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ENTRESTO Sacubitril and Valsartan 15 mg; 16 mg Pellet, 60-count — NDC 00078-1238-20 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

ENTRESTO Sacubitril and Valsartan 15 mg; 16 mg Pellet, 60-count — NDC 0078-1238-20 (Billing 00078-1238-20)

by Novartis Pharmaceuticals Corporation · 60 PELLET in 1 BOTTLE

This is a package of 60 pellets of ENTRESTO Sacubitril and Valsartan 15 mg; 16 mg Pellet from Novartis Pharmaceuticals Corporation, marketed since Apr 2024 and currently FDA-listed; retail pharmacies pay about $11.61 per pellet (NADAC). It is this product's only package size.

NDC 00078-1238-20
🏷️ FDA NDC (as labeled) 0078-1238-20 billing pads the labeler segment with a zero
Rx only Brand On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Sep 10, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 0078-1238-20
Product NDC 0078-1238
11-digit billing NDC 00078123820
NCPDP billing unit EA — each (per item)
RxCUI 1656340, 1656346, 1656349, 1656351, 1656354, 1656356, 2679793, 2679797,
UNII 17ERJ0MKGI, 80M03YXJ7I
Application # NDA218591
SPL Set ID 000dc81d-ab91-450c-8eae-8eb74e72296f
Established class (EPC) Angiotensin 2 Receptor Blocker
Mechanism of action Angiotensin 2 Receptor Antagonists
DEA schedule Non-controlled
Marketing category NDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2024-04-12
Route ORAL
Dosage form PELLET
Substance SACUBITRIL; VALSARTAN

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 40992002606830
GCN Seq No 085970
GCN 55585
HICL code 042256
Ingredient (HICL) Sacubitril/Valsartan
HIC1 code A
Therapeutic class — broad (HIC1) Cardiovascular System
HIC2 code A4
Therapeutic class — intermediate (HIC2) Antihypertensives
HIC3 code A4L
Therapeutic class — specific (HIC3) Angiotensin Recept-Neprilysin Inhibitor Comb(Arni)
AHFS code 24:32.12.00
AHFS class Angiotensin Ii Recep Antagonist/Neprolys
FDB label name ENTRESTO SPRINKLE 15-16 MG PLT
FDB brand name Entresto Sprinkle
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 085970
  • GCN: 55585
  • GPI-14 (Medi-Span): 40992002606830
  • HICL (First Databank): 042256
  • AHFS class code: 24:32.12.00
  • RxCUI (RxNorm): 1656340
Why two NDCs? The FDA registers this code as 0078-1238-20 — a 4-4-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the labeler segment → 00078-1238-20. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Angiotensin II receptor blockers (ARBs), other combinations class.

Drug family (ATC) Angiotensin II receptor blockers (ARBs), other combinations
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name ENTRESTO SPRINKLE 15-16 MG PLT Ingredient Sacubitril/Valsartan
📖 What it is MedlinePlus · NLM

The combination of valsartan and sacubitril is usually used in combination with other medications to lower the risk of death and hospitalization in adults with certain types of heart failure. The combination of valsartan and sacubitril is also used to treat certain types of heart failure in children 1 year of age and older. Valsartan is in a class of medications called angiotensin II receptor antagonists. It works by blocking the action of certain natural substances that tighten the blood vessels, allowing the blood to flow more smoothly and the heart to pump more efficiently. Sacubitril is in...

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • Sacubitril and valsartan works on two fronts at once. One part (sacubitril) helps your body's own protective heart hormones stick around longer, which helps your kidneys get rid of...
  • What exactly is this medication supposed to do for my heart failure?
  • That's a really important question. A few combinations need to be avoided or watched carefully. You should never take this with an ACE inhibitor like lisinopril or enalapril at the...
  • Can I take it with my other medications? I'm also on ibuprofen sometimes for pain.
📖 Read our full Valsartan and Sacubitril guide →

Supplement & herbal interactions

🌿 Drug–supplement interaction checker →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer eaPer package
Retail pharmacies payNADAC · weekly $11.607 $696.40 / 60 pellets
Medicaid paysCMS SDUD · 12 mo $11.53 $691.88 / 60 pellets
NADAC price history (per ea) — tap or hover for the price & month
Dec 2025 May 2026 Jul 2026 Sep 2026 $11.649 $11.285
▲ Up 3% over the last 7 months.
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
00078-1238-20 You're viewing this Main listing 60 PELLET in 1 BOTTLE 2024-04-12 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Entresto 15 mg/1; 16 mgthis 00078-1238-20 Novartis 60 pellets $11.607 — Availability likely —
About this product: this is the brand-name version. We did not find an FDA-approved generic match for this exact strength, form and route.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2024
First FDA approval
Apr 2024
📍
2026
Currently FDA-listed
2 years listed
🛡️
2037
Latest patent/protection listed
not a guaranteed launch date
🔒No FDA-approved generic found

We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.

🛡️ Latest patent/protection date listed: FDA patent/protection data lists protections through Feb 2037. This may affect when a full generic version becomes widely available, but it is not a guaranteed launch date.
📅 FDA approved Apr 12, 2024 RLD RS ⏳ ~10.3 yr to latest listed protection

Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.

Patents & exclusivity — FDA Orange Book
US 10722471 — method of use (U-3896)
US 10722471 — method of use (U-3896)
US 9388134 — method of use (U-1723)
US 9388134 — method of use (U-1723)
US 8877938 — drug substance
US 8877938 — drug substance
2024 2026 2028 2030 2032 2034 2036
Today
LOE
Substance patent Formulation patent Method-of-use patent Exclusivity Pediatric +6mo
🏛️FDA exclusivity
FDA-granted marketing protection. It’s separate from patents and may be shorter than patent protection.
🧪Product / substance patents
Patents covering the active ingredient, product, formulation, or related drug features.
🎯Method-of-use patents
Patents covering specific approved uses. These can sometimes be carved out with a “skinny label,” but not always.
🛈 What do these terms mean?
Patent
Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
Substance patent
Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
Formulation (product) patent
Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
Method-of-use patent
A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
Skinny label
A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
Exclusivity
FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
Paragraph IV
A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
RLD / RS
Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
TE / AB rating
FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
LOE (loss of exclusivity)
The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.

Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.

Listed patents (6)
PatentTypeUse codeExpires
US 10722471 ↗ Method of use U-3896 Feb 2, 2037
US 10722471 ↗ Method of use U-3896 Feb 2, 2037
US 9388134 ↗ Method of use U-1723 Nov 8, 2026
US 9388134 ↗ Method of use U-1723 Nov 8, 2026
US 8877938 ↗ Drug substance — May 27, 2027
US 8877938 ↗ Drug substance — May 27, 2027
Common questions
Is there a generic version of ENTRESTO SPRINKLE 15-16 MG PLT?
No FDA-approved generic equivalent is currently listed in the FDA Orange Book for ENTRESTO SPRINKLE 15-16 MG PLT. Based on the patents and exclusivity currently listed, the Orange Book estimate is that full-label generic entry may be delayed until Feb 2037 — an estimate, not a guaranteed launch date.
The FDA approved a generic — why can’t I get it at my pharmacy yet?
FDA approval and pharmacy availability are two different things. The FDA can approve a generic years before it actually reaches pharmacies, because the brand company may still hold patents or have a settlement that delays the launch. A manufacturer also has to choose to make and sell it, and have supply ready. So a drug can be “FDA-approved generic exists” and still be brand-only at the counter today.
Why do different websites show different generic release dates?
Generic availability is not based on one single date. Some sources use the first exclusivity expiration, some use the last product patent, and others use the latest method-of-use patent. Patent challenges, settlements, licenses, and label carve-outs can also change the real-world launch date. This page shows the underlying Orange Book dates so you can see why estimates may differ.
What does “FDA listed” mean?
It means the product appears in the FDA’s official NDC directory. That’s a good sign a product exists and is intended for the U.S. market, but on its own it does not confirm a pharmacy can fill it today. Where we have recent retail pricing data (NADAC) for a product, we label it “Availability likely” instead.
What does a patent or protection date mean here?
It’s the latest date currently listed in the FDA Orange Book for a patent or exclusivity on the brand product. It can affect when a full generic version becomes widely available — but it is not a guaranteed generic launch date. Generics sometimes arrive earlier (through a settlement or patent challenge) or later (a manufacturer still has to make and sell one).
What does “current Orange Book estimate” mean?
It means we are using the latest patent and exclusivity dates currently listed in the FDA Orange Book. It is not a guaranteed launch date.
Can a generic come out before the last patent expires?
Sometimes. A generic company may challenge a patent, settle with the brand manufacturer, receive a license, or obtain approval with a narrower label that avoids a patented use. In other cases, the last listed protection may delay full-label generic competition.
Can a generic come out after the listed dates?
Yes. Even after patents or exclusivity expire, a generic still needs FDA approval and a manufacturer must choose to market it. Supply, litigation, business decisions, or regulatory issues can delay actual availability.
What is the difference between patents and exclusivity?
Patents are legal protections usually issued by the U.S. Patent and Trademark Office. FDA exclusivity is marketing protection granted by the FDA. They are separate, and either one can affect generic timing.
Why are there multiple patent dates?
One drug can have several patents covering different things: the active ingredient, a formulation, a manufacturing process, or a specific approved use. That is why a page may show several expiration dates instead of one simple generic date.
Built from FDA Orange Book patent and exclusivity data. Dates are refreshed from public FDA data when available; the marker is max(latest patent expiry, latest exclusivity expiry). Paragraph-IV settlements and first-filer 180-day exclusivity can shift the real date; a method-of-use patent may allow an earlier skinny-label generic for non-protected indications. Generic launch timing is an estimate, not a guarantee.
Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

What it looks like

Color White / Yellow / Pink
ShapeCapsule
ImprintNVR;10
Size15 mm
ScoringNot scored
One label can cover several strengths, so colors may be combined — always confirm a loose pill against the dispensed prescription label or a pharmacist.
Where does this data come from?
Physical description (imprint, shape, color, scoring, coating) from this product’s FDA Structured Product Labeling (SPL), mirrored from DailyMed / openFDA.

Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.

  • UNII 5138Q19F1X
    Ammonia is a colorless gas made from nitrogen and hydrogen. It's used in medicines as a pH buffer to maintain the correct acidity level and help keep the product stable.
  • UNII OP1R32D61U
    Microcrystalline cellulose is a purified form of cellulose, a natural fiber from plant sources. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and give the medicine its shape and size.
  • UNII 905HNO1SIH
    A synthetic polymer made from methacrylate compounds that forms a film coating on tablets or capsules. It helps control how quickly the medicine dissolves and releases its active ingredient in the digestive system.
  • UNII 1K09F3G675
    Ferric oxide red is an inorganic iron compound used as a colorant in medicines. It gives tablets, capsules, or other dosage forms a red or reddish tint for identification and appearance.
  • UNII EX438O2MRT
    Ferric oxide yellow is a naturally occurring iron compound used as a colorant in medications. It gives tablets, capsules, and other forms a yellow or golden hue for identification and appearance.
  • UNII 2165RE0K14
    A plant-based thickener made from cellulose that helps control how quickly the medicine dissolves and releases its active ingredient. It also binds ingredients together and improves the tablet's texture and handling during manufacturing.
  • UNII 3NXW29V3WO
    Hypromellose is a plant-based thickener made from cellulose. It's used in medicines as a binder to hold ingredients together, a coating for tablets, and a thickener for liquids.
  • UNII 70097M6I30
    Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
  • UNII WZH3C48M4T
    Potassium hydroxide is a strong alkaline chemical used in medicines to adjust and maintain the pH level of liquid formulations, helping keep the product stable and the active ingredients effective.
  • UNII 6DC9Q167V3
    Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
  • UNII 46N107B71O
    Shellac is a natural resin secreted by the lac beetle. It's used as a coating on tablets and capsules to control how quickly the medicine dissolves and to improve appearance and stability.
  • UNII ETJ7Z6XBU4
    Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
  • UNII 368GB5141J
    A detergent and foaming agent derived from coconut or palm oil. In medications, it helps break down and mix oil and water-based ingredients, aids in tablet disintegration, and improves how the drug dissolves and spreads in the mouth or digestive system.
  • UNII 4ELV7Z65AP
    Stearic acid is a fatty acid derived from plant or animal sources. It acts as a binder and lubricant in tablets and capsules, helping them hold together and flow smoothly during manufacturing.
  • UNII 7SEV7J4R1U
    A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
  • UNII 15FIX9V2JP
    Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.

16 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerNovartis Pharmaceuticals Corporation
Application holderNOVARTIS PHARMACEUTICALS CORP
FDA applicationNDA218591 (NDA)
Labeler code00078
First marketedApr 2024
Product typeHuman Prescription Drug
Portfolio209 products on file
The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📦 Storage and Handling 📋 Description 💬 Information for Patients 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Patient Package Insert 📖 Instructions for Use 📄 Recent Major Changes 📄 Package Label / Principal Display Panel
🚨 Boxed Warning 76 words ▾

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue ENTRESTO as soon as possible (5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue ENTRESTO as soon as possible. ( 5.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

( 5.1 )

🎯 Indications and Usage 192 words ▾

1 INDICATIONS AND USAGE ENTRESTO is a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and is indicated: to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. ( 1.1 ) for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.

ENTRESTO reduces NT-proBNP and is expected to improve cardiovascular outcomes. ( 1.2 )

1.1Adult Heart Failure ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)] .

1.2Pediatric Heart Failure ENTRESTO is indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. ENTRESTO reduces NT-proBNP and is expected to improve cardiovascular outcomes.

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION The recommended starting dosage for adults is 49 mg/51 mg orally twice daily. The target maintenance dose is 97 mg/103mg orally twice daily. ( 2.2 ) Adjust adult doses every 2 to 4 weeks to the target maintenance dose, as tolerated by the patient.

( 2.2 ) For pediatric patients, see the Full Prescribing Information for recommended dosage, titrations, preparation and administration instructions. ( 2.3 , 2.4 , 2.5 ) Reduce starting dose to half the usually recommended starting dosage for: patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents. ( 2.6 ) patients with severe renal impairment.

( 2.7 ) patients with moderate hepatic impairment. ( 2.8 )

2.1General Considerations ENTRESTO is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to ENTRESTO allow a washout period of 36 hours between administration of the two drugs [see Contraindications (4) and Drug Interactions (7.1)] .

2.2Adult Heart Failure The recommended starting dose of ENTRESTO is 49/51 mg orally twice-daily. Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.

2.3Pediatric Heart Failure For the recommended dosage for pediatric patients aged 1 year and older, refer to Table 1 if using the tablets, or Table 2 if using the oral pellets. Take the recommended dose orally twice daily. Adjust pediatric patient doses every 2 weeks, as tolerated by the patient.

Table 1: Recommended Dose and Titration for Pediatric Patients Using Tablets † Use of the oral suspension or oral pellets (see Table 2) is recommended in these patients. Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan [see Dosage and Administration (2.4, 2.5)] . ‡ Doses of 72 mg/78 mg can be achieved using three 24 mg/26 mg tablets [see Dosage Forms and Strengths (3)] . Titration Step Dose (twice daily) Weight (kg) Starting Second Final Less than 40 kg † 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg At least 40 kg, less than 50 kg 24 mg/26 mg 49 mg/51 mg 72 mg/78 mg ‡ At least 50 kg 49 mg/51 mg 72 mg/78 mg ‡ 97 mg/103 mg Table 2: Recommended Dose and Titration for Pediatric Patients using ENTRESTO SPRINKLE † † When using capsules, more than one capsule may be needed to achieve recommended doses.

Oral pellets are contained within each capsule. Use the entire contents of the capsules to achieve the dose. ‡ Recommended mg/kg doses are of the combined amount of sacubitril and valsartan [see Dosage and administration (2.4)] . * For patients 50 kg or more, see Table 1. Titration Step Dose (twice daily) Weight (kg) * Starting Second Final Less than 13 (use oral suspension ‡ ) 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg 13 to less than 19 12 mg/12 mg (Two 6 mg/6 mg capsules) 18 mg/18 mg (Three 6 mg/6 mg capsules) 24 mg/24 mg (Four 6 mg/6 mg capsules) 19 to less than 26 18 mg/18 mg (Three 6 mg/6 mg capsules) 24 mg/24 mg (Four 6 mg/6 mg capsules) 30 mg/32 mg (Two 15 mg/16 mg capsules) 26 to less than 34 24 mg/24 mg (Four 6 mg/6 mg capsules) 30 mg/32 mg (Two 15 mg/16 mg capsules) 45 mg/48 mg (Three 15 mg/16 mg capsules) 34 to less than 50 * 30 mg/32 mg (Two 15 mg/16 mg capsules) 45 mg/48 mg (Three 15 mg/16 mg capsules) 60 mg/64 mg (Four 15 mg/16 mg capsules)

2.4Preparation of Oral Suspension Using Tablets ENTRESTO oral suspension can be substituted at the recommended tablet dosage in patients unable to swallow tablets. ENTRESTO 800 mg/200 mL oral suspension can be prepared in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL). Use ENTRESTO 49/51 mg tablets in the preparation of the suspension.

To make an 800 mg/200 mL (4 mg/mL) oral suspension, transfer eight tablets of ENTRESTO 49/51 mg film-coated tablets into a mortar. Crush the tablets into a fine powder using a pestle. Add 60 mL of Ora-Plus ® into the mortar… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 196 words ▾

3 DOSAGE FORMS AND STRENGTHS ENTRESTO film-coated tablets are supplied as unscored, ovaloid 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. 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 SPRINKLE film-coated oral pellets are contained in a hard capsule in the following strengths: ENTRESTO SPRINKLE 6/6 mg, (sacubitril 6 mg and valsartan 6 mg) consists of a white colored cap with “04” and a transparent body with “NVR” and both parts with arrows. ENTRESTO SPRINKLE 15/16 mg, (sacubitril 15 mg and valsartan 16 mg) consists of a yellow colored cap with “10” and a transparent body with “NVR” and both parts with arrows. Film-coated tablets: 24/26 mg; 49/51 mg; 97/103 mg ( 3 ) Film-coated oral pellets within capsules: 6 mg/6 mg; 15 mg/16 mg ( 3 )

⛔ Contraindications 112 words ▾

4 CONTRAINDICATIONS ENTRESTO is contraindicated: in patients with hypersensitivity to any component in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy [see Warnings and Precautions (5.2)] with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor [see Drug Interactions (7.1)] with concomitant use of aliskiren in patients with diabetes [see Drug Interactions (7.1)] Hypersensitivity to any component. ( 4 ) History of angioedema related to previous ACEi or ARB therapy.

( 4 ) Concomitant use with ACE inhibitors. ( 4 , 7.1 ) Concomitant use with aliskiren in patients with diabetes. ( 4 , 7.1 )

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS Observe for signs and symptoms of angioedema and hypotension. ( 5.2 , 5.3 ) Monitor renal function and potassium in susceptible patients. ( 5.4 , 5.5 )

5.1Fetal Toxicity ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO.

However, if there is no appropriate alternative to 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 [see Use in Specific Populations (8.1)] .

5.2Angioedema ENTRESTO may cause angioedema [see Adverse Reactions (6.1)] . If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be re-administered.

In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and take measures necessary to ensure maintenance of a patent airway.

ENTRESTO 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 [see Adverse Reactions (6.1)] . ENTRESTO must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy [see Contraindications (4)] .

ENTRESTO should not be used in patients with hereditary angioedema.

5.3Hypotension ENTRESTO lowers blood pressure and may cause symptomatic hypotension [see Adverse Reactions (6.1)] . 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 occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required.

5.4Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO [see Adverse Reactions (6.1)] . 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 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)] . 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.

5.5Hyperkalemia Through its actions on the RAAS, hyperkalemia may occur with ENTRESTO [see Adverse Reactions (6.1)] . Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hype… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Angioedema [see Warnings and Precautions (5.2)] Hypotension [see Warnings and Precautions (5.3)] Impaired Renal Function [see Warnings and Precautions (5.4)] Hyperkalemia [see Warnings and Precautions (5.5)] Adverse reactions occurring greater than or equal to 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 6,622 heart failure patients were treated with ENTRESTO in the PARADIGM-HF (vs. enalapril) and PARAGON-HF (vs. valsartan) clinical trials. Of these, 5,085 were exposed for at least 1 year.

Adult Heart Failure In PARADIGM-HF, patients were required to complete sequential enalapril and ENTRESTO run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing ENTRESTO and enalapril. During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%). During the ENTRESTO run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%).

Because of this run-in design, the adverse reaction rates described below are lower than expected in practice. In the double-blind period, safety was evaluated in 4,203 patients treated with ENTRESTO and 4,229 treated with enalapril. In PARADIGM-HF, patients randomized to ENTRESTO received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3,271 patients were treated for more than one year.

Discontinuation of therapy because of an adverse event during the double-blind period occurred in 450 (10.7%) of ENTRESTO-treated patients and 516 (12.2%) of patients receiving enalapril. Adverse reactions occurring at an incidence of greater than or equal to 5% in patients who were treated with ENTRESTO in the double-blind period of PARADIGM-HF are shown in Table 3. In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and ENTRESTO run-in periods.

In the double-blind period, the incidence of angioedema was higher in patients treated with ENTRESTO than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patients was 2.4% with ENTRESTO and 0.5% with enalapril [see Warnings and Precautions (5.2)] . Orthostasis was reported in 2.1% of patients treated with ENTRESTO compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF.

Falls were reported in 1.9% of patients treated with ENTRESTO compared to 1.3% of patients treated with enalapril. Table 3: Adverse Reactions Reported in greater than or equal to 5% of Patients Treated with ENTRESTO in the Double-Blind Period of PARADIGM-HF ENTRESTO (n = 4,203) % Enalapril (n = 4,229) % Hypotension 18 12 Hyperkalemia 12 14 Cough 9 13 Dizziness 6 5 Renal failure/acute renal failure 5 5 In PARAGON-HF, no new adverse reactions were identified. Pediatric Heart Failure The adverse reactions observed in pediatric patients 1 year to less than 18 years old who received treatment with ENTRESTO were consistent with those observed in adult patients.

Laboratory Abnormalities Hemoglobin and Hematocrit Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 5% of both ENTRESTO- and enalapril-treated patients in the d… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions ~1 min read ▾

7 DRUG INTERACTIONS Avoid concomitant use with aliskiren in patients with estimated glomerular filtration rate (eGFR) less than 60. ( 7.1 ) Potassium-sparing diuretics: May lead to increased serum potassium. ( 7.2 ) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): May lead to increased risk of renal impairment. ( 7.3 ) Lithium: Increased risk of lithium toxicity. ( 7.4 )

7.1Dual Blockade of the Renin-Angiotensin-Aldosterone System Concomitant use of ENTRESTO with an ACE inhibitor is contraindicated because of the increased risk of angioedema [see Contraindications (4)] . Avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan. The concomitant use of ENTRESTO with aliskiren is contraindicated in patients with diabetes [see Contraindications (4)] .

Avoid use with aliskiren in patients with renal impairment (eGFR less than 60 mL/min/1.73 m 2 ).

7.2Potassium-Sparing Diuretics As with other drugs that block angiotensin II or its effects, 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 [see Warnings and Precautions (5.5)] .

7.3Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of 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.

7.4Lithium 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.

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 ) Severe Hepatic Impairment: Use not recommended. ( 2.8 , 8.6 )

8.1Pregnancy Risk Summary ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death ( see Clinical Considerations ). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

In animal reproduction studies, ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits ( see Data ). When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO. However, if there is no appropriate alternative to 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.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to ENTRESTO for hypotension, oliguria, and hyperkalemia.

In neonates with a history of in utero exposure to ENTRESTO, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [LBQ657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively).

ENTRESTO is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an ENTRESTO dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of ENTRESTO are attributed to the angiotensin receptor antagonist activity. Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with ENTRESTO during organogenesis, gestation and lactation may affect pup development and survival.

8.2Lactation Risk Summary There is no information regarding the p… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~3 min read ▾

8.1Pregnancy Risk Summary ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death ( see Clinical Considerations ). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

In animal reproduction studies, ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits ( see Data ). When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO. However, if there is no appropriate alternative to 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.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to ENTRESTO for hypotension, oliguria, and hyperkalemia.

In neonates with a history of in utero exposure to ENTRESTO, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [LBQ657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively).

ENTRESTO is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an ENTRESTO dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of ENTRESTO are attributed to the angiotensin receptor antagonist activity. Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with ENTRESTO during organogenesis, gestation and lactation may affect pup development and survival.

🧒 Pediatric Use ~2 min read ▾

8.4Pediatric Use The safety and effectiveness of ENTRESTO have been established for the treatment of heart failure in pediatric patients 1 year to less than 18 years. Use of ENTRESTO was evaluated in a multinational, randomized, double-blind trial comparing ENTRESTO and enalapril in 375 patients aged 1 month to less than 18 years (ENTRESTO n = 187; Enalapril n = 188) (PANORAMA-HF) [see Clinical Studies (14.2)] . The safety profile in pediatric patients (1 year to less than 18 years) receiving ENTRESTO was similar to that seen in adult patients.

Limited safety and efficacy data in patients aged 1 month to less than 1 year were inadequate to support conclusions on safety and efficacy in this age group. Juvenile Animal Toxicity Data Sacubitril given orally to juvenile rats from postnatal day (PND) 7 to PND 35 or PND 70 (an age approximately equivalent to neonatal through pre-pubertal development or adulthood in humans) at doses greater than or equal to 400 mg/kg/day (approximately 2-fold the AUC exposure to the active metabolite of sacubitril, LBQ657, at an ENTRESTO pediatric clinical dose of 3.1 mg/kg twice daily) resulted in decreases in body weight, bone length, and bone mass.

The decrease in body weight was transient from PND 10 to PND 20 and the effects for most bone parameters were reversible after treatment stopped. Exposure at the No-Observed-Adverse-Effect-Level (NOAEL) of 100 mg/kg/day was approximately 0.5-fold the AUC exposure to LBQ657 at the 3.1 mg/kg twice daily dose of ENTRESTO. The mechanism underlying bone effects in rats and the translatability to pediatric patients are unknown.

Valsartan given orally to juvenile rats from PND 7 to PND 70 (an age approximately equivalent to neonatal through adulthood in humans) produced persistent, irreversible kidney damage at all dose levels. Exposure at the lowest tested dose of 1 mg/kg/day was approximately 0.2-fold the exposure at 3.1 mg/kg twice daily dose of ENTRESTO based on AUC. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life.

This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age. It is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney.

🧓 Geriatric Use 120 words ▾

8.5Geriatric Use There were 4,143 and 3,971 heart failure patients 65 years of age and older in PARADIGM-HF and PARAGON-HF, respectively [see Clinical Studies (14)] . Of the total number of ENTRESTO-treated patients, 2,087 (49.6%) and 1,995 (82.9%) were 65 years of age and older, while 786 (18.7%) and 1,100 (45.7%) were 75 years of age and older in PARADIGM-HF and PARAGON-HF, respectively. No overall differences in safety or effectiveness of ENTRESTO have been observed between patients 65 years of age and older and younger adult patients in either study.

No relevant pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population [see Clinical Pharmacology (12.3)] .

🆘 Overdosage 81 words ▾

10 OVERDOSAGE Limited data are available with regard to overdosage in human subjects with ENTRESTO. In healthy volunteers, a single dose of ENTRESTO 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of ENTRESTO.

Symptomatic treatment should be provided. ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding.

🧬 Clinical Pharmacology ~3 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action ENTRESTO contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. ENTRESTO inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan. The cardiovascular and renal effects of ENTRESTO in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan.

Valsartan inhibits the effects of angiotensin II by selectively blocking the AT 1 receptor, and also inhibits angiotensin II-dependent aldosterone release.

12.2Pharmacodynamics The pharmacodynamic effects of ENTRESTO were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of ENTRESTO resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan.

In a 21-day study in HFrEF patients, ENTRESTO significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. ENTRESTO also blocked the AT 1 -receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, ENTRESTO decreased plasma NT-proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.

In PARAMOUNT, a randomized, double-blind, 36-week study in patients with heart failure with LVEF greater than or equal to 45% comparing 97/103 mg of ENTRESTO (n=149) to 160 mg of valsartan (n =152) twice-daily, ENTRESTO decreased NT-proBNP by 17% while valsartan increased NT-proBNP by 8% at Week 12 (p = 0.005). In PARAGON-HF, ENTRESTO decreased NT-proBNP by 24% (Week 16) and 19% (Week 48) compared to 6% and 3% reductions on valsartan, respectively. In PANORAMA-HF, a reduction in NT-proBNP was observed at Weeks 4 and 12 for ENTRESTO (40% and 50%) compared to baseline.

The NT-proBNP levels continued to decrease over the duration of the study with a reduction of 65% for ENTRESTO at Week 52 compared to baseline. QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of ENTRESTO 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization. Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF).

Administration of ENTRESTO 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 or CSF Aβ 1-42 . The clinical relevance of this finding is unknown [see Nonclinical Toxicology (13)] . Blood Pressure: Addition of a 50 mg single dose of sildenafil to ENTRESTO at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (approximately 5/4 mmHg, systolic/diastolic BP) compared to administration of ENTRESTO alone.

Co-administration of ENTRESTO did not significantly alter the BP effect of intravenous nitroglycerin.

12.3Pharmacokinetics 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 greater than o… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 106 words ▾

12.1Mechanism of Action ENTRESTO contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. ENTRESTO inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan. The cardiovascular and renal effects of ENTRESTO in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan.

Valsartan inhibits the effects of angiotensin II by selectively blocking the AT 1 receptor, and also inhibits angiotensin II-dependent aldosterone release.

📦 How Supplied / Storage and Handling 139 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING ENTRESTO (sacubitril/valsartan) tablets are unscored, ovaloid, biconvex, and film-coated. ENTRESTO film-coated oral pellets are round, biconvex in shape, and provided in a hard capsule. All strengths are packaged in bottles as described below.

ENTRESTO Tablets Sacubitril/valsartan mg/mg Color Debossment Side 1/side 2 NDC 0078-XXXX-XX Bottle of 60 Bottle of 180 24/26 Violet white NVR/LZ 0659-20 0659-67 49/51 Pale yellow NVR/L1 0777-20 0777-67 97/103 Light pink NVR/L11 0696-20 0696-67 ENTRESTO SPRINKLE Sacubitril/valsartan mg/mg Color Print NDC 0078-XXXX-XX Bottle of 60 6/6 White cap and transparent body “NVR” and both parts with arrows and “04” 1231-20 15/16 Yellow cap and transparent body “NVR” and both parts with arrows and “10” 1238-20 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) [see USP Controlled Room Temperature].

Protect from moisture.

📦 Storage and Handling 25 words ▾

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) [see USP Controlled Room Temperature]. Protect from moisture.

📋 Description ~2 min read ▾

11 DESCRIPTION ENTRESTO (sacubitril and valsartan) is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker. ENTRESTO contains a complex comprised of anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively. Following oral administration, the complex dissociates into sacubitril (which is further metabolized to LBQ657) and valsartan.

The complex is chemically described as Octadecasodiumhexakis(4-{[(1 S ,3 R )-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)hexakis( N -pentanoyl- N -{[2´-(1 H -tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)—water (1/15). Its empirical formula (hemipentahydrate) is C 48 H 55 N 6 O 8 Na 3

2.5H 2 O. Its molecular mass is 957.99 g/mol and its schematic structural formula is: ENTRESTO is available as film-coated tablets for oral administration, 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. The tablet inactive ingredients are colloidal silicon dioxide, crospovidone, low-substituted hydroxypropylcellulose, magnesium stearate (vegetable origin), microcrystalline cellulose, and talc.

The film-coat inactive ingredients are hypromellose, iron oxide red (E172), polyethylene glycol 4000, talc, and titanium dioxide (E171). The film-coat for the 24 mg of sacubitril and 26 mg of valsartan tablet and the 97 mg of sacubitril and 103 mg of valsartan tablet also contains iron oxide black (E172). The film-coat for the 49 mg of sacubitril and 51 mg of valsartan tablet contains iron oxide yellow (E172).

ENTRESTO SPRINKLE is available as film-coated oral pellets within capsules for oral administration, containing 6 mg of sacubitril and 6 mg of valsartan; and 15 mg of sacubitril and 16 mg of valsartan. The oral pellet inactive ingredients are colloidal silicon dioxide, hydroxypropylcellulose, magnesium stearate (vegetable origin), microcrystalline cellulose, and talc. The film-coat inactive ingredients are basic butylated methacrylate copolymer, sodium lauryl sulfate, stearic acid, and talc.

The capsule shell inactive ingredients are hypromellose and titanium dioxide (E171). The capsule shell for the 15 mg of sacubitril and 16 mg of valsartan oral pellets also contains iron oxide yellow (E172). The printing ink contains shellac, propylene glycol, iron oxide red (E172), ammonia solution (concentrated), and potassium hydroxide.

Valsartan structural formula

💬 Information for Patients 155 words ▾

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use). 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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] . Lactation: Advise patients that breastfeeding is not recommended during treatment with ENTRESTO [see Use in Specific Populations (8.2)] . 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 [see Contraindications (4) and Warnings and Precautions (5.2)] . Administering ENTRESTO SPRINKLE oral pellets: Advise patients to read and follow the Instructions for Use for ENTRESTO SPRINKLE. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2024-28

🧬 Pharmacokinetics ~3 min read ▾

12.3Pharmacokinetics 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 greater than or equal to 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. Following twice-daily dosing of ENTRESTO, steady-state levels of sacubitril, LBQ657, and valsartan are reached in 3 days.

At steady state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold. ENTRESTO administration with food has no clinically significant effect on the systemic exposures of sacubitril, LBQ657, or valsartan. Although there is a decrease in exposure to valsartan when ENTRESTO is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect.

ENTRESTO can therefore be administered with or without food. Distribution Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94% to 97%). Based on the comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent (0.28%).

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 (less than 10%). Elimination Following oral administration, 52% to 68% of sacubitril (primarily as LBQ657) and approximately 13% of valsartan and its metabolites are excreted in urine; 37% to 48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces. Sacubitril, LBQ657, and valsartan are eliminated from plasma with a mean elimination half-life (T 1/2 ) of approximately 1.4 hours, 11.5 hours, and 9.9 hours, respectively.

Linearity/Nonlinearity The pharmacokinetics of sacubitril, LBQ657, and valsartan were linear over an ENTRESTO dose range of 24 mg sacubitril/26 mg valsartan to 194 mg sacubitril/206 mg valsartan. Drug Interactions: Effect of Co-administered Drugs on ENTRESTO: Because CYP450 enzyme-mediated metabolism of sacubitril and valsartan is minimal, coadministration with drugs that impact CYP450 enzymes is not expected to affect the pharmacokinetics of ENTRESTO. Dedicated drug interaction studies demonstrated that coadministration of furosemide, warfarin, digoxin, carvedilol, a combination of levonorgestrel/ethinyl estradiol, amlodipine, omeprazole, hydrochlorothiazide (HCTZ), metformin, atorvastatin, and sildenafil, did not alter the systemic exposure to sacubitril, LBQ657 or valsartan.

Effect of ENTRESTO on Co-administered Drugs: In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. The effects of ENTRESTO on the pharmacokinetics of coadministered drugs are summarized in Figure 1. Figure 1: Effect of ENTRESTO on Pharmacokinetics of Coadministered Drugs Specific Populations Effect of specific populations on the pharmacokinetics of LBQ657 and valsartan are shown in Figure 2.

Figure 2: Pharmacokinetics of ENTRESTO in Specific Populations Note: Child-Pugh Classification was used for hepatic impairment. Pediatric Patients: The pharmacokinetics of ENTRESTO were evaluated in pediatric heart failure patients 1 to less than 18 years old administered oral doses of 0.8 mg/kg and 3.1 mg/kg of ENTRESTO. Pharmacokinetic data indicated that exposure to ENTRESTO in pediatric and adult patients is similar.

F… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics ~2 min read ▾

12.2Pharmacodynamics The pharmacodynamic effects of ENTRESTO were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of ENTRESTO resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan.

In a 21-day study in HFrEF patients, ENTRESTO significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. ENTRESTO also blocked the AT 1 -receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, ENTRESTO decreased plasma NT-proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.

In PARAMOUNT, a randomized, double-blind, 36-week study in patients with heart failure with LVEF greater than or equal to 45% comparing 97/103 mg of ENTRESTO (n=149) to 160 mg of valsartan (n =152) twice-daily, ENTRESTO decreased NT-proBNP by 17% while valsartan increased NT-proBNP by 8% at Week 12 (p = 0.005). In PARAGON-HF, ENTRESTO decreased NT-proBNP by 24% (Week 16) and 19% (Week 48) compared to 6% and 3% reductions on valsartan, respectively. In PANORAMA-HF, a reduction in NT-proBNP was observed at Weeks 4 and 12 for ENTRESTO (40% and 50%) compared to baseline.

The NT-proBNP levels continued to decrease over the duration of the study with a reduction of 65% for ENTRESTO at Week 52 compared to baseline. QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of ENTRESTO 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization. Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF).

Administration of ENTRESTO 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 or CSF Aβ 1-42 . The clinical relevance of this finding is unknown [see Nonclinical Toxicology (13)] . Blood Pressure: Addition of a 50 mg single dose of sildenafil to ENTRESTO at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (approximately 5/4 mmHg, systolic/diastolic BP) compared to administration of ENTRESTO alone.

Co-administration of ENTRESTO did not significantly alter the BP effect of intravenous nitroglycerin.

🔬 Clinical Studies ~3 min read ▾

14 CLINICAL STUDIES Dosing in clinical trials was based on the total amount of both components of ENTRESTO, i.e., 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.

14.1Adult Heart Failure PARADIGM-HF PARADIGM-HF was a multinational, randomized, double-blind trial comparing ENTRESTO and 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 four weeks and on maximally tolerated doses of beta-blockers. Patients with a systolic blood pressure of less than 100 mmHg at screening were excluded.

The primary objective of PARADIGM-HF was to determine whether ENTRESTO, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to an RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF). After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice-daily, followed by ENTRESTO 100 mg twice-daily, increasing to 200 mg twice-daily.

Patients who successfully completed the sequential run-in periods were randomized to receive either ENTRESTO 200 mg (N = 4,209) twice-daily or enalapril 10 mg (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.

The population was 66% Caucasian, 18% Asian, and 5% Black; the mean age was 64 years and 78% were male. At randomization, 70% of patients were NYHA Class II, 24% were NYHA Class III, and 0.7% were NYHA Class IV. The mean left ventricular ejection fraction was 29%.

The underlying cause of heart failure was coronary artery disease in 60% of patients; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR less than 60 mL/min/1.73m 2 , and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Few patients had an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) (15%).

PARADIGM-HF demonstrated that ENTRESTO, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril), in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, 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; see Table 4 and Figure 3. Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure, which accounted for 26%.

ENTRESTO also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], p = 0.0009) (Table 4). This finding was driven entirely by a lower incidence of cardiovascular mortality on ENTRESTO. Table 4: Treatment Effect for the Primary Composite Endpoint, Its Components, and All-cause Mortality in PARADIGM-HF * Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity. ** Includes patients who had heart failure hospitalization prior to death.

ENTRESTO N = 4,187 n (%) Enalapril N = 4,212 n (%) Hazard Ratio (95% CI) p -value Primary composite endpoint of cardiovascular death or heart failure hospitalization 914 (21.8) 1,117 (26.5) 0.80 (0.73, 0.87) < 0.0001 Cardiovascular death as first event 377 (9.0) 459 (10.9) Heart failure hospitalization as first event 537 (12.8) 658 (15.6) Number of patients with events: * Cardiovascular death ** 558 (13.3) 693 (16.5) 0.80 (0.71, 0.89) Heart failure hospitalizations 537 (12.8) 658 (15.6) 0.79 (0.… [Excerpted — this section continues on DailyMed.]

🧪 Nonclinical Toxicology ~1 min read ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for ENTRESTO. The LBQ657 C max at the high dose (HD) of 1200 mg/kg/day in male and female mice was, respectively, 14 and 16 times that in humans at the MRHD. The LBQ657 C max in male and female rats at the HD of 400 mg/kg/day was, respectively, 1.7 and 3.5 times that at the MRHD.

The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the MRHD on a mg/m 2 basis. Mutagenicity and clastogenicity studies conducted with ENTRESTO, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level. Impairment of Fertility ENTRESTO did not show any effects on fertility in rats up to a dose of 73 mg sacubitril/77 mg valsartan/kg/day (≤ 1.0-fold and ≤ 0.18-fold the MRHD on the basis of the AUCs of valsartan and LBQ657, respectively).

13.2Animal Toxicology and/or Pharmacology The effects of ENTRESTO on amyloid-β concentrations in CSF and brain tissue were assessed in young (2 to 4 years old) cynomolgus monkeys treated with ENTRESTO (24 mg sacubitril/26 mg valsartan/kg/day) for 2 weeks. In this study, ENTRESTO affected CSF Aβ clearance, increasing CSF Aβ 1-40, 1-42, and 1-38 levels in CSF; there was no corresponding increase in Aβ levels in the brain. In addition, in a toxicology study in cynomolgus monkeys treated with ENTRESTO at 146 mg sacubitril/154 mg valsartan/kg/day for 39-weeks, there was no amyloid-β accumulation in the brain.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 176 words ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for ENTRESTO. The LBQ657 C max at the high dose (HD) of 1200 mg/kg/day in male and female mice was, respectively, 14 and 16 times that in humans at the MRHD. The LBQ657 C max in male and female rats at the HD of 400 mg/kg/day was, respectively, 1.7 and 3.5 times that at the MRHD.

The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the MRHD on a mg/m 2 basis. Mutagenicity and clastogenicity studies conducted with ENTRESTO, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level. Impairment of Fertility ENTRESTO did not show any effects on fertility in rats up to a dose of 73 mg sacubitril/77 mg valsartan/kg/day (≤ 1.0-fold and ≤ 0.18-fold the MRHD on the basis of the AUCs of valsartan and LBQ657, respectively).

📄 Patient Package Insert ~3 min read ▾

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: April 2024 PATIENT INFORMATION ENTRESTO (en-TRESS-toh) (sacubitril and valsartan) tablets, for oral use ENTRESTO SPRINKLE (en-TRESS-toh SPRINK-el) (sacubitril and valsartan) oral pellets What is the most important information I should know about ENTRESTO or ENTRESTO SPRINKLE?

ENTRESTO or ENTRESTO SPRINKLE can harm or cause death to your unborn baby. Talk to your doctor about other ways to treat heart failure if you plan to become pregnant. Tell your doctor right away if you become pregnant during treatment with ENTRESTO or ENTRESTO SPRINKLE.

What is ENTRESTO or ENTRESTO SPRINKLE? ENTRESTO or ENTRESTO SPRINKLE is a prescription medicine used to treat: adults with long-lasting (chronic) heart failure to help reduce the risk of death and hospitalization. ENTRESTO or ENTRESTO SPRINKLE works better when the heart cannot pump a normal amount of blood to the body. certain children 1 year of age and older who have symptomatic heart failure.

It is not known if ENTRESTO or ENTRESTO SPRINKLE is safe and effective in children under 1 year of age. Do not take ENTRESTO or ENTRESTO SPRINKLE if you: are allergic to any of the ingredients in ENTRESTO or ENTRESTO SPRINKLE. See the end of this Patient Information leaflet for a complete list of ingredients in ENTRESTO or ENTRESTO SPRINKLE. have had an allergic reaction, including swelling of your face, lips, tongue, throat, or trouble breathing while taking a type of medicine called an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB). take an ACE inhibitor medicine.

Do not take ENTRESTO or ENTRESTO SPRINKLE for at least 36 hours before or after you take an ACE inhibitor medicine . Talk with your doctor or pharmacist before taking ENTRESTO or ENTRESTO SPRINKLE if you are not sure if you take an ACE inhibitor medicine. have diabetes and take a medicine that contains aliskiren. Before taking ENTRESTO or ENTRESTO SPRINKLE, tell your doctor about all of your medical conditions, including if you: have a history of hereditary angioedema have kidney or liver problems have diabetes are pregnant or plan to become pregnant.

See “What is the most important information I should know about ENTRESTO or ENTRESTO SPRINKLE?” are breastfeeding or plan to breastfeed. It is not known if ENTRESTO or ENTRESTO SPRINKLE passes into your breast milk. You should not breastfeed during treatment with ENTRESTO or ENTRESTO SPRINKLE.

You and your doctor should decide if you will take ENTRESTO or ENTRESTO SPRINKLE or breastfeed. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking ENTRESTO or ENTRESTO SPRINKLE with certain other medicines may affect each other.

Taking ENTRESTO or ENTRESTO SPRINKLE with other medicines can cause serious side effects. Especially tell your doctor if you take: potassium supplements or a salt substitute nonsteroidal anti-inflammatory drugs (NSAIDs) lithium other medicines for high blood pressure or heart problems, such as an ACE inhibitor, ARB, or aliskiren Keep a list of your medicines to show your doctor and pharmacist when you get a new medicine. How should I take ENTRESTO or ENTRESTO SPRINKLE?

Take ENTRESTO or ENTRESTO SPRINKLE exactly as your doctor tells you to take it. Take ENTRESTO or ENTRESTO SPRINKLE 2 times each day. Your doctor may change your dose of ENTRESTO or ENTRESTO SPRINKLE during treatment.

If you or your child cannot swallow tablets, or if tablets are not available in the prescribed strength, you or your child may take ENTRESTO tablets prepared as a liquid (oral) suspension or may take ENTRESTO SPRINKLE. If you or your child switches between taking ENTRESTO and the liquid suspension prepared from ENTRESTO tablets, or to ENTRESTO SPRINKLE, your doctor will adjust the dose as needed. If you or your child are prescribed ENTRESTO tablets to be prepared as a liqu… [Excerpted — this section continues on DailyMed.]

📖 Instructions for Use ~3 min read ▾

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Issued: April 2024 INSTRUCTIONS FOR USE ENTRESTO ® SPRINKLE [en-TRESS-toh SPRINK-el] (sacubitril and valsartan) oral pellets This Instructions for Use contains information on how to take or give ENTRESTO SPRINKLE.

Read this Instructions for Use before you or your child start taking ENTRESTO SPRINKLE, and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your or your child’s medical condition or treatment.

Ask your doctor or pharmacist if you have any questions about how to take or give ENTRESTO SPRINKLE. Important Information You Need to Know Before Taking or Giving ENTRESTO SPRINKLE. ENTRESTO SPRINKLE contains oral pellets inside of a capsule.

The capsule must be opened and the oral pellets inside must be sprinkled on soft food before you take or give ENTRESTO SPRINKLE. Do not swallow the capsule or the empty capsule shells. Do not chew or crush the oral pellets.

Use all of the oral pellets in the capsule. Do not use part of a capsule to try to prepare a dose. Do not take or give ENTRESTO SPRINKLE through a nasogastric tube (NG Tube), gastrostomy tube (G Tube), or other feeding tubes because it may clog the tube.

ENTRESTO SPRINKLE is available in 2 strengths: 6 mg/6 mg (sacubitril 6 mg and valsartan 6 mg) and 15 mg/16 mg (sacubitril 15 mg and valsartan 16 mg). You can see the difference between the 2 strengths by the color of the capsule cap and the imprint on it. The capsule containing the 6 mg/6 mg strength has a white cap with the number “04” printed on it.

The capsule containing the 15 mg/16 mg strength has a yellow cap with the number “10” printed on it. Check to make sure you have received the prescribed strength of ENTRESTO SPRINKLE before taking or giving the dose. Preparing to Take or Give ENTRESTO SPRINKLE Supplies needed: A clean small bowl, cup, or spoon to measure and hold the soft food that you or your child likes, such as applesauce, yogurt, or pudding.

Bottle with capsules containing ENTRESTO SPRINKLE. Step 1. Wash and dry your hands ( Figure A ).

Figure A Step 2. Place the following items on a clean flat surface: A small bowl, cup or spoon with about 1 to 2 teaspoonfuls of soft food that you or your child likes for each capsule of ENTRESTO SPRINKLE prescribed (see Figure B ). Bottle with capsules containing ENTRESTO SPRINKLE.

Check that you have the right strength of ENTRESTO SPRINKLE. Figure B Step 3. Open the bottle and remove the number of capsules that you will need for your or your child’s prescribed dose of ENTRESTO SPRINKLE.

Step 4. To open the capsule (see Figure C and Figure D ): Hold the capsule upright (with the colored cap on top) so that the oral pellets are in the bottom of the capsule ( Figure C ). Hold the capsule over the soft food.

Gently pinch the middle of the capsule and pull slightly to separate the 2 ends of the capsule ( Figure D ). Take care not to spill the contents while opening the capsule. Figure C Figure D Step 5.

Empty all of the oral pellets from the capsule onto the food ( Figure E ). Check the capsule to make sure that you did not miss any oral pellets. Tap the capsule to remove any remaining oral pellets.

Repeat Steps 4 and 5 if you need more than 1 capsule for the prescribed dose. Figure E Step 6. Taking or Giving ENTRESTO SPRINKLE Take or give the food with the oral pellets right away after adding the oral pellets ( Figure F ).

Make sure that you or your child eat all of the food containing the oral pellets. Make sure that you or your child do not chew the oral pellets to avoid a change of taste. Figure F Step 7.

Cleaning Up and Disposing of (throwing away) ENTRESTO SPRINKLE Throw away the empty shells of the capsule in the household trash ( Figure G ). Wash your hands and all the items used to take or give ENTRESTO SPRINKLE. Ask your pharmacist how to throw away expired medicines or medicines you no longer u… [Excerpted — this section continues on DailyMed.]

📄 Recent Major Changes 9 words ▾

Dosage and Administration ( 2.3 , 2.5 ) 4/2024

📄 Package Label / Principal Display Panel ~2 min read ▾

PRINCIPAL DISPLAY PANEL NDC 0078-0659-20 Entresto ® (sacubitril/valsartan) tablets 24 mg / 26 mg Rx only 60 Tablets NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0659-20 Entresto® (sacubitril/valsartan) tablets 24 mg / 26 mg Rx only 60 Tablets NOVARTIS

PRINCIPAL DISPLAY PANEL NDC 0078-0777-20 Entresto ® (sacubitril/valsartan) tablets 49 mg / 51 mg Rx only 60 Tablets NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0777-20 Entresto® (sacubitril/valsartan) tablets 49 mg / 51 mg Rx only 60 Tablets NOVARTIS

PRINCIPAL DISPLAY PANEL NDC 0078-0696-20 Entresto ® (sacubitril/valsartan) tablets 97 mg / 103 mg Rx only 60 Tablets NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0696-20 Entresto® (sacubitril/valsartan) tablets 97 mg / 103 mg Rx only 60 Tablets NOVARTIS

PRINCIPAL DISPLAY PANEL NDC 0078-1231-20 Entresto ® Sprinkle (sacubitril/valsartan) oral pellets 6 mg/6 mg Open capsule shell to administer pellets. Do Not swallow capsule whole. Do Not chew or crush pellets.

Rx only 60 Capsules NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-1231-20 Entresto® Sprinkle (sacubitril/valsartan) oral pellets 6 mg/6 mg Open capsule shell to administer pellets. Do Not swallow capsule whole. Do Not chew or crush pellets.

Rx only 60 Capsules NOVARTIS

PRINCIPAL DISPLAY PANEL NDC 0078-1238-20 Entresto ® Sprinkle (sacubitril/valsartan) oral pellets 15 mg/16 mg Open capsule shell to administer pellets. Do Not swallow capsule whole. Do Not chew or crush pellets.

Rx only 60 Capsules NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-1238-20 Entresto® Sprinkle (sacubitril/valsartan) oral pellets 15 mg/16 mg Open capsule shell to administer pellets. Do Not swallow capsule whole. Do Not chew or crush pellets.

Rx only 60 Capsules NOVARTIS

PRINCIPAL DISPLAY PANEL Physician Sample Not for Sale Entresto ® (sacubitril/valsartan) tablets 24 mg / 26 mg Rx only 28 Tablets NOVARTIS PRINCIPAL DISPLAY PANEL Physician Sample Not for Sale Entresto® (sacubitril/valsartan) tablets 24 mg / 26 mg Rx only 28 Tablets NOVARTIS

PRINCIPAL DISPLAY PANEL Physician Sample Not for Sale Entresto ® (sacubitril/valsartan) tablets 49 mg / 51 mg Rx only 28 Tablets NOVARTIS PRINCIPAL DISPLAY PANEL Physician Sample Not for Sale Entresto® (sacubitril/valsartan) tablets 49 mg / 51 mg Rx only 28 Tablets NOVARTIS

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

Medicaid utilization & spend

📍 This exact package only: Medicaid data is reported per full 11-digit NDC — labeler, product and pack size — so every number here is for this package alone, not the drug overall. Other pack sizes report separately.
💊 Pharmacy benefit only: These are Medicaid outpatient pharmacy claims, billed by NDC. They exclude the medical benefit — clinic- or hospital-administered drugs billed under HCPCS J-codes — so drugs used mostly that way (e.g. Avastin, Lucentis, Keytruda) can look low or missing here. That’s expected, not an error.
📅 Q1 2025 – Q1 2026 · 5 quarters of data
ⓘ The newest quarter is usually incomplete when first published; states restate recent quarters in later CMS releases, so the latest figures typically revise upward. State coverage-policy changes can also shift quarter-to-quarter totals.
Prescriptions last 4 qtrs
40
Units reimbursed last 4 qtrs
3.6K
Gross reimbursed last 4 qtrs
$41.5K
Avg / prescription
$1,036.66
Avg / unit
$11.5313
Latest quarter Q1 2026
13Rx
Medicaid pays / ea
$11.5313
gross reimbursed
vs
NADAC / ea
$11.6067
acquisition cost
=
Spread
−$0.0754
-1% vs cost
What Medicaid paid per ea (before rebates; includes the pharmacy’s dispensing fee) compared with NADAC — the average price pharmacies pay to buy the drug. A positive spread means Medicaid reimbursed more than the purchase price, before manufacturer rebates.
Fee-for-service vs managed care ⓘ
100% FFS
Fee-for-service · 40 Rx Managed care · 0 Rx
State Medicaid map
Alaska: no data reported AK Maine: no data reported ME Washington: no data reported WA Idaho: no data reported ID Montana: no data reported MT North Dakota: no data reported ND Minnesota: no data reported MN Wisconsin: no data reported WI Michigan: no data reported MI New York: 2,096 units · 10.7 per 100k residents NY Vermont: no data reported VT New Hampshire: no data reported NH Oregon: no data reported OR Nevada: no data reported NV Wyoming: no data reported WY South Dakota: no data reported SD Iowa: no data reported IA Illinois: no data reported IL Indiana: no data reported IN Ohio: no data reported OH Pennsylvania: no data reported PA New Jersey: no data reported NJ Massachusetts: no data reported MA California: 1,500 units · 3.8 per 100k residents CA Utah: no data reported UT Colorado: no data reported CO Nebraska: no data reported NE Missouri: no data reported MO Kentucky: no data reported KY West Virginia: no data reported WV Virginia: no data reported VA Maryland: no data reported MD Connecticut: no data reported CT Rhode Island: no data reported RI Arizona: no data reported AZ New Mexico: no data reported NM Kansas: no data reported KS Arkansas: no data reported AR Tennessee: no data reported TN North Carolina: no data reported NC South Carolina: no data reported SC Delaware: no data reported DE Oklahoma: no data reported OK Louisiana: no data reported LA Mississippi: no data reported MS Alabama: no data reported AL Georgia: no data reported GA D.C.: no data reported DC Hawaii: no data reported HI Texas: no data reported TX Florida: no data reported FL
Units reimbursed · per 100k residents
3.810.7
gray = no data reported ⓘ
Colors are per 100,000 residents, so big states don’t automatically dominate. Tap or hover a state for its actual totals.
Tap or hover a state
…for its Medicaid breakdown
🏆 Top states by units · per 100k residents
1 New York 10.7 /100k
2 California 3.8 /100k
National units — by quarter
💵 About the dollar figures: “reimbursed” is what Medicaid paid pharmacies before confidential manufacturer rebates, so the program’s real net cost is lower than these numbers. Fee-for-service and managed-care claims are combined unless split above. Source: CMS State Drug Utilization Data; per-100k rates use 2023 Census population estimates.

Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Entresto — the program that covers self-administered drugs. 1 manufacturer.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Entresto. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$39.74M
Claims incl. refills
122.1K
Beneficiaries
103.7K
Spend / beneficiary
$383.36
Spend / claim
$325.48
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.

Reported adverse events (FAERS)

Read carefully: FAERS reports are voluntary and unverified. Counts are not incidence, do not establish causation, are subject to reporting bias, and cannot be used to compare one drug to another. Shown for signal context only. Reports for Sacubitril and Valsartan — the ingredient across all brands.

Top reported reactions

Hypotension11,577
Death9,146
Dyspnoea8,999
Dizziness8,718
Fatigue8,713
Cough7,867
Weight Decreased5,209

Age at onset

Neonate11
Infant1
Child3
Adolescent1
Adult1,973
Elderly3,830

Reporter sex

0 reports
Male · 64%
Female · 36%
Unknown · 0%

Serious outcomes

Hospitalization20,918
Death14,147
Life-threatening2,392
Disabling1,083
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 19,265 1,425
Most recent year is provisional (FAERS lags ~3 months).
Where does this data come from?
Adverse-event reports from the FDA Adverse Event Reporting System (FAERS) via openFDA. FAERS reports are voluntary and unverified — counts are not incidence and don’t establish causation.
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For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.