARAGON-HF study, NT-proBNP was decreased by 24% at week 16 and 19% at week 48 in the sacubitril; valsartan group compared to 6% and 3%, respectively, in the valsartan group.[59904]
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, OATP1B1, OATP1B3, MRP2
Valsartan does not inhibit CYP450 isoenzymes at clinically relevant concentrations. In vitro studies indicate CYP2C9 is the isoenzyme responsible for the formation of valeryl-4-hydroxy valsartan. An in vitro study with human liver tissue indicates that it is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2.[29130][62719] In vitro data also indicate that sacubitril inhibits OATP1B1 and OSTP1B3 transporters.[59904]
After oral administration, the peak plasma concentrations of sacubitril, its metabolite, and valsartan are reached in 0.5, 2, and 1.5 hours, respectively. Oral absolute bioavailability of sacubitril is estimated to be 60% or more. Valsartan when combined in the sacubitril; valsartan combination product is more bioavailable than valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril; valsartan is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed formulations. Steady state concentrations of sacubitril, its metabolite, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate; however, the metabolite of sacubitril accumulates by 1.6-fold. Food has no clinically significant effect on the systemic exposure of sacubitril; valsartan.[59904]
The exposure to sacubitril; valsartan is similar in pediatric and adult patients.[59904]
No relevant pharmacokinetic differences have been observed for sacubitril; valsartan in patients 65 years and older compared to the overall population.[59904]
Gender does not have a clinically significant effect on the systemic exposure of sacubitril or valsartan.[59904]
When pregnancy is detected, discontinue sacubitril; valsartan as soon as possible and consider alternative therapy. If sacubitril; valsartan must be used during pregnancy, advise pregnant patients of the potential risk of fetal harm. When used during the second and third trimesters of pregnancy, drugs that affect the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) can cause reduced fetal renal function and increased fetal and neonatal morbidity and death. Use of drugs that affect the renin-angiotensin system during pregnancy can cause fetal death or injury such as hypotension, neonatal skull hypoplasia, reversible or irreversible renal failure and death. Anhydramnios and oligohydramnios have also been reported. Development of oligohydramnios may be associated with decreased fetal renal function leading to anuria and renal failure and results in fetal limb contractures, craniofacial deformation, hypotension, hypoplastic lung development, and death.[59904] An observational cohort study evaluating the outcomes of angiotensin receptor blockers (ARBs) use during the first trimester of pregnancy found an increased rate of major birth defects compared to non-hypertensive pregnancies, 5.4% and 3%, respectively; the difference did not reach statistical significance. The authors noted that there was a higher risk of major birth defects with ARB therapy beyond 6 weeks of gestation compared to discontinuation of ARBs before week 6, 7.3% and 2.8%, respectively. The rates of prematurity and reduced birth weight were also increased in the ARB group. There were no statistically significant differences in the rates of major birth defects, spontaneous abortions, or preterm births between women with chronic hypertension treated with an ARB versus methyldopa.[64367] Once pregnancy is detected, perform ultrasound examination if sacubitril; valsartan exposure occurs beyond the first trimester. In rare cases, when another antihypertensive agent cannot be used to treat a pregnant patient, perform serial ultrasound examinations to assess the intraamniotic environment. If oligohydramnios occurs, discontinue sacubitril; valsartan unless it is life-saving to the mother. It should be noted that oligohydramnios may not appear until after the fetus has sustained an irreversible injury. Closely observe newborns with histories of in utero exposure to sacubitril; valsartan for hypotension, oliguria, and hyperkalemia. If oliguria occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function. The effect of sacubitril; valsartan on labor and delivery has not been evaluated.[59904]
Breast-feeding is not recommended during treatment with sacubitril; valsartan. There are no data on the presence of sacubitril or valsartan in human milk, the effects on the breastfed child, or the effects on milk production.[59904] Alternative therapies may be considered. Due to low concentrations in breast milk, guidelines generally consider the ACE inhibitors captopril and enalapril to be compatible with breast-feeding unless high doses are required.[63903] [68837] In addition, benazepril and quinapril are excreted in low quantities into breast milk and have been suggested as options during breast-feeding.[65551] [68835] [68836] If a patient is switched from sacubitril; valsartan to one of the alternative ACE inhibitors, allow a 36-hour washout period prior to starting the ACE inhibitor.[59904] Consider the benefits of breast-feeding, the risk of potential drug exposure to the breastfed child, and the risk of an untreated or inadequately treated condition.
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