Frequently Asked Questions

All you have to do is choose your desired category and question from the lists below, and get your answer right away:

MOA

Neprilysin is an enzyme that breaks down vasoactive agents, such as natriuretic peptides, in the body. Neprilysin inhibition increases levels of these peptides. As you may know, some of these vasoactive peptides are associated with beneficial effects such as vasodilation, natriuresis, and aldosterone suppression.1-3

The PARADIGM-HF study demonstrated that inhibition of the RAAS by an ARB (the valsartan component of ENTRESTO) combined with neprilysin inhibition (the sacubitril component of ENTRESTO) can significantly reduce the risk of CV mortality and HF hospitalization compared with RAAS inhibition alone with an ACE inhibitor (enalapril).1

Learn more about the mechanism of action of ENTRESTO here.

Neprilysin degrades vasodilators (such as natriuretic peptides) and vasoconstrictive agents (such as angiotensin II). Sacubitril inhibits neprilysin, increasing the levels of both of these agents. Therefore, it is necessary to block the effects of the increased levels of angiotensin II with an ARB.1,4,5 For this reason, ENTRESTO combines neprilysin inhibition with angiotensin receptor blockade.

ENTRESTO contains sacubitril, a neprilysin inhibitor. Neprilysin metabolizes BNP; in the PARADIGM-HF study, the inhibition of neprilysin by ENTRESTO was associated with increases in BNP.1,2

On the other hand, NT-proBNP is not a substrate of neprilysin. ln PARADIGM-HF, NT-proBNP levels decreased more in patients taking ENTRESTO compared with those taking enalapril.1

This difference is explained by the fact that BNP levels are directly affected by ENTRESTO, whereas levels of NT-proBNP are not.

PARADIGM-HF: NT-proBNP and BNP6
Paradigm-HF NT-proBNP and BNP, Chart Paradigm-HF NT-proBNP and BNP, Chart
BNP=B-type natriuretic peptide; NT-proBNP=N-terminal pro-B-type natriuretic peptide.

Safety/Tolerability

Important Hypotension Safety Information

ENTRESTO lowers blood pressure and may cause symptomatic hypotension.

Patients with an activated RAAS, such as volume- and/or salt-depleted patients (eg, those being treated with high doses of diuretics), are at greater risk.

As detailed in the table below, hypotension was a commonly reported adverse event during the double-blind period of the PARADIGM-HF trial. However, discontinuations due to hypotension were low and similar between treatment groups.1,7

Hypotension Safety Chart Hypotension Safety Chart

It should be noted that due to the run-in design of the PARADIGM-HF study, the adverse reaction rates described above are lower than expected in practice.1,7

To address hypotension1:

  1. Correct Volume or Salt Depletion, Icon Correct volume or salt depletion prior to administration of ENTRESTO, or start at a lower dose.
  2. Hypertension Next Steps, Icon If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (eg, hypovolemia). If hypotension persists despite these measures, reduce the dosage or temporarily discontinue ENTRESTO.
  3. Permanent Discontinuation, Icon Permanent discontinuation of therapy is usually not required.

More information about the safety and tolerability profile of ENTRESTO is available here.

Understandably, the tolerability and adverse event profile is a key consideration in prescribing a new medication for your patients.

In TITRATION, 76% of randomized patients achieved and maintained the target dose of ENTRESTO without interruption or adjustment.8

Titration Study8

  • TITRATION was a 12-week tolerability study that randomized 498 patients with HFrEF who were either naïve to or on varying doses of ACEi or ARB therapy prior to study entry
  • The primary objective was to characterize the safety and tolerability of both a 3-week and 6-week ENTRESTO up-titration regimen
  • After a 1-week run-in phase where all subjects (n=540) received ENTRESTO 24/26 mg twice a day, 498 patients were randomized to continue with either a 3-week condensed regimen or a 6-week conservative regimen. (After patients were initiated on ENTRESTO 24/26 mg twice daily, they were then up-titrated to 49/51 mg twice daily, and then up-titrated again to the target dose of 97/103 mg twice daily)

Efficacy

The best place to start is by reviewing the indication. ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for HF in patients with chronic HF (NYHA Class II-IV) and reduced ejection fraction. ENTRESTO is usually administered in conjunction with other HF therapies, in place of an ACE inhibitor or other ARB.1

You may already be aware of PARADIGM-HF, the largest HF trial ever conducted.9 This study, which demonstrated the superiority of ENTRESTO compared with the ACE inhibitor enalapril, enrolled over 8400 patients with reduced ejection fraction (left ventricular ejection fraction ≤40%).1 Patients had to have been on an ACE inhibitor or ARB (equivalent to at least 10 mg of enalapril daily) and on maximally tolerated doses of beta blockers (unless contraindicated or not tolerated) for at least 4 weeks.1,10

The substantial number of subjects enrolled in the PARADIGM-HF study represented a broad range of HFrEF patients.1

Selected Baseline Demographics and Follow-up Duration1

Selected Baseline Demographics & Follow-Up Duration, Chart Selected Baseline Demographics & Follow-Up Duration, Chart

The results for the primary end point (the first event in the composite of CV death or HF hospitalization) were consistent across prespecified subgroups, including1:

For a more in-depth overview of the effects of ENTRESTO in various subgroups, please see the forest plot in Section 14, Figure 4 of the Prescribing Information.

The NNT is an estimation of the impact of a therapy through the number of patients that need to be treated in order to have an impact on one patient.11 In the PARADIGM-HF study, the primary end point 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.1 Below you will find additional end point data.

  • Primary end point: 20% RRR for ENTRESTO vs enalapril1
    • The ARR was 4.7%
    • The NNT for the primary end point was 21. ln other words, 21 patients would have to be treated with ENTRESTO instead of enalapril to prevent 1 primary end point event over the duration of the study7
  • CV death: 20% RRR for ENTRESTO vs enalapril1*
    • The ARR was 3.2%
    • The NNT for CV death was 32. In other words, 32 patients would have to be treated with ENTRESTO instead of enalapril to prevent 1 CV death over the duration of the study7
  • First HF hospitalization: 21% RRR for ENTRESTO vs enalapril1*
    • The ARR was 2.8%
    • The NNT for first HF hospitalization was 36.11 In other words, 36 patients would have to be treated with ENTRESTO instead of enalapril to prevent 1 first HF hospitalization over the duration of the study
*Analyses of the components of the primary composite end point were not prospectively planned to be adjusted for multiplicity.
Includes all CV death with or without previous hospitalization.

Since 2010, US hospitals with higher-than-expected risk-standardized 30-day readmission rates are at risk for substantial financial penalties as part of the Hospital Readmissions Reduction Program from Centers for Medicare and Medicaid Services (CMS).12 In a study evaluating 30-day readmissions in Medicare patients, 35% of the HF patient readmissions within 30 days were due to HF.13 So it’s clear that readmissions have an impact on both patients and hospitals.

A post-hoc analysis of data from the PARADIGM-HF study demonstrated that patients taking ENTRESTO had a 38% lower rate of HF-related readmission within 30 days of a HF hospitalization when compared to patients taking enalapril.* To learn more, please review the statistical analysis and study limitations.12

  • Of the 1074 HF discharges in the ENTRESTO arm, there were 104 (9.7%) HF-related readmissions within 30 days12
  • Of the 1302 HF discharges in the enalapril arm, there were 175 (13.4%) HF-related readmissions within 30 days12
  • Rates of readmission for HF within 30 days were reduced in subjects assigned to ENTRESTO vs enalapril (9.7% vs 13.4%, respectively); odds ratio (95% CI): 0.62 (0.45, 0.87)12
*Among patients hospitalized at least once for HF, patient characteristics were similar at baseline between treatment groups.12

Guideline

The 2017 ACC/AHA/HFSA Guideline Update includes a strong recommendation for the use of ENTRESTO. In the update, ENTRESTO, a fixed combination of an ARB and a neprilysin inhibitor, is referred to as an ARNI.14

There are 2 specific Class I recommendations that refer to the use of ENTRESTO.

The first recommendation is for the use of ENTRESTO as an alternative to ACE inhibitors or ARBs to reduce morbidity and mortality in patients with chronic HFrEF.14

Pharmacological Treatment for Stage C HFrEF14
Guideline Update, Recommended Alternative to ACE Inhibitors or ARBs Guideline Update, Recommended Alternative to ACE Inhibitors or ARBs

The second recommendation specifically advises to switch mild to moderately symptomatic patients15 who are otherwise tolerating an ACEi or ARB to ENTRESTO to further reduce morbidity and mortality.14

Guideline Update, Recommended Switching Symptomatic HFrEF Patients to ENTRESTO Guideline Update, Recommended Switching Symptomatic HFrEF Patients to ENTRESTO

The guideline update also identifies certain patients who should not receive ENTRESTO.14

Guideline Update, Which Patients Should Not Receive ENTRESTO Guideline Update, Which Patients Should Not Receive ENTRESTO

The guideline issued ENTRESTO a Class I, Level of Evidence B-R recommendation for use as a replacement for ACE inhibitor or ARB therapy in patients with chronic symptomatic NYHA Class II or Ill HFrEF who tolerate an ACE inhibitor or an ARB.14

This means that mild to moderately symptomatic patients15 who are currently tolerating an ACE inhibitor or an ARB should be switched to ENTRESTO to further reduce morbidity and mortality.14

The guideline recommendation for ENTRESTO was made owing to robust evidence from PARADIGM-HF—the largest clinical trial ever conducted in HF.9 In this trial, 70% of patients in the study population were NYHA Class II and 24% were Class III.1

The PARADIGM-HF trial was stopped early because of compelling efficacy. ENTRESTO was superior to enalapril in reducing the risk of CV death or first HF hospitalization; treatment effect reflected a reduction in both.7

As a result of these outcomes, the guideline issued this specific recommendation for ENTRESTO. ENTRESTO should be administered in conjunction with an evidence-based beta blocker and, in select patients, an aldosterone antagonist.14

ENTRESTO is contraindicated with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor. Also avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan.1

Educating patients

ENTRESTO is the first and only combination medicine of its kind for the treatment of HF.1,16 Three leading cardiology organizations recently updated their guideline to include ENTRESTO as a recommended treatment for HFrEF, also known as systolic HF.14,17

ENTRESTO contains 2 active ingredients that work in different ways to counteract the effects of HF.1

The first ingredient, valsartan, has been used for years to treat HF.17 The second ingredient, sacubitril, works unlike any other HF treatment and can only be found in ENTRESTO.

Explaining ENTRESTO to Patients Explaining ENTRESTO to Patients
ENTRESTO helps make it easier for your heart to do its job.1

Materials designed to help your patients learn more about ENTRESTO are available here.

Dosage forms and strengths

ENTRESTO is supplied as unscored, ovaloid, film-coated tablets in the following strengths1:

  • 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
  • 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
  • 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

ENTRESTO is supplied as unscored, ovaloid, biconvex, film-coated tablets in 3 strengths, containing 24 mg of sacubitril and 26 mg of valsartan; 49 mg of sacubitril and 51 mg of valsartan; and 97 mg of sacubitril and 103 mg of valsartan. All strengths are available in bottles (60 or 180 tablets) and unit-dose blister packages (10 strips of 10 tablets).1

The NDC numbers are as follows:

ENTRESTO 24/26 mg are violet white and debossed with "NVR" on one side and "LZ" on the other side1:

  • Bottle of 60: NDC 0078-0659-20
  • Bottle of 180: NDC 0078-0659-67
  • Blister packages of 100: NDC 0078-0659-35 (for hospitals)

ENTRESTO 49/51 mg are pale yellow and debossed with "NVR" on one side and "L1" on the other side1:

  • Bottle of 60: NDC 0078-0777-20
  • Bottle of 180: NDC 0078-0777-67
  • Blister packages of 100: NDC 0078-0777-35 (for hospitals)

ENTRESTO 97/103 mg are light pink and debossed with "NVR" on one side and "L11" on the other side1:

  • Bottle of 60: NDC 0078-0696-20
  • Bottle of 180: NDC 0078-0696-67
  • Blister packages of 100: NDC 0078-0696-35 (for hospitals)

Dosing

The short answer is that the washout period must be observed in order to reduce the risk of angioedema.1

In addition to metabolizing natriuretic peptides, neprilysin, like ACE, is involved in the degradation of bradykinin.2,3 Therefore, the combination of neprilysin inhibition with ACE inhibition could increase the risk of bradykinin-mediated angioedema.19

Treatment with ENTRESTO must not begin until 36 hours after the last dose of ACE inhibitor therapy is administered. Conversely, ACE inhibitor therapy must not begin until 36 hours after the last dose of ENTRESTO is given.1

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. ENTRESTO should not be used in patients with hereditary angioedema. If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be readministered.1

The valsartan in ENTRESTO has greater bioavailability than the valsartan in other commercial formulations. So, the 103-mg dose of valsartan in ENTRESTO is equivalent to the 160-mg dose of Diovan. The same is true of the 26-mg and 51-mg doses of valsartan in ENTRESTO, compared with the 40-mg and 80-mg doses of valsartan in other formulations of Diovan, respectively.1

ENTRESTO should not be coadministered with Diovan because of the angiotensin II receptor-blocking activity of valsartan in ENTRESTO.1

Diovan is a registered trademark of Novartis AG.

PARADIGM-HF study design

There are actually 2 reasons. First, data on the safety and tolerability of ENTRESTO needed to be obtained, primarily because of limited phase II clinical trial experience.20

Secondly, the investigators wanted to ensure that target doses of both study drugs (ENTRESTO and enalapril) had an acceptable side-effect profile and could be tolerated by all patients prior to randomization and throughout the follow-up.

This allowed for a fair comparison of ENTRESTO to the evidence-based doses of enalapril that have been shown to reduce mortality.7,20,21

PARADIGM-HF Study Design
There were two 36-hour washout periods during the run-in period to minimize the potential risk of angioedema due to overlapping ACE-neprilysin inhibition—the first after completing the enalapril run-in period, and the second after completing the ENTRESTO run-in period.10
*All patients were on an ACE inhibitor or ARB prior to the run-in period.1
Patients were treated for up to 4.3 years.1

PARADIGM-HF sought to provide evidence to support the replacement of ACE inhibitors or ARBs in the treatment of chronic HFrEF.1 Enalapril is the most widely studied ACE inhibitor in HFrEF and has been shown to reduce mortality rates21-23; it demonstrated an 18% reduction in CV death compared with placebo in the landmark SOLVD-Treatment trial.21

A head-to-head comparison with enalapril makes the data more relevant and the results more meaningful than a placebo-controlled trial.20,21

An analysis of data from the PARADIGM-HF study examined the incremental effects of ENTRESTO vs enalapril on nonfatal HF progression in surviving patients.1 ENTRESTO reduced the rate of first HF hospitalization as early as 30 days after treatment randomization.1 The effect was sustained for up to 42 months.1,6,7

Cost

Visit Literature and Handouts to view and download the $10 Co-pay Card and Free Trial Offer brochures. You may also Contact a Novartis Representative to receive printed brochures that contain the card and voucher, respectively.

You can contact the ENTRESTO Central Patient Support Program to confirm a patient's eligibility for the $10 Co-pay Card offer and/or Free Trial Offer voucher by calling 1-888-ENTRESTO (1-888-368-7378).

Valid only for those with commercial insurance. Offer not valid under Medicare, Medicaid, or any other federal or state program, for cash-paying patients, where product is not covered by patient’s commercial insurance, or where plan reimburses you for entire cost of your prescription drug. Offer is not valid where prohibited by law. Valid only in the US and Puerto Rico. This program is only valid for those patients 18 years and older. This program is not health insurance. Offer may not be combined with any other rebate, coupon, or offer. This card is the property of Novartis Pharmaceuticals Corporation and must be returned upon request. Novartis reserves the right to rescind, revoke, or amend the program without notice. Patient certifies responsibility for complying with applicable limitations, if any, of any commercial insurance and reporting receipt of program rewards, if necessary, to any commercial insurer.

Eligible patients with commercial insurance are responsible for the first $10 for a 30-day, 60-day, or 90-day fill at retail or mail order. The program pays the balance of the co-pay per fill, up to a total maximum of $2500 per calendar year. If patient reaches the program cap per calendar year of $2500, the patient will be responsible for the difference. This program is subject to modification or termination at any time.

The Free Trial Offer voucher is good for a 30-day (maximum 60 tablets) free trial of ENTRESTO. See voucher Terms and Conditions for additional details.

Learn more about ENTRESTO Central and these cost-saving offers here.

Eligible patients can activate a $10 Co-pay Card by calling 1-888-ENTRESTO (1-888-368-7378) or by visiting ENTRESTO.com. After activating the card, the patient can present it, along with a valid prescription for ENTRESTO and an insurance card, at any participating pharmacy or through mail order. This program is subject to modification or termination at any time. The Free Trial Offer does not require activation.

If the $10 Co-pay Card has already been activated and is rejected, or if the Free Trial Offer is rejected, the pharmacy can contact McKesson at 1-844-685-3406. You or the patient may call the ENTRESTO Central Patient Support Program at 1-888-ENTRESTO (1-888-368-7378) to investigate why the offer is not working.

Support

Novartis is committed to helping you and your patients with HFrEF get started on ENTRESTO. To date, more than 200,000 patients have been prescribed ENTRESTO.24

About 50% of patients do not require a prior authorization (PA),25 but for those who do, we can help you and your staff through the PA process.

Through ENTRESTO Central, patients can participate in a 6-month adherence program, and receive an educational kit on HF with tips and tools for healthy diet and exercise, as well as a symptom and medication tracker, and mobile follow-up.

PLAN-SPECIFIC PA INFORMATION

  • Provides information on coverage status and PA criteria*
ENTRESTO-coverage.com
  • Provides links to download the right blank PA forms for your patients’ insurance coverage, where available
ENTRESTO-coverage.com

PA FILING SUPPORT

  • Online tool that automates PA for all plans—available 24/7
COVERMYMEDS.COM
Central Enrollment Form Central Enrollment Form
  • Assists with filing PA requests and appeals
  • Live agent support
  • Visit ENTRESTO.com OR call
    1-888-ENTRESTO (1-888-368-7378) Monday through Friday (excluding holidays), 8:00 am to 8:00 pm ET
ENTRESTO CENTRAL ENROLLMENT FORM
CoverMyMeds is a registered trademark of CoverMyMeds LLC.
*Not prescribing criteria. Please see full Prescribing Information, including Boxed WARNING, before making any prescribing decision. The information provided in this communication is not a guarantee of coverage or payment (partial or full). Actual benefits are determined by each plan administrator in accordance with its respective policy and procedures. Nothing herein may be construed as an endorsement, approval, recommendation, representation, or warranty of any kind by a plan or insurer referenced on this web site.

Every patient is eligible for a 30-day Free Trial Offer* of ENTRESTO. This trial period allows you to evaluate the tolerability of ENTRESTO in patients new to the treatment, at no cost to your patients.

Novartis has also implemented cost-saving programs. In addition to checking the insurance plan to determine the out-of-pocket cost of ENTRESTO, ENTRESTO Central also helps patients find programs that may provide savings or resources with Patient Assistance Now.

To enroll, patients may visit ENTRESTO.com or call 1-888-ENTRESTO (1-888-368-7378).

ENTRESTO is preferred and affordable for your patients25:

Medicare Part D

  • 9 out of 10 patients have preferred access on Medicare Part D
  • Dual-eligible, low-income subsidy patients pay a generic-like co-pay of no more than $8.35 per month for ENTRESTO

Commercial

  • Approximately 2 out of 3 patients have preferred access on commercial plans
  • Eligible commercially insured patients NOW pay as little as a $10 co-pay for up to a 30-, 60-, or 90-day supply
*No purchase required. Submit claim to McKesson Corporation using BIN #610524. This free trial is not health insurance. Void where prohibited by law. Product dispensed pursuant to terms and conditions of voucher. Claims shall not be submitted to any public or private third-party payer or any federal or state health care program for reimbursement. Valid only in the US and Puerto Rico. This offer is only valid tor those patients 18 years and older. Offer not valid if reproduced or submitted to any other payer. It is illegal tor any person to sell, purchase, or trade, or offer to sell, purchase, or trade, or to counterfeit the voucher. This is the property of Novartis Pharmaceuticals Corporation and must be returned upon request. Novartis Pharmaceuticals Corporation reserves the right to rescind, revoke, or amend offer without notice.
Brand-name drugs that are covered at a lower tier/co-pay, and/or with fewer restrictions, than nonpreferred brands in the same pharmacologic class.
Co-pay amounts are for 2018.

The ENTRESTO Central Patient Support Program is designed to help support your patients throughout their treatment. It offers a range of support services to help your patients navigate their health insurance benefits, save on their out-of-pocket prescription costs, and learn about treatment with ENTRESTO.

Once a patient enrolls, a reimbursement specialist will check the patient's insurance plan to see if the cost of ENTRESTO is covered. If there are any restrictions to coverage, ENTRESTO Central will work with the patient's insurance company.

ENTRESTO Central offers 2 possible ways your patients may save on their out-of-pocket costs:
All patients can get a 1-month supply of ENTRESTO at no cost. Limitations apply. The Free Trial Offer voucher is good for a 30-day (maximum 60 tablets) free trial of ENTRESTO. See voucher Terms and Conditions for additional details.

Patients who have commercial insurance may qualify for our $10 Co-pay Card offer. Limitations apply. Valid only for those with commercial insurance. Offer not valid under Medicare, Medicaid, or any other federal or state program, for cash-paying patients, where product is not covered by patient’s commercial insurance, or where plan reimburses you for entire cost of your prescription drug. Offer is not valid where prohibited by law. Valid only in the US and Puerto Rico. This program is only valid for those patients 18 years and older. This program is not health insurance. Offer may not be combined with any other rebate, coupon, or offer. This card is the property of Novartis Pharmaceuticals Corporation and must be returned upon request. Novartis reserves the right to rescind, revoke, or amend the program without notice. Patient certifies responsibility for complying with applicable limitations, if any, of any commercial insurance and reporting receipt of program rewards, if necessary, to any commercial insurer.

Eligible patients with commercial insurance are responsible for the first $10 for a 30-day, 60-day, or 90-day fill at retail or mail order. The program pays the balance of the co-pay per fill, up to a total maximum of $2500 per calendar year. If patient reaches the program cap per calendar year of $2500, the patient will be responsible for the difference. This program is subject to modification or termination at any time.

You can get more information about these offers by visiting ENTRESTO.com or by calling
1-888-ENTRESTO (1-888-368-7378).

Visit Literature and Handouts to view and download available materials, or you may Contact a Novartis Representative.

You may Order Samples of ENTRESTO by Contacting a Novartis Representative.

Novartis will only fulfill 1 order per month.

See compelling evidence from a head-to-head study of ENTRESTO vs enalapril.

Discover the demonstrated safety and tolerability profile of ENTRESTO vs enalapril.

 

References: 1. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; November 2017. 2. Mann DL, Zipes DP, Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Saunders; 2015. 3. Erdös EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J. 1989;3(2):145-151. 4. Camm JA, Lüscher TF, Serruys PW, eds. ESC Textbook of Cardiovascular Medicine. 2nd ed. Oxford, UK: Oxford University Press; 2009:685-719. 5. Stephenson SL, Kenny AJ. Metabolism of neuropeptides. Hydrolysis of the angiotensins, bradykinin, substance P and oxytocin by pig kidney microvillar membranes. Biochem J. 1987;241(1):237-247. 6. Packer M, McMurray JJV, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54-61. 7. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 8. Senni M, McMurray JJV, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016;18(9):1193-1202. doi:10.1002/ejhf.548. 9. McMurray JJV, Packer M, Desai AS, et al. 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. 10. Data on file. Clinical Study Protocol CLCZ696B2314. Novartis Pharmaceuticals Corp; 2013. 11. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310:452-454. 12. Desai AS, Claggett BL, Packer M, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68(3):241-248. 13. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363. 14. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137-1146. 16. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2014;2(6):663-670. 17. 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. Circulation. 2013;128(16):e240-e327. 18. Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011. 19. Hegde LG, Yu C, Renner T, et al. Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal plasma extravasation in the rat. J Cardiovasc Pharmacol. 2011;57(4):495-504. 20. McMurray JJV, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15(9):1062-1073. 21. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293-302. 22. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327(10):685-691. 23. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987;316(23):1429-1435. 24. Data on file. LTD ENTRESTO Patient Estimate. Novartis Pharmaceuticals Corp; 2017. 25. Data on file. Access Grid. Novartis Pharmaceuticals Corp; 2017.

INDICATION

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

WARNING: FETAL TOXICITY
  • 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. ENTRESTO should not be used in patients with hereditary 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%).

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References: 1. ENTRESTO [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; November 2017. 2. Mann DL, Zipes DP, Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Saunders; 2015. 3. Erdös EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J. 1989;3(2):145-151. 4. Camm JA, Lüscher TF, Serruys PW, eds. ESC Textbook of Cardiovascular Medicine. 2nd ed. Oxford, UK: Oxford University Press; 2009:685-719. 5. Stephenson SL, Kenny AJ. Metabolism of neuropeptides. Hydrolysis of the angiotensins, bradykinin, substance P and oxytocin by pig kidney microvillar membranes. Biochem J. 1987;241(1):237-247. 6. Packer M, McMurray JJV, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54-61. 7. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. 8. Senni M, McMurray JJV, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016;18(9):1193-1202. doi:10.1002/ejhf.548. 9. McMurray JJV, Packer M, Desai AS, et al. 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. 10. Data on file. Clinical Study Protocol CLCZ696B2314. Novartis Pharmaceuticals Corp; 2013. 11. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310:452-454. 12. Desai AS, Claggett BL, Packer M, et al. Influence of sacubitril/valsartan (LCZ696) on 30-day readmission after heart failure hospitalization. J Am Coll Cardiol. 2016;68(3):241-248. 13. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363. 14. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161. 15. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137-1146. 16. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC Heart Fail. 2014;2(6):663-670. 17. 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. Circulation. 2013;128(16):e240-e327. 18. Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011. 19. Hegde LG, Yu C, Renner T, et al. Concomitant angiotensin AT1 receptor antagonism and neprilysin inhibition produces omapatrilat-like antihypertensive effects without promoting tracheal plasma extravasation in the rat. J Cardiovasc Pharmacol. 2011;57(4):495-504. 20. McMurray JJV, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15(9):1062-1073. 21. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293-302. 22. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327(10):685-691. 23. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med. 1987;316(23):1429-1435. 24. Data on file. LTD ENTRESTO Patient Estimate. Novartis Pharmaceuticals Corp; 2017. 25. Data on file. Access Grid. Novartis Pharmaceuticals Corp; 2017.

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION

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.

INDICATION

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

WARNING: FETAL TOXICITY
  • 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. ENTRESTO should not be used in patients with hereditary 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%).

Tap here for full Prescribing Information, including Boxed WARNING.