CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` 207620Orig1s018
`
`
`
`Trade Name:
`
` ENTRESTO
`
`sacubitril and valsartan
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`Novartis Pharmaceuticals Corp.
`
`February 16, 2021
`
`• 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.
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`213026Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`
`
`
`
`X
`X
`
`
`
`
`X
`
`
`
`
`

`

`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`207620Orig1s018
`
`
`APPROVAL LETTER
`
`

`

`
`
`NDA 207620/S-018
`
`
`
`SUPPLEMENT APPROVAL
`
`Novartis Pharmaceuticals Corp.
`Attention: Amol Parekh, PharmD
`Global Program Regulatory Director
`One Health Plaza
`Building 315
`East Hanover, NJ 07936
`
`Dear Dr. Parekh:
`
`Please refer to your supplemental new drug application (sNDA) dated April 20, 2020,
`received April 20, 2020, and your amendments, submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act (FDCA) for Entresto (sacubitril/valsartan), Film
`Coated Tablets.
`
`This Prior Approval supplemental new drug application provides for updates to the
`United States Prescribing Information (USPI) and the Patient Package Insert (PPI)
`related to the PARAGON-HF trial, including substantive revisions to Indications and
`Usage and Clinical Studies; additional revisions were made throughout labeling.
`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved, effective
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`labeling.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`the FDA automated drug registration and listing system (eLIST), as described at
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`Prescribing Information, and Patient Package Insert), with the addition of any labeling
`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
`reportable changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`
`1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`Reference ID: 4747255
`
`

`

`NDA 207620/S-018
`Page 2
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`changes for this NDA, including CBE supplements for which FDA has not yet issued an
`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`format, that includes the changes approved in this supplemental application, as well as
`annual reportable changes. To facilitate review of your submission(s), provide a
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
`supplement number(s) and annual report date(s).
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`new active ingredients (which includes new salts and new fixed combinations), new
`indications, new dosage forms, new dosing regimens, or new routes of administration
`are required to contain an assessment of the safety and effectiveness of the product for
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`or inapplicable.
`
`Because none of these criteria apply to your application, you are exempt from this
`requirement.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. For information about submitting promotional materials, see the
`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`Prescription Drugs.3
`
`You must submit final promotional materials and Prescribing Information, accompanied
`by a Form FDA 2253, at the time of initial dissemination or publication
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`Instructions for completing the form can be found at FDA.gov.5
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
` 3
`
` For the most recent version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/media/128163/download.
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4747255
`
`

`

`NDA 207620/S-018
`Page 3
`
`
`
`If you have any questions, contact Alexis Childers, Regulatory Project Manager, at 301-
`796-0442.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiology and Nephrology
`Office of Cardiology, Hematology,
`Endocrinology, & Nephrology
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`• Content of Labeling
`o Prescribing Information
`o Patient Package Insert
`
`
`
`
`
`
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4747255
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`02/16/2021 10:15:01 AM
`
`Reference ID: 4747255
`
`(
`
`
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`
`207620Orig1s018
`
`
`LABELING
`
`

`

`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
`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)
`
`24/26 mg
`
`49/51 mg
`
`----------------------------RECENT MAJOR CHANGES--------------------------
` 2/2021
`• Indications and Usage, Adult Heart Failure (1.1)
`----------------------------INDICATIONS AND USAGE---------------------------
`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. (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-----------------------
`Titration Step Dose (twice daily)
`Indication
`Starting
`Second
`Final
`Adult Heart Failure
`49/51 mg
`97/103 mg
`Pediatric Heart Failure
`1.6 mg/kg
`2.3 mg/kg
`3.1 mg/kg
`Patients less than 40 kg
`Pediatric Heart Failure
`Patients at least 40 kg, less
`than 50 kg
`Pediatric Heart Failure
`Patients at least 50 kg
`
`• Adjust adult doses every 2 to 4 weeks and pediatric doses every 2 weeks
`to the target maintenance dose, as tolerated by the patient. (2.2, 2.3)
`• Reduce starting dose to half the usually recommended starting dosage for:
`– patients not currently taking an ACE inhibitor or ARB or previously
`taking a low dose of these agents (2.5)
`– patients with severe renal impairment (2.6)
`– patients with moderate hepatic impairment (2.7)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`• Film-coated tablets: 24/26 mg; 49/51 mg; 97/103 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 ≥ 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 eGFR < 60. (7.1)
`• Potassium-sparing diuretics: May lead to increased serum potassium. (7.2)
`• 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 or drug should be discontinued. (8.2)
`• Severe Hepatic Impairment: Use not recommended. (2.7, 8.6)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`Revised: 2/2021
`
`_______________________________________________________________________________________________________________________________________
`7.2
`Potassium-Sparing Diuretics
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: FETAL TOXICITY
`7.3
`Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including
`1
`INDICATIONS AND USAGE
`Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
`1.1
`Adult Heart Failure
`7.4
`Lithium
`1.2
`Pediatric Heart Failure
`USE IN SPECIFIC POPULATIONS
`DOSAGE AND ADMINISTRATION
`8.1
`Pregnancy
`2.1
`General Considerations
`8.2
`Lactation
`2.2
`Adult Heart Failure
`8.4
`Pediatric Use
`2.3
`Pediatric Heart Failure
`8.5
`Geriatric Use
`2.4
`Preparation of Oral Suspension
`8.6
`Hepatic Impairment
`2.5
`8.7
`Renal Impairment
`Dose Adjustment for Patients Not Taking an ACE inhibitor or
`ARB or Previously Taking Low Doses of These Agents
`10 OVERDOSAGE
`2.6
`Dose Adjustment for Severe Renal Impairment
`DESCRIPTION
`11
`Dose Adjustment for Hepatic Impairment
`2.7
`12
`CLINICAL PHARMACOLOGY
`DOSAGE FORMS AND STRENGTHS
`12.1 Mechanism of Action
`CONTRAINDICATIONS
`12.2
`Pharmacodynamics
`WARNINGS AND PRECAUTIONS
`12.3
`Pharmacokinetics
`5.1
`Fetal Toxicity
`NONCLINICAL TOXICOLOGY
`5.2
`Angioedema
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`5.3
`Hypotension
`13.2 Animal Toxicology and/or Pharmacology
`5.4
`Impaired Renal Function
`CLINICAL STUDIES
`5.5
`Hyperkalemia
`14.1 Adult Heart Failure
`ADVERSE REACTIONS
`14.2
`Pediatric Heart Failure
`6.1
`Clinical Trials Experience
`16 HOW SUPPLIED/STORAGE AND HANDLING
`6.2
`Postmarketing Experience
`PATIENT COUNSELING INFORMATION
`17
`DRUG INTERACTIONS
`7
`*Sections or subsections omitted from the full prescribing information are not
`7.1
`Dual Blockade of the Renin-Angiotensin-Aldosterone System
`listed.
`_______________________________________________________________________________________________________________________________________
`
`72/78 mg
`
`97/103 mg
`
`8
`
`13
`
`14
`
`72/78 mg
`
`49/51 mg
`
`2
`
`3
`4
`5
`
`6
`
`Reference ID: 4747255
`
`

`

`
`
`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)
`
`INDICATIONS AND USAGE
`1
`Adult Heart Failure
`1.1
`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)].
`1.2
`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.
`
`DOSAGE AND ADMINISTRATION
`2
`General Considerations
`2.1
`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)].
`2.2
`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.
`2.3
`Pediatric Heart Failure
`Refer to Table 1 for the recommended dose for pediatric patients aged one year and older. Take the recommended dose
`orally twice daily. Adjust pediatric patient doses every 2 weeks, as tolerated by the patient.
`Table 1: Recommended Dose Titration
`Titration Step Dose (twice daily)
`Starting
`Second
`Final
`
`
`
`1.6 mg/kg
`
`2.3 mg/kg
`
`3.1 mg/kg
`
`24/26 mg
`
`49/51 mg
`
`72/78 mg‡
`
`Pediatric Patients
`Less than 40 kg†
`Pediatric Patients
`At least 40 kg, less than 50 kg
`Pediatric Patients
`At least 50 kg
`†Use of the Oral Suspension recommended in these patients. Recommended mg/kg doses are of the combined amount of both
`sacubitril and valsartan [see Dosage and Administration (2.4)].
`‡Doses of 72/78 mg can be achieved using three 24/26 mg tablets [see Dosage Forms and Strengths (3)].
`2.4
`Preparation of Oral Suspension
`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.
`
`49/51 mg
`
`72/78 mg‡
`
`97/103 mg
`
`Reference ID: 4747255
`
`

`

`
`
`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.
`2.5
`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 [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 [see Dosage and Administration (2.3, 2.4)].
`2.6
`Dose Adjustment for Severe Renal Impairment
`In adults and pediatric patients with severe renal impairment (eGFR < 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 [see Dosage and Administration (2.3, 2.4)].
`No starting dose adjustment is needed for mild or moderate renal impairment.
`2.7
`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 [see Dosage and Administration (2.3, 2.4)].
`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 is supplied as unscored, ovaloid, film-coated 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.
`
`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)]
`
`Reference ID: 4747255
`
`

`

`
`
`• 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.
`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.
`5.3
`Hypotension
`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.
`5.4
`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 [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.
`5.5
`Hyperkalemia
`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 (2.6)].
`
`Reference ID: 4747255
`
`

`

` 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)]
`6.1
`Clinical 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 ≥ 5% in patients who were treated with ENTRESTO in the double-blind
`period of PARADIGM-HF are shown in Table 2.
`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 2: Adverse Reactions Reported in ≥ 5% of Patients Treated with ENTRESTO in the Double-Blind Period of
`PARADIGM-HF
`
`
`ENTRESTO
`(n = 4,203)
`%
`18
`Hypotension
`12
`Hyperkalemia
`9
`Cough
`6
`Dizziness
`5
`Renal failure/acute renal failure
`In PARAGON-HF, no new adverse reactions were identified.
`Pediatric Heart Failure
`
`Enalapril
`(n = 4,229)
`%
`12
`14
`13
`5
`5
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`The adverse reactions observed in pediatric patients 1 to < 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 > 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 >20% were
`observed in approximately 7% of ENTRESTO-treated patients and 9% of valsartan-treated patients in the double-blind
`period in PARAGON-HF.
`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 > 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 > 50%.
`Serum Potassium
`During the double-blind period of PARADIGM-HF, approximately 16% of both ENTRESTO- and enalapril-treated
`patients had potassium concentrations > 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 > 5.5 mEq/L.
`6.2
`Postmarketing Experience
`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
`
`DRUG INTERACTIONS
`7
`Dual Blockade of the Renin-Angiotensin-Aldosterone System
`7.1
`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 < 60 mL/min/1.73 m²).
`7.2
`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 [see Warnings and Precautions (5.5)].
`7.3
`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.
`7.4
`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.
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Risk Summary
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`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. 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. 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S.
`general population, the estimated background risk of major birth defects and miscarriage in clinically recognized
`pregnancies is 2-4% and 15-20%, 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. Patien