ENTRESTO, Sacubitril-Valsartan Form

Sacubitril/valsartan (Entresto®) is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB). FDA Approved Indication(s) Entresto is indicated: • To reduce the risk of cardiovascular death and hospitalization for heart failure in in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.
o LVEF is a variable measure, so use clinical judgment in deciding whom to treat. • For the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.
o Entresto reduces NT-proBNP and is expected to improve cardiovascular outcomes. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that Entresto is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Heart Failure (must meet all):

1. Diagnosis of chronic heart failure of NYHA Class II, III, or IV;
   
   2. Prescribed by or in consultation with a cardiologist;
   3. Age ≥ 1 year;
   4. At the time of request, member has none of the following contraindications: a. Concomitant use with ACE inhibitors; b. If member has a diagnosis of diabetes, concomitant use with aliskiren;
2. For members with LVEF ≥ 41% (i.e., heart failure with mildly reduced or preserved ejection fraction), failure of Jardiance, unless contraindicated or clinically significant adverse effects are experienced;

3. Dose does not exceed both of the following (a and b):
   a. Sacubitril 194 mg/valsartan 206 mg per day;
   b. 2 tablets for adults per day.
   Approval duration: 12 months Page 1 of 7

   CLINICAL POLICY Sacubitril/Valsartan B. Other diagnoses/indications (must meet 1 or 2):

4. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
5. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Heart Failure (must meet all):
6. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Entresto for heart failure and has received this medication for at least 30 days;
7. Member is responding positively to therapy;
   3. If request is for a dose increase, new dose does not exceed both of the following (a and b): a. Sacubitril 194 mg/valsartan 206 mg per day;
      b. 2 tablets for adults per day. Approval duration: 12 months B. Other diagnoses/indications (must meet 1 or 2):

8. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or Page 2 of 7

   CLINICAL POLICY Sacubitril/Valsartan

9. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   III. Diagnoses/Indications for which coverage is NOT authorized:
   A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents.
   IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ACE: angiotensin-converting enzyme ARB: angiotensin II receptor blocker
   FDA: Food and Drug Administration HFrEF: heart failure with reduced ejection fraction LVEF: left ventricular ejection fraction NYHA: New York Heart Association
   Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
   Drug Name Dosing Regimen Jardiance® (empagliflozin) 10 mg PO QD Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Dose Limit/ Maximum Dose 25 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Hypersensitivity to any component. o History of angioedema related to previous ACE inhibitor or ARB therapy. o Concomitant use of Entresto with an ACE inhibitor is contraindicated because of the increased risk of angioedema. o Concomitant use of Entresto and ARB should be avoided since Entresto contains an ARB. o Concomitant use with aliskiren in patients with diabetes. • Boxed warning(s): 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. Appendix D: General Information • The PARAGON-HF trial compared Entresto against valsartan in patients with New York Heart Association class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease for the primary outcome of Page 3 of 7

   CLINICAL POLICY Sacubitril/Valsartan composite of total hospitalizations for heart failure and death from cardiovascular causes. The results did not find a statistically significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. • The 2022 AHA/ACC/HFSA guideline for the management of heart failure defines HFrEF as a clinical diagnosis of heart failure and LVEF ≤ 40%. V. Dosage and Administration
   Maximum Dose Sacubitril 194 mg/valsartan 206 mg per day Indication Chronic heart failure Dosing Regimen Adults The recommended starting dose is 49/51 mg (sacubitril/valsartan) PO BID. Double the dose after 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) BID, as tolerated by the patient. Therapy may be initiated at 24/26 mg (sacubitril/valsartan) PO BID for:
   • patients not currently taking an ACE inhibitor or an ARB or previously taking a low dose of these agents
   • patients with severe renal impairment
   • patients with moderate hepatic impairment
   Double the dose every 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/ valsartan) BID, as tolerated by the patient. Pediatric patients age ≥ 1 year Administer weight-based dosing sacubitril/valsartan PO BID. Adjust the dose every 2 weeks, as tolerated by the patient per the following: • Weight < 40 kg:
   Use of oral suspension prepared using the 49/51 mg tablets is recommended. Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan. o Starting dose: 1.6 mg/kg PO BID o Second titration dose: 2.3 mg/kg PO BID o Third titration dose: 3.1 mg/kg PO BID • Weight ≥ 40 kg and < 50 kg:
   o Starting dose: 24/26 mg PO BID o Second titration dose: 49/51 mg PO BID
   o Third titration dose: 72/78 mg PO BID • Weight ≥ 50 kg:
   o Starting dose: 49/51 mg PO BID Page 4 of 7

   CLINICAL POLICY Sacubitril/Valsartan Indication Dosing Regimen Maximum Dose o Second titration dose: 72/78 mg PO BID o Third titration dose: 97/103 mg PO BID VI. Product Availability
   Film-coated tablets (sacubitril/valsartan): 24 mg/26 mg, 49 mg /51 mg, 97 mg/103 mg
   VII.