` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
`
` ENTRESTO safely and effectively. See full prescribing information for
` ENTRESTO.
`
`ENTRESTO® (sacubitril and valsartan) tablets, for oral use
`
`
`
`
`
`
`
`
`
`ENTRESTO® SPRINKLE (sacubitril and valsartan) oral pellets
`
`
`Initial U.S. Approval: 2015
`
`
`
`
`
`
`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)
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`
`
`
`
`
`
`• Dosage and Administration. (2.3, 2.5)
`4/2024
`
`----------------------------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)
`-----------------------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:
`
`
`
`
`2
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: FETAL TOXICITY
`
`
`INDICATIONS AND USAGE
`1
`
`
`1.1
`Adult Heart Failure
`
`
`1.2
`Pediatric Heart Failure
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`General Considerations
`
`
`2.2
`Adult Heart Failure
`
`
`2.3
`Pediatric Heart Failure
`
`
`2.4
`Preparation of Oral Suspension Using Tablets
`
`
`
`2.5
`Preparation and Administration of Oral Pellets
`
`
`2.6
`Dose Adjustment for Patients Not Taking an ACE inhibitor or
`
`
`
`
`ARB or Previously Taking Low Doses of These Agents
`
`
`
`2.7
` Dose Adjustment for Severe Renal Impairment
`
`
`
`2.8
`Dose Adjustment for Hepatic Impairment
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`Fetal Toxicity
`
`
`
`5.2
`Angioedema
`
`
`5.3
`Hypotension
`
`
`5.4
`Impaired Renal Function
`
`
`5.5
`Hyperkalemia
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`
`
`Postmarketing Experience
`6.2
`
`DRUG INTERACTIONS
`
`
`7.1
`Dual Blockade of the Renin-Angiotensin-Aldosterone System
`
`
`
`Potassium-Sparing Diuretics
`7.2
`
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`
`
`Reference ID: 5363847
`
`
`
`
`
`
`
`
`
`
`ο 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)
`
`
`
`ο patients with severe renal impairment. (2.7)
`
`
`
`ο patients with moderate hepatic impairment. (2.8)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
`
`
`
`
`• 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-----------------------------
`
`
`
`
`• 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 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)
`-------------------------------ADVERSE REACTIONS------------------------------
`
`
`
`
`
`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.
`
`-------------------------------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)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`
`
`
`
`• Lactation: Breastfeeding not recommended. (8.2)
`
`• Severe Hepatic Impairment: Use not recommended. (2.8, 8.6)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 04/2024
`
`
`8
`
`
`Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including
`7.3
`
`
`
`Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
`
`
`Lithium
`7.4
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2
`Lactation
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`
`8.6
`Hepatic Impairment
`
`
`8.7
`Renal Impairment
`
`
`10 OVERDOSAGE
`
`
`DESCRIPTION
`11
`
`
`12
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`CLINICAL STUDIES
`
`
`14.1 Adult Heart Failure
`
`
`Pediatric Heart Failure
`14.2
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`PATIENT COUNSELING INFORMATION
`17
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`listed.
`
`
`13
`
`
`14
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
` 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)
`
`
`
`
`
`
`
`
`
`
`1
` INDICATIONS AND USAGE
`1.1
`
`
` 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 [see Clinical Studies (14.1)].
` Pediatric Heart Failure
`
`1.2
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
` DOSAGE AND ADMINISTRATION
`2.1
` 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 [see
`
`
`
`
` Contraindications (4) and Drug Interactions (7.1)].
`
`
`
`
` Adult Heart Failure
`
`2.2
`
`
`
` 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
`2.3
`
` 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
`
`
` Titration Step Dose (twice daily)
`
`
` Final
`
`
` Starting
` Second
`
`
`
` Weight (kg)
`
`
`
`
`
`
` Less than 40 kg†
`
`At least 40 kg, less than 50 kg
`
`
`1.6 mg/kg
`
`
`2.3 mg/kg
`
`
`3.1 mg/kg
`
`
`24 mg/26 mg
`
`
`
`49 mg/51 mg
`
`
`
`
`72 mg/78 mg‡
`
`
`49 mg/51 mg
`
`
`
`72 mg/78 mg‡
`
`
`
`97 mg/103 mg
`
`
`
`At least 50 kg
`
`†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)].
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5363847
`
`

`

`
`
`
`
`
`
` Table 2: Recommended Dose and Titration for Pediatric Patients using ENTRESTO SPRINKLE†
`
`
`
`
` Titration Step Dose (twice daily)
`
` Second
`
`Weight (kg)*
`
`
`
`
` Starting
`
`
`
` Final
`
` Less than 13
`
`
` (use oral suspension‡)
`
`
`
`
`
`13 to less than 19
`
`
`
`
`19 to less than 26
`
`
`
`26 to less than 34
`
`
`1.6 mg/kg
`
`
`2.3 mg/kg
`
`
`3.1 mg/kg
`
`
`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)
`
`
`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)
`
`
`
`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*
`
`60 mg/64 mg
`45 mg/48 mg
`30 mg/32 mg
`
`
`
`(Four 15 mg/16 mg capsules)
`(Three 15 mg/16 mg capsules)
`(Two 15 mg/16 mg capsules)
`
`
`
`† 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.
`
`
`Preparation of Oral Suspension Using Tablets
`2.4
`
`
`
`
`
`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
`2.5
`
`
`
`
`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
`2.6
`
`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 [see Dosage and Administration (2.2, 2.3)].
`
`
`Reference ID: 5363847
`
`

`

`
`
`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 [see Dosage and Administration (2.3, 2.4, 2.5)].
`
`
`
`
`Dose Adjustment for Severe Renal Impairment
`2.7
`
`
`
`In adults and pediatric patients with severe renal impairment estimated glomerular filtration rate (eGFR less than
`
`
`
`
`
`30 mL/min/1.73 m2), start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose
`
`
`
`
`
`
`
`
`
`to follow the recommended dose escalation thereafter [see Dosage and Administration (2.2, 2.3)].
`
`
`
`
`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 [see Dosage and Administration (2.3, 2.4, 2.5)].
`
`
`
`
`No starting dose adjustment is needed for mild or moderate renal impairment.
`
`
`
`
`
`2.8
`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 [see Dosage and Administration (2.2, 2.3)].
`
`
`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 [see Dosage and Administration (2.3, 2.4, 2.5)].
`
`
`
`
`
`
`
`
`No starting dose adjustment is needed for mild hepatic impairment.
`
`
`Use in patients with severe hepatic impairment is not recommended.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`
`
`
`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.
`
`
`CONTRAINDICATIONS
`4
`
`
`
`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)]
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`Fetal Toxicity
`5.1
`
`
`
`
`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.
`
`
`Reference ID: 5363847
`
`

`

`
`
`
`
`
`
`
`
`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)].
`
`
`5.2
`Angioedema
`
`
`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.
`
`
`Hypotension
`5.3
`
`
`
`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.
`
`
`
`Impaired Renal Function
`5.4
`
`
`
`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.
`
`
`
`
`
`
`Hyperkalemia
`5.5
`
`
`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 hyperkalemia such as
`
`
`
`
`severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of
`
`
`
`
`
`
`ENTRESTO may be required [see Dosage and Administration (2.7)].
`
`
`
`
`
`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)]
`
`
`
`
`
`
`
`Reference ID: 5363847
`
`

`

`
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`
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`
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`
`
`
`
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`
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`
`
`
` Clinical Trials Experience
`6.1
`
`
`
`
`
` 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)
`
` %
` Hypotension
`
`
` 18
` Hyperkalemia
`
`
` 12
`
` Cough
`
` 9
` Dizziness
`
`
` 6
` Renal failure/acute renal failure
`
` 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 double-blind period in PARADIGM-HF. Decreases in hemoglobin/hematocrit of greater
`
`
`
`
`
` than 20% were observed in approximately 7% of ENTRESTO-treated patients and 9% of valsartan-treated patients in the
`
`
`
`
`
`double-blind period in PARAGON-HF.
`
`
`
` Enalapril
`
` (n = 4,229)
`
` %
`
` 12
`
` 14
`
` 13
`
` 5
`
` 5
`
`
`
`
`
`
`
`Reference ID: 5363847
`
`

`

`
`
` Serum Creatinine
`
`
` During the double-blind period in PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated
`
`
`
` patients had increases in serum creatinine of greater than 50%. During the double-blind period in PARAGON-HF,
` approximately 17% of ENTRESTO-treated patients and 21% of valsartan-treated patients had increases in serum
`
`
`
`
` creatinine of greater than 50%.
`
` Serum Potassium
`
` During the double-blind period of PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated
`
`
`
`
` patients had potassium concentrations greater than 5.5 mEq/L. During the double-blind period of PARAGON-HF,
` approximately 18% of ENTRESTO-treated patients and 20% of valsartan-treated patients had potassium concentrations
`
`
`
` greater than 5.5 mEq/L.
` Postmarketing Experience
`6.2
`
` The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are
`
`
`
`
`
`
` reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or
` establish a causal relationship to drug exposure.
`
`
` Hypersensitivity including rash, pruritus, and anaphylactic reaction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`7
` DRUG INTERACTIONS
`
`7.1
`
`
` 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
`
`
`[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 m²).
`
`
`
`
`
`
`
`
`Potassium-Sparing Diuretics
`7.2
`
`
` 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)].
`
`
`
` Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2
`
`
`7.3
`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
`7.4
`
` 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.
`
`
`
`
`
`
`
`
`
`8
` USE IN SPECIFIC POPULATIONS
`8.1
`
` Pregnancy
` 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
`
`
`
`
`
`
`Reference ID: 5363847
`
`

`

`
`
`
`
` 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