Entresto

— THERAPEUTIC CATEGORIES —
  • CHF and arrhythmias
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Entresto Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Sacubitril, valsartan; 24mg/26mg, 49mg/51mg, 97mg/103mg; tabs.

    Pharmacological Class

    Neprilysin inhibitor + angiotensin II receptor blocker.

    How Supplied

    Tabs—60, 180

    How Supplied

    Entresto is supplied as unscored, ovaloid, biconvex, film-coated tablets in the following strengths:

    • Entresto 24/26 mg, (sacubitril 24 mg and valsartan 26 mg) are violet white and debossed with “NVR” on one side and “LZ” on the other side.
      • Bottles of 60, 180
    • Entresto 49/51 mg, (sacubitril 49 mg and valsartan 51 mg) are pale yellow and debossed with “NVR” on one side and “L1” on the other side.
      • Bottles of 60, 180
    • Entresto 97/103 mg, (sacubitril 97 mg and valsartan 103 mg) are light pink and debossed with “NVR” on one side and “L11” on the other side.
      • Bottles of 60, 180

    Storage

    Store at 20° C to 25° C (68° F to 77° F), excursions permitted between 15° C and 30° C (59° F and 86° F). Protect from moisture.

    Manufacturer

    Novartis Pharmaceuticals Corp

    Generic Availability

    NO

    Mechanism of Action

    Sacubitril inhibits neprilysin, resulting in the increased levels of natriuretic peptides. Valsartan selectively blocks the angiotensin II type-1 receptor, resulting in the inhibition of the effects of angiotensin II, and also inhibits angiotensin II-dependent aldosterone release.

    Entresto Indications

    Indications

    To reduce risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure (benefits are most clearly evident in those with LVEF below normal). To treat symptomatic heart failure with systemic left ventricular systolic dysfunction in children aged ≥1yr.

    Entresto Dosage and Administration

    Adult

    Initially 49mg/51mg twice daily; double the dose after 2–4 weeks to target maintenance dose of 97mg/103mg twice daily as tolerated. Not currently on ACEI/ARB, previously on low doses of ACEI/ARB, severe renal impairment (eGFR <30mL/min/1.73m2), or moderate hepatic impairment (Child-Pugh B): initially 24mg/26mg twice daily; double the dose every 2–4 weeks to target maintenance dose of 97mg/103mg twice daily as tolerated. If switching from or to an ACEI: allow 36 hour wash-out period between taking the two drugs.

    Children

    <1yr: not established. Administer twice daily; adjust dose every 2 weeks as tolerated. ≥1yr: <40kg (use oral susp; see full labeling): initially 1.6mg/kg, titrate to 2.3mg/kg, then to target dose of 3.1mg/kg; ≥40–<50kg: initially 24mg/26mg, titrate to 49mg/51mg, then to target dose of 72mg/78mg; ≥50kg: initially 49mg/51mg, titrate to 72mg/78mg, then to target dose of 97mg/103mg. Not currently on ACEI/ARB, previously on low doses of ACEI/ARB, severe renal impairment (eGFR <30mL/min/1.73m2), or moderate hepatic impairment (Child-Pugh B): initiate at half the usual dose (for 40–50kg: initially 0.8mg/kg with oral susp); follow recommended dose escalation every 2 weeks. If switching from or to an ACEI: allow 36 hour wash-out period between taking the two drugs. 

    Administration

    Preparation of Oral Suspension 

    Entresto oral suspension can be substituted at the recommended tablet dosage in those unable to swallow tablets. 

    Entresto 800mg/200mL oral suspension can be prepared in a concentration of 4mg/mL (sacubitril/valsartan 1.96/2.04mg/mL). Use Entresto 49/51mg tablets in the preparation of the suspension. 

    To make an 800mg/200mL (4mg/mL) oral suspension:

    • Transfer 8 tablets of Entresto 49/51mg film-coated tablets into a mortar. 
    • Crush the tablets into a fine powder using a pestle. 
    • Add 60mL of Ora-Plus® into the mortar and triturate gently with pestle for 10 minutes, to form a uniform suspension. 
    • Add 140mL of Ora-Sweet® SF into mortar and triturate with pestle for another 10 minutes, to form a uniform suspension. 
    • Transfer the entire contents from the mortar into a clean 200mL amber colored PET or glass bottle. 
    • Place a press-in bottle adapter and close the bottle with a child resistant cap. 

    The oral suspension can be stored for up to 15 days. Do not store above 25° C (77° F) and do not refrigerate. Shake before each use. 

    Entresto Contraindications

    Contraindications

    History of angioedema related to previous ACE inhibitor or ARB therapy. Concomitant ACE inhibitors. Concomitant aliskiren in patients with diabetes.

    Entresto Boxed Warnings

    Boxed Warning

    Fetal toxicity.

    Entresto Warnings/Precautions

    Warnings/Precautions

    Fetal toxicity may develop; discontinue if pregnancy is detected. Discontinue if angioedema occurs; do not re-administer. Give SC epinephrine for airway obstruction if indicated. Black patients may have higher risk of angioedema than non-Black patients. Avoid in hereditary angioedema. May cause symptomatic hypotension. Correct salt/volume depletion prior to initiation or start at a lower dose. Adjust concomitant diuretic or antihypertensive doses if hypotension occurs. Reduce dose or temporarily discontinue if hypotension persists. Monitor renal function in renal artery stenosis, severe CHF. Monitor serum creatinine and down-titrate or interrupt dose if significant renal dysfunction develops. Monitor for hyperkalemia esp. in severe renal impairment, diabetes, hypoaldosteronism, or high K+ diet. Severe hepatic impairment: not recommended. Neonates. Pregnancy (2nd & 3rd trimesters); consider alternative therapy. Nursing mothers: not recommended.

    Warnings/Precautions

    Fetal Toxicity 

    • Entresto can cause fetal harm when given to a pregnant woman.
    • Use of drugs that act on the renin-angiotensin system during the 2nd and 3rd trimesters of pregnancy reduces fetal renal function and increases fetal/neonatal morbidity and death.
    • When pregnancy is detected, consider alternatives and discontinue Entresto. However, if there is no appropriate alternative therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.

    Angioedema 

    • Entresto may cause angioedema. If angioedema occurs, discontinue immediately, treat appropriately, and monitor for airway compromise. Entresto must not be re-administered. 
    • Angioedema associated with laryngeal edema may be fatal; treat appropriately, eg, subcutaneous epinephrine/adrenaline solution 1:1000 (0.3mL to 0.5mL) and ensure maintenance of a patent airway. 
    • has been associated with a higher rate of angioedema in Black than in non-Black patients. 
    • Patients with a prior history of angioedema may be at increased risk of angioedema with Entresto. Do not use Entresto in those with a known history of angioedema related to previous ACE inhibitor or ARB therapy. Entresto should not be used in patients with hereditary angioedema.

    Hypotension 

    • Entresto lowers blood pressure and may cause symptomatic hypotension. 
    • Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, being treated with high doses of diuretics), are at greater risk. 
    • Correct volume or salt depletion prior to initiation or start at a lower dose. 
    • If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (eg, hypovolemia). 
    • If hypotension persists despite such measures, reduce the dosage or temporarily discontinue Entresto. Permanent discontinuation of therapy is usually not required.

    Impaired Renal Function 

    • Inhibiting the renin-angiotensin-aldosterone system (RAAS) can decrease renal function in susceptible individuals treated with Entresto. 
    • In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (eg, those with severe CHF), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. 
    • In patients who develop a clinically significant decrease in renal function; closely monitor serum creatinine, and down-titrate or interrupt Entresto. 
    • As with all drugs that affect the RAAS, Entresto may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis.
    • In patients with renal artery stenosis, monitor renal function. 

    Hyperkalemia 

    • Hyperkalemia may occur with Entresto.
    • Monitor serum potassium periodically and treat appropriately, especially in those with risk factors for hyperkalemia (eg, severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet).
    • Dosage reduction or interruption of Entresto may be required.

    Pregnancy Considerations

    Entresto can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the 2nd and 3rd trimesters of pregnancy reduces fetal renal function and increases fetal/neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the 1st trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. 

    When pregnancy is detected, consider alternatives and discontinue Entresto. However, if there is no appropriate alternative therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.

    Nursing Mother Considerations

    There is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. 

    Sacubitril/valsartan is present in rat milk. 

    Because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with Entresto.

    Pediatric Considerations

    Safety and effectiveness have not been established in pediatric patients <1 year of age.

    Geriatric Considerations

    No relevant pharmacokinetic differences have been observed in elderly (≥65 years) or very elderly (≥75 years) patients compared to the overall population.

    Renal Impairment Considerations

    No dose adjustment is required in patients with mild (eGFR 60–90mL/min/1.73m2) to moderate (eGFR 30–60mL/min/1.73m2) renal impairment.

    The recommended initial dose in patients with severe renal impairment (eGFR <30mL/min/1.73m2) is 24/26mg twice daily.

    Hepatic Impairment Considerations

    No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh A).

    The recommended initial dose in patients with moderate hepatic impairment (Child-Pugh B) is 24/26mg twice daily.

    The use of Entresto in patients with severe hepatic impairment (Child-Pugh C) is not recommended, as no studies have been conducted in these patients.

    Entresto Pharmacokinetics

    Absorption

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

    The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5 hours, 2 hours, and 1.5 hours, respectively.

    The oral absolute bioavailability of sacubitril is estimated to be ≥60%. The valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in Entresto is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively. 

    Distribution

    Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94–97%).

    The average apparent volumes of distribution of valsartan and sacubitril are 75 and 103 L, respectively.

    Metabolism

    Sacubitril is readily converted to LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent.

    Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (<10%).

    Elimination

    Following oral administration, 52–68% of sacubitril (primarily as LBQ657) and ~ 13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces.

    Mean elimination half-life: ~1.4 hours (sacubitril), 11.5 hours (LBQ657), and 9.9 hours (valsartan).

    Entresto Interactions

    Interactions

    See Contraindications. Dual inhibition of the renin-angiotensin system: avoid concomitant with an ARB. Concomitant aliskiren in renal impairment (eGFR <60mL/min/1.73m2); avoid. Concomitant K+ supplements, K+ -sparing diuretics, K+ -containing salt substitutes may cause hyperkalemia. Worsening renal function and possible acute renal failure with NSAIDs, including selective COX-2 inhibitors (monitor renal function periodically in elderly and/or volume depleted). May increase lithium levels; monitor.

    Entresto Adverse Reactions

    Adverse Reactions

    Hypotension, hyperkalemia, cough, dizziness, renal failure, increased serum creatinine, decreased hemoglobin/hematocrit.

    Entresto Clinical Trials

    Clinical Trials

    Adult Heart Failure 

    PARADIGM-HF

    • A multinational, randomized, double-blind trial comparing Entresto versus enalapril in 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤40%).
    • Patients had to have been on an ACE inhibitor or ARB for at least 4 weeks and on maximally tolerated doses of beta-blockers.
    • Patients with a systolic blood pressure of <100mmHg at screening were excluded. 
    • The primary objective of PARADIGM-HF was to determine whether Entresto, a combination of sacubitril and a RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF).

    Patients who successfully completed the sequential run-in periods were randomized to receive either Entresto 200mg (N=4,209) twice-daily or enalapril 10mg (N=4,233) twice-daily. The primary endpoint was the first event in the composite of CV death or hospitalization for HF. The median follow-up duration was 27 months and patients were treated for up to 4.3 years.

    PARADIGM-HF demonstrated that Entresto was superior to enalapril alone based on a time-to-event analysis (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73, 0.87, P <0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization. Entresto also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], P =0.0009). This finding was driven entirely by a lower incidence of cardiovascular mortality on Entresto.

    PARAGON-HF

    • A multicenter, randomized, double-blind trial comparing Entresto versus valsartan in 4,796 adult patients with symptomatic heart failure with left ventricular ejection fraction ≥45%, and structural heart disease [either left atrial enlargement (LAE) or left ventricular hypertrophy (LVH)].
    • Patients with a systolic blood pressure of <110mmHg and patients with any prior echocardiographic LVEF <40% at screening were excluded. 
    • The primary objective of PARAGON-HF was to determine whether Entresto reduced the rate of the composite endpoint of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death. 

    Patients who successfully completed the sequential run-in periods were randomized to receive either Entresto 200mg (N=2,419) twice-daily or valsartan 160mg (N=2,403) twice-daily. The median follow-up duration was 35 months and patients were treated for up to 4.7 years. 

    PARAGON-HF demonstrated that Entresto had a numerical reduction in the rate of the composite endpoint of total HF hospitalizations and CV death, based on an analysis using a proportional rates model (rate ratio [RR] 0.87; 95% CI [0.75, 1.01], P =0.06). The treatment effect was primarily driven by the reduction in total HF hospitalizations in patients randomized to Entresto (RR 0.85; 95% CI [0.72, 1.00]).

     

    Pediatric Heart Failure 

    PANORAMA-HF 

    • A multinational, randomized, double-blind trial comparing Entresto versus enalapril based on an analysis in 110 pediatric patients 1 to <18 years old with heart failure (NYHA/Ross class II-IV) due to systemic left ventricular systolic dysfunction (LVEF ≤40%).
    • Patients with systemic right ventricles and single ventricles were excluded from the trial.
    • The Entresto target maintenance dose in pediatric patients 1 to <18 years old was 3.1mg/kg twice daily. 

    The endpoint was the between-group difference in the change in plasma NT-proBNP from baseline to 12 weeks. The reduction from baseline in NT-proBNP was 44% and 33% in the Entresto vs enalapril groups, respectively. While the between-group difference was not statistically significant, the reductions for Entresto and enalapril were similar to or greater than what was seen in adults; these reductions did not appear to be attributable to post-baseline changes in background therapy. 

    Since Entresto improved outcomes and reduced NT-proBNP in PARADIGM-HF, the effect on NT-proBNP was considered a reasonable basis to infer improved cardiovascular outcomes in pediatric patients.

    Entresto Note

    Not Applicable

    Entresto Patient Counseling

    Patient Counseling

    Advise patients to read the FDA-approved patient labeling (Patient Information). 

    Pregnancy

    • Advise female patients of childbearing age about the consequences of exposure to Entresto during pregnancy.
    • Discuss treatment options with women planning to become pregnant.
    • Ask patients to report pregnancies to their physicians as soon as possible. 

    Angioedema

    • Advise patients to discontinue use of their previous ACE inhibitor or ARB.
    • Advise patients to allow a 36 hour wash-out period if switching from or to an ACE inhibitor.

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