This article was sponsored by Novartis Pharmaceuticals Corporation.

Full Prescribing Information INCLUDING Boxed WARNING

  • When pregnancy is detected, discontinue ENTRESTO as soon as possible
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

ENTRESTO™ (sacubitril/valsartan) tablets 24/26 mg, 49/51 mg, 97/103 mg, from Novartis Pharmaceuticals Corporation, are a combination of an angiotensin receptor blocker (ARB) and a novel neprilysin inhibitor, indicated to reduce the risk of cardiovascular (CV) death and hospitalization for heart failure in patients with chronic heart failure (New York Heart Association [NYHA] class II through IV) and reduced ejection fraction (HFrEF). ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an angiotensin-converting enzyme (ACE) inhibitor or other ARB. ENTRESTO was clinically proven in the PARADIGM-HF study to be superior to enalapril (P <.0001).1

Pivotal Clinical Trial: PARADIGM-HF
Researchers evaluated ENTRESTO in the largest clinical trial performed to date in patients with HF: the randomized, double-blind, multinational PARADIGM-HF trial.2 A total of 8442 adult patients with symptomatic chronic HF (NYHA class II-IV) and left ventricular ejection fraction of 40% or lower were randomized in a 1:1 ratio to receive ENTRESTO or enalapril plus background therapy for HFrEF.1
All patients enrolled in the PARADIGM-HF clinical trial had received an ACE inhibitor or ARB for a minimum of 4 weeks before entering the study. Additionally, patients were receiving maximally tolerated doses of beta-blockers and had systolic blood pressure of 100 mm Hg or higher at screening.1,3 

After discontinuing their existing ACE inhibitor or ARB therapy, patients entered a run-in period that included dosage titration of ENTRESTO. Patients were then randomized to receive either ENTRESTO at a maintenance dose of 97/103 mg twice daily (n = 4209) or enalapril 10 mg twice daily (n = 4233). Concomitant medications included beta-blockers (94% of patients), diuretics (82% of patients), and mineralocorticoid antagonists (58% of patients).1

Investigators evaluated a primary composite end point of HF-related hospitalization or CV death.1,3 In the event-driven trial, after a median follow-up of 27 months, a preplanned interim efficacy analysis indicated compelling efficacy of ENTRESTO, and the trial was stopped early.3

ENTRESTO was superior in reducing the relative risk of CV death or first heart failure hospitalization, with the primary end point driven by reductions in both components.1,3 Researchers observed a 20% relative risk reduction and a 4.7 percentage-point absolute risk reduction of experiencing the primary end point in patients receiving ENTRESTO versus enalapril (HR 0.80, 95% CI: 0.73-0.87; P <.0001; Figure1). Slightly more than 1 in 4 patients (26.5%) receiving traditional therapy with enalapril experienced an event designated as a component of the primary end point versus slightly more than 1 in 5 patients (21.8%) receiving ENTRESTO.1,3

Mechanism of Action
ENTRESTO contains 2 medications, valsartan, which inhibits the effects of angiotensin II, and sacubitril, a neprilysin inhibitor, which increases levels of natriuretic peptides that are normally degraded by neprilysin.1

Because medications that work on the renin-angiotensin aldosterone system may cause injury and death to a developing fetus, ENTRESTO carries a black box warning for fetal toxicity. If a patient taking ENTRESTO becomes pregnant, the medication should be discontinued as soon as possible.1

Dosing and Administration
ENTRESTO is available in 3 strengths: sacubitril 24 mg/valsartan 26 mg (24/26 mg), sacubitril 49 mg/valsartan 51 mg (49/51 mg), and sacubitril 97 mg/valsartan 103 mg (97/103 mg). During the dosage titration phase, and throughout treatment, tablets should be taken twice daily at approximately the same time each day with or without food.1

Before starting ENTRESTO, it is important to establish the appropriate time to start treatment. Patients transitioning from an ACE inhibitor to ENTRESTO should not take their first dose of ENTRESTO until at least 36 hours after taking their last ACE inhibitor dose. This restriction does not apply to patients taking ARBs.1

The appropriate starting dose of ENTRESTO depends on whether the patient previously received treatment with a high dose or low dose of an ACE inhibitor or ARB. For patients previously taking an ACE inhibitor, at a dose of more than 10 mg of enalapril daily (or, equivalently, lisinopril >10 mg daily or ramipril >5 mg daily), or an ARB dose greater than 160 mg of valsartan daily (or, equivalently, losartan >50 mg daily or olmesartan >10 mg daily), the recommended starting dose of ENTRESTO is 49/51 mg taken twice daily. Patients taking lower doses of ACE inhibitors or ARBs or patients who were not taking ACE inhibitors or ARBs before starting ENTRESTO should start treatment with the 24/26 mg twice-daily dose.1,4

The appropriate starting dose of ENTRESTO also depends on the patient’s renal function and hepatic function. No dose adjustment is needed in patients with mild to moderate renal impairment or in patients with mild hepatic impairment. However, patients with severe renal impairment (defined by an estimated glomerular filtration rate <30 mL/min/1.73 m2) or patients with moderate hepatic impairment (Child-Pugh class B) should initiate treatment with ENTRESTO 24/26 mg twice daily. Use in patients with severe hepatic impairment is not recommended.1

During titration, the dose should be doubled every 2 to 4 weeks as tolerated by the patient until reaching the maintenance dose of 97/103 mg taken twice daily.1 TITRATION was a 12-week tolerability study in 498 patients with HFrEF who were either naïve to or on varying doses of ACE inhibitor or ARB therapy prior to study entry. The primary objective was to characterize the safety and tolerability of both 3-week and 6-week ENTRESTO uptitration regimens. After a 1-week run-in phase where all participants received ENTRESTO 24/26 mg twice daily, patients were randomized (n = 498) to continue with either a 3-week condensed regimen or a 6-week conservative regimen. (Following the initial dose of ENTRESTO 24/26 mg twice daily, patients were up-titrated to 49/51 mg twice daily, and then up-titrated again to the target dose of 97/103 mg twice daily). More than three-fourths of all randomized patients (76%) successfully completed titration to the recommended maintenance dose (among all randomized patients who received at least 1 dose of study medication and excluding those who discontinued due to reasons not related to adverse events or death).4

Adverse Events
Common adverse events occurring in 5% or more of patients taking ENTRESTO in the double-blind period included hypotension (18% with ENTRESTO vs 12% with enalapril), hyperkalemia (12% with ENTRESTO vs 14% with enalapril), cough (9% with ENTRESTO vs 13% with enalapril), dizziness (6% with ENTRESTO vs 5% with enalapril), and renal failure/acute renal failure (5% with ENTRESTO vs 5% with enalapril). Because of the run-in design of the study, these adverse reaction rates are lower than expected in practice. In the double-blind period, the incidence of angioedema was higher in patients treated with ENTRESTO than enalapril (0.5% ENTRESTO vs 0.2% with enalapril).1

Certain interactions between ENTRESTO and other medications may increase the need for laboratory monitoring. For example, more intensive monitoring may be necessary in patients taking potassium-sparing diuretics or potassium supplements (due to the risk of hyperkalemia), in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) (due to the risk of renal impairment), and in patients taking lithium (due to the risk of increased lithium levels). In addition, periodic monitoring of serum creatinine levels and serum potassium levels is recommended in all patients taking ENTRESTO.1

Role of the Pharmacist
Patients can be told of the availability of ENTRESTO and informed that in a recent study, ENTRESTO was proven superior to a standard-of-care ACE inhibitor (enalapril) in reducing hospitalization for heart failure and cardiovascular death in patients with HFrEF.1,3,5 They can also be educated on the importance of taking the medication as prescribed, along with the benefits of continuing therapy.

Before starting the ENTRESTO dosing titration, patients taking ACE inhibitors must stop taking their ACE inhibitor for 36 hours. Patients taking ARBs do not need the waiting period.1
To determine the appropriate starting dose for ENTRESTO, distinguish between a high dose and low dose of ACE inhibitors and ARBs. Inform patients of their starting dose and the importance of taking ENTRESTO as prescribed. If applicable, adjustments for renal or hepatic impairment must also be considered in determining the appropriate starting dose of ENTRESTO. Once the correct starting dose is determined, the dosage of ENTRESTO should be doubled every 2 to 4 weeks as tolerated until patients reach the target maintenance dose of 97/103 mg twice daily.1

Patients should understand that ENTRESTO takes the place of their existing ACE inhibitor or ARB and is not used in combination with these medications. As with ACE inhibitors and ARBs, monitoring of serum creatinine levels and potassium levels is recommended with ENTRESTO, and more intensive monitoring may be done in patients taking NSAIDs, potassium-sparing diuretics, or potassium supplements.1

ENTRESTO is an important option in HFrEF management. Educating patients and helping them manage the process of transitioning to this therapy can help them reduce their risk of CV death and hospitalization for heart failure.

ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.
Important Safety Information
  • When pregnancy is detected, discontinue ENTRESTO as soon as possible
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus
ENTRESTO is contraindicated in patients with hypersensitivity to any component. ENTRESTO is contraindicated in patients with a history of angioedema related to previous angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy. 
ENTRESTO is contraindicated with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor. ENTRESTO is contraindicated with concomitant use of aliskiren in patients with diabetes.
Angioedema: ENTRESTO may cause angioedema.  Angioedema associated with laryngeal edema may be fatal. ENTRESTO has been associated with a higher rate of angioedema in Black patients and in patients with a prior history of angioedema. If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be re-administered.
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 (e.g., those being treated with high doses of diuretics), are at greater risk. Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose. If hypotension persists despite dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia) reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.
Impaired Renal Function: Decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO. 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 ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and down-titrate or interrupt ENTRESTO in patients who develop a clinically significant decrease in renal function.
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. Avoid use with aliskiren in patients with renal impairment (eGFR <60 mL/min/1.73 m2).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, with ENTRESTO may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically.
Hyperkalemia: Hyperkalemia may occur with ENTRESTO. Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of ENTRESTO may be required.
Concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
ARBs: Avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan.
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with ENTRESTO.
Common Adverse Events: In a clinical trial, the most commonly observed adverse events with ENTRESTO vs enalapril, occurring at a frequency of at least 5% in either group, were hypotension (18 %, 12%), hyperkalemia (12%, 14%), cough (9%, 13%) dizziness (6%, 5%) and renal failure/acute renal failure (5%, 5%).

Please click here for full Prescribing Information, including BOXED WARNING.

  1. Entresto [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.
  2. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Baseline characteristics and treatment of patients in prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014;16(7):817-825. doi: 10.1002/ejhf.115.
  3. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi: 10.1056/NEJMoa1409077.
  4. Data on file. CSR CLCZ696B2228. Novartis Pharmaceuticals Corp; 2014.
  5. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013;62(16)e147-239. doi: 10.1016/j.jacc.2013.05.019.

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