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)
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`• Indications and Usage (1.2)
`10/2019
`
`
`
`
`
`
`• Dosage and Administration (2.3, 2.4, 2.5, 2.6, 2.7)
`10/2019
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`ENTRESTO is a combination of sacubitril, a neprilysin inhibitor, and
`
`
`
`valsartan, an angiotensin II receptor blocker indicated:
`
`
`
`• to reduce the risk of cardiovascular death and hospitalization for heart
`
`
`
`
`
`failure in patients with chronic heart failure (NYHA Class II-IV) and
`
`
`
`reduced ejection fraction. (1.1)
`
`
`ENTRESTO is usually administered in conjunction with other heart failure
`
`
`therapies, in place of an ACE inhibitor or other ARB. (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)
`
` Final
`
`
` Starting
` Second
`
`
` 49/51 mg
` 97/103 mg
` 3.1 mg/kg
`
` 1.6 mg/kg
`
` 2.3 mg/kg
`
`
`
`
`
`
`
`
`Indication
`
`
` Adult Heart Failure
`
` Pediatric Heart Failure
` 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
`
`
`
`
`
` 24/26 mg
`
`
`
` 49/51 mg
`
`
`
` 72/78 mg
`
`
`
` 49/51 mg
`
`
`
` 72/78 mg
`
`
`
` 97/103 mg
`
`
`
`
`• 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: 10/2019
`
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`7.3
`Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including
`
`
`
`
`WARNING: FETAL TOXICITY
`
`Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`7.4
`Lithium
`
`
`
`USE IN SPECIFIC POPULATIONS
`Adult Heart Failure
`1.1
`
`
`
`
`8.1
`Pregnancy
`1.2
`Pediatric Heart Failure
`
`
`
`DOSAGE AND ADMINISTRATION
`8.2
`Lactation
`
`
`
`
`8.4
`Pediatric Use
`2.1
`General Considerations
`
`
`
`
`8.5
`Geriatric Use
`2.2
`Adult Heart Failure
`
`
`
`
`8.6
`Hepatic Impairment
`2.3
`Pediatric Heart Failure
`
`
`
`
`8.7
`Renal Impairment
`2.4
`Preparation of Oral Suspension
`
`
`
`10 OVERDOSAGE
`2.5
`Dose Adjustment for Patients Not Taking an ACE inhibitor or
`
`
`
`
`
`
`DESCRIPTION
`11
`ARB or Previously Taking Low Doses of These Agents
`
`
`
`
`
`
`12
`CLINICAL PHARMACOLOGY
`2.6
`Dose Adjustment for Severe Renal Impairment
`
`
`
`
`
`12.1 Mechanism of Action
`2.7
`Dose Adjustment for Hepatic Impairment
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`12.2
`Pharmacodynamics
`
`
`
`CONTRAINDICATIONS
`12.3
`Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`WARNINGS AND PRECAUTIONS
`
`
`
`
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`5.1
`Fetal Toxicity
`
`
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`5.2
`Angioedema
`
`
`
`CLINICAL STUDIES
`5.3
`Hypotension
`
`
`
`
`14.1 Adult Heart Failure
`5.4
`Impaired Renal Function
`
`
`
`
`
`Pediatric Heart Failure
`14.2
`5.5
`Hyperkalemia
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`ADVERSE REACTIONS
`
`
`
`
`PATIENT COUNSELING INFORMATION
`17
`6.1
`Clinical Trials Experience
`
`
`Postmarketing Experience
`6.2
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`DRUG INTERACTIONS
`listed.
`
`
`7.1
`Dual Blockade of the Renin-Angiotensin-Aldosterone System
`
`
`Potassium-Sparing Diuretics
`7.2
`_______________________________________________________________________________________________________________________________________
`
`
`8
`
`
`13
`
`
`14
`
`
`2
`
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`Reference ID: 4499982
`
`

`

`
`
`
`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
`
`Adult Heart Failure
`1.1
`
`
`
`
`
`
`
`
`ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with
`
`
`chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
`
`
`
`ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or
`
`other ARB.
`
`
`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
`
`
`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.
`
`
`Pediatric Heart Failure
`2.3
`
`
`
`
`
`
`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)
`
` Final
`
`
` Starting
` Second
`
`
`
`1.6 mg/kg
`
`
`2.3 mg/kg
`
`
`3.1 mg/kg
`
`
`
`24/26 mg
`
`
`49/51 mg
`
`
`72/78 mg‡
`
`
`
` 49/51 mg
`
`
`72/78 mg‡
`
`
`97/103 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)]
`
`
`
`
`
` Preparation of Oral Suspension
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4499982
`
`

`

`
`
`
`
`
` 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 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)].
`
`
`
`
`Dose Adjustment for Severe Renal Impairment
`2.6
`
`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: 4499982
`
`

`

`
`
`• 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. In the double-blind period of PARADIGM-HF, 0.5% of patients treated with
`
`ENTRESTO and 0.2% of patients treated with enalapril had 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. 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. In the double-blind period of PARADIGM-HF, 18% of patients treated with ENTRESTO and 12% of patients treated
`
`
`with enalapril reported hypotension as an adverse event [see Adverse Reactions (6.1)], with hypotension reported as a
`
`
`
`
`serious adverse event in approximately 1.5% of patients in both treatment arms. 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. In the double-blind period of PARADIGM-HF, 5% of
`
`
`patients in both the ENTRESTO and enalapril groups reported renal failure as an adverse event [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.
`
`
`
`
`
`
`Reference ID: 4499982
`
`

`

`
`
`
`Hyperkalemia
`5.5
`
`
`
`
`
`Through its actions on the RAAS, hyperkalemia may occur with ENTRESTO. In the double-blind period of
`
`
`PARADIGM-HF, 12% of patients treated with ENTRESTO and 14% of patients treated with enalapril reported
`
`
`
`
`
`hyperkalemia as an adverse event [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)].
`
`
`
`ADVERSE REACTIONS
`6
`
`
`
`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.
`
`Adult Heart Failure
`
`
`
`
`
`
`
`In the PARADIGM-HF trial, subjects 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 are shown in Table 2.
`
`
`
`
`
`
`
`Table 2: Adverse Reactions Reported in ≥ 5% of Patients Treated with ENTRESTO in the Double-Blind Period
`
`
`ENTRESTO
` Enalapril
`
`
`
`(n = 4,203)
`
` (n = 4,229)
`
`
` %
` %
` Hypotension
`
`
` 18
`
` 12
` Hyperkalemia
`
`
` 12
`
` 14
`
` Cough
`
` 13
`
` 9
` Dizziness
`
`
` 6
`
` 5
` Renal failure/acute renal failure
`
` 5
`
` 5
`
`
`
`
`
`
`
`
` In the PARADIGM-HF trial, 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
`
`
`
`
`
`Reference ID: 4499982
`
`

`

`
`(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.
`
`Pediatric Heart Failure
`
`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.
`
`
`
`
`Serum Creatinine
`
`
`Increases in serum creatinine of > 50% were observed in 1.4% of patients in the enalapril run-in period and 2.2% of
`
`
`
`
`
`
`patients in the ENTRESTO run-in period. During the double-blind period, approximately 16% of both ENTRESTO- and
`
`
`
`enalapril-treated patients had increases in serum creatinine of > 50%.
`
`
`
`
`Serum Potassium
`
`
`Potassium concentrations > 5.5 mEq/L were observed in approximately 4% of patients in both the enalapril and
`
`
`
`
`
`
`
`
`ENTRESTO run-in periods. During the double-blind period, approximately 16% of both ENTRESTO- and enalapril­
`
`
`
`
`treated patients had potassium concentrations > 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
`
`
`
`
`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).
`
`
`
`
`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.
`
`
`
`
`
`
`Reference ID: 4499982
`
`

`

`
`
`
` 8
` USE IN SPECIFIC POPULATIONS
`
`
`
` Pregnancy
` 8.1
` 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. 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. 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 ≥ 49 mg
`
`
`
`
`
`sacubitril/51 mg valsartan/kg/day (≤ 0.14 [LBQ657, the active metabolite] and 1.5 [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 ≥ 5 mg sacubitril/5 mg valsartan/kg/day (4-fold and 0.06-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 ≥ 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 (4.5-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.
`
`
`Lactation
`8.2
`
`Risk Summary
`
`
`
`
`
`There is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or
`
`
`the effects on milk production. Sacubitril/valsartan is present in rat milk. Because of the potential for serious adverse
`
`
`
`
`reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not
`
`recommended during treatment with ENTRESTO.
`
`Reference ID: 4499982
`
`

`

`
`
`
` Data
`
`
`
`
`
`
`
` Following an oral dose (15 mg sacubitril/15 mg valsartan/kg) of [14C] ENTRESTO to lactating rats, transfer of LBQ657
` into milk was observed. After a single oral administration of 3 mg/kg [14C] valsartan to lactating rats, transfer of valsartan
`
`
`
`
`
`
`into milk was observed.
`
`
`8.4
`Pediatric Use
`
`
`
`The safety and effectiveness of ENTRESTO in pediatric heart failure patients 1 to <18 years old are supported by the
`
`
`
`reduction from baseline to 12 weeks in NT-proBNP in a randomized, double-blind clinical study [see Clinical Studies
`
`
`
`
`
`(14.2)]. The analysis of NT-proBNP included 90 patients age 6 to 18 years and 20 patients age 1 to 6 years.
`
`
`
`Safety and effectiveness have not been established in pediatric patients less than 1 year of age.
`
`
`Animal 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 ≥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.
`
`
`
`8.5
`Geriatric Use
`
`
`No relevant pharmacokinetic differences have been observed in