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 2.5 H 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

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. 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

Adult 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

Pediatric 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.

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 Film-coated oral pellets within capsules: 6 mg/6 mg; 15 mg/16 mg

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. Adjust adult doses every 2 to 4 weeks to the target maintenance dose, as tolerated by the patient. 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. patients with severe renal impairment. patients with moderate hepatic impairment

General 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

Adult 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

Pediatric 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 is recommended in these patients. Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan . ‡ Doses of 72 mg/78 mg can be achieved using three 24 mg/26 mg tablets . 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 . * 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) 2.4 Preparation 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 and triturate gently with pestle for 10 minutes, to form a uniform suspension. Add 140 mL of Ora-Sweet ® SF into mortar and triturate with pestle for another 10 minutes, to form a uniform suspension. Transfer the entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle. Place a press-in bottle adapter and close the bottle with a child resistant cap. The oral suspension can be stored for up to 15 days. Do not store above 25°C (77°F) and do not refrigerate. Shake before each use. * Ora-Sweet SF ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc

Preparation and Administration of Oral Pellets ENTRESTO SPRINKLE are oral pellets contained within capsules. Do not swallow the capsules. Do not chew or crush the oral pellets. ENTRESTO SPRINKLE can also be substituted in patients unable to swallow tablets. Use the entire contents of the capsules to achieve the dose. To administer ENTRESTO oral pellets, open the capsule and sprinkle the full content onto 1 to 2 teaspoons of soft food. Consume the food containing the oral pellets immediately after adding them. Empty capsule shells must be discarded after use and not swallowed. Do not administer ENTRESTO oral pellets via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction of enteral tubes

Dose Adjustment for Patients Not Taking an ACE inhibitor or ARB or Previously Taking Low Doses of These Agents In patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents, start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose every 2 to 4 weeks in adults and every 2 weeks in pediatric patients to follow the recommended dose escalation thereafter . Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets

Dose Adjustment for Severe Renal Impairment In adults and pediatric patients with severe renal impairment estimated glomerular filtration rate (eGFR less than 30 mL/min/1.73 m 2 ), start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter . Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets . No starting dose adjustment is needed for mild or moderate renal impairment

Dose Adjustment for Hepatic Impairment In adults and pediatric patients with moderate hepatic impairment (Child-Pugh B classification), start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter . Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets . No starting dose adjustment is needed for mild hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

Observe for signs and symptoms of angioedema and hypotension. Monitor renal function and potassium in susceptible patients. 5.1 Fetal 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

Angioedema ENTRESTO may cause angioedema . 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 . ENTRESTO must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy . ENTRESTO should not be used in patients with hereditary angioedema

Hypotension ENTRESTO lowers blood pressure and may cause symptomatic hypotension . Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (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

Impaired 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 . 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 . As with all drugs that affect the RAAS, ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function

Hyperkalemia Through its actions on the RAAS, hyperkalemia may occur with ENTRESTO . Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of ENTRESTO may be required .

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

Dual Blockade of the Renin-Angiotensin-Aldosterone System Concomitant use of ENTRESTO with an ACE inhibitor is contraindicated because of the increased risk of angioedema . 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 . Avoid use with aliskiren in patients with renal impairment (eGFR less than 60 mL/min/1.73 m 2 )

Potassium-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

Nonsteroidal 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

Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with ENTRESTO.