`
`
`
`
`
`
`
`
`
`Revised: 7/2015
`
`
`----------------------------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)
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`
` The recommended starting dose of ENTRESTO is 49/51 mg
`
`(sacubitril/valsartan) twice-daily. Double the dose of ENTRESTO after 2 to
`4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan)
`
`twice-daily, as tolerated by the patient. (2.1)
`
` Reduce the starting dose to 24/26 mg (sacubitril/valsartan) twice-daily for:
`- patients not currently taking an angiotensin-converting enzyme inhibitor
`
`
`
`(ACEi) or an angiotensin II receptor blocker (ARB) or previously taking
`
`a low dose of these agents (2.2)
`
`- patients with severe renal impairment (2.3)
`
`
`- patients with moderate hepatic impairment (2.4)
`
`
`Double the dose of ENTRESTO every 2 to 4 weeks to the target
`
`maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as
`
`
`tolerated by the patient. (2.2, 2.3, 2.4)
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`
` Film-coated tablets (sacubitril/valsartan): 24/26 mg; 49/51 mg; 97/103 mg
`
`
`(3)
`--------------------------------CONTRAINDICATIONS-----------------------------
`
` Hypersensitivity to any component. (4)
`
`
` History of angioedema related to previous ACE inhibitor 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------------------------------
`
` Dual blockade of the renin-angiotensin system: Do not use with an ACEi,
`
`do not use with aliskiren in patients with diabetes, and avoid use with an
`ARB. (4, 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. (2.4, 8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
`_______________________________________________________________________________________________________________________________________
` 
`Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including
`7.3
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
` 
` 
`Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
`WARNING: FETAL TOXICITY
` 
` 
` 
` 
`7.4
`Lithium
`INDICATIONS AND USAGE
`1
` 
` 
` 
`1.1
`Heart Failure
`USE IN SPECIFIC POPULATIONS
` 
` 
` 
` 
`8.1
`Pregnancy
`2
`DOSAGE AND ADMINISTRATION
`
` 
` 
` 
` 
`8.2
`Lactation
`2.1
`Dosing
` 
` 
` 
`8.4
`Pediatric Use
`Dose Adjustment for Patients Not Taking an ACE inhibitor or
`2.2
`
` 
` 
` 
`8.5
`Geriatric Use
`ARB or Previously Taking Low Doses of These Agents
` 
` 
` 
` 
`8.6
`Hepatic Impairment
`2.3
`Dose Adjustment for Severe Renal Impairment
` 
` 
` 
` 
`8.7
`Renal Impairment
`2.4
`Dose Adjustment for Hepatic Impairment
` 
` 
`OVERDOSAGE
`DOSAGE FORMS AND STRENGTHS
` 
` 
`DESCRIPTION
`CONTRAINDICATIONS
` 
` 
`CLINICAL PHARMACOLOGY
`WARNINGS AND PRECAUTIONS
` 
` 
` 
` 
`12.1 Mechanism of Action
`5.1
`Fetal Toxicity
` 
` 
` 
` 
`12.2
`Pharmacodynamics
`5.2
`Angioedema
` 
` 
` 
` 
`12.3
`Pharmacokinetics
`5.3
`Hypotension
` 
` 
` 
`NONCLINICAL TOXICOLOGY
`5.4
`Impaired Renal Function
` 
` 
` 
` 
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`5.5
`Hyperkalemia
` 
` 
` 
`13.2 Animal Toxicology and/or Pharmacology
`ADVERSE REACTIONS
` 
` 
` 
` 
`CLINICAL STUDIES
`14
`6.1
`Clinical Trials Experience
` 
` 
` 
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`DRUG INTERACTIONS
` 
` 
` 
` 
`PATIENT COUNSELING INFORMATION
`17
`7.1
`Dual Blockade of the Renin-Angiotensin-Aldosterone System
` 
` 
`Potassium-Sparing Diuretics
`7.2
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`_______________________________________________________________________________________________________________________________________
`
` 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)
`
`
`
`
`
`
`
` 
`8
`
` 
`10
` 
`11
` 
`12
`
` 
`13
`
` 
`3
` 
`4
` 
`5
`
` 
`6
` 
`7
`
`Reference ID: 3788834
`
`

`

`
`
`
` 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
`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.
`
`DOSAGE AND ADMINISTRATION
`2
`Dosing
`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)].
`
`The recommended starting dose of ENTRESTO is 49/51 mg 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.
`
`2.2
`Dose Adjustment for Patients Not Taking an ACE inhibitor or ARB or Previously Taking Low Doses of
`
`These Agents
`
`A starting dose of 24/26 mg twice-daily is recommended for patients not currently taking an ACE inhibitor or an
`angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents. Double the dose of
`ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.
`Dose Adjustment for Severe Renal Impairment
`2.3
`
`
`A starting dose of 24/26 mg twice-daily is recommended for patients with severe renal impairment (eGFR <30
`mL/min/1.73 m2). Double the dose of ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice
`
`daily, as tolerated by the patient.
`No starting dose adjustment is needed for mild or moderate renal impairment.
`Dose Adjustment for Hepatic Impairment
`2.4
`
`A starting dose of 24/26 mg twice-daily is recommended for patients with moderate hepatic impairment (Child-Pugh B
`
`classification). Double the dose of ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice
`daily, as tolerated by the patient.
`No starting dose adjustment is needed for mild hepatic impairment.
`Use in patients with severe hepatic impairment is not recommended.
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`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.
`
`Reference ID: 3788834
`
`

`

`
`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)]
`
`
` 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)].
`
`
`5
`WARNINGS AND PRECAUTIONS
`
`5.1
`Fetal Toxicity
`
`ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin
`system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal
`
`
`morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO.
`However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the
`drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus [see Use in
`Specific Populations (8.1)].
`
`Angioedema
`5.2
`
`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 should not be used in patients with a known history of angioedema related to previous ACE
`inhibitor or ARB therapy [see Contraindications (4)].
`
`5.3
`Hypotension
`ENTRESTO lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin
`system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater
`risk. 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.
`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. 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
`
`Reference ID: 3788834
`
`

`

`
` 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. 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 (2.1)].
` 
`
`
`
`
`
`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.
`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 1.
`
`Table 1: Adverse Reactions Reported in ≥5% of Patients Treated with ENTRESTO in the Double-Blind Period
`
`ENTRESTO
`Enalapril
`
`(n = 4,203)
`
`
`(n = 4,229)
`%
`%
`
`
`18
`12
`
`
`12
`14
`
`9
`13
`5
`6
`
`Hypotension
`Hyperkalemia
`Cough
`Dizziness
`
`Reference ID: 3788834
`
`

`

`
`
`5
`5
`Renal failure/acute renal failure
`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
`(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.
`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.
`
`
` 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: 3788834
`
`

`

`
`
`
` USE IN SPECIFIC POPULATIONS
`8
`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.
`
`8.2
`Lactation
`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: 3788834
`
`

`

`
`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
`
`Safety and effectiveness in pediatric patients have not been established.
`8.5
`Geriatric Use
`No relevant pharmacokinetic differences have been observed in elderly (≥65 years) or very elderly (≥75 years) patients
`compared to the overall population [see Clinical Pharmacology (12.3)].
`
`8.6
`Hepatic Impairment
`
`No dose adjustment is required when administering ENTRESTO to patients with mild hepatic impairment (Child-Pugh A
`
`classification). The recommended starting dose in patients with moderate hepatic impairment (Child-Pugh B
`classification) is 24/26 mg twice daily. The use of ENTRESTO in patients with severe hepatic impairment (Child-Pugh C
`classification) is not recommended, as no studies have been conducted in these patients [see Dosage and Administration
`(2.4), Clinical Pharmacology (12.3)].
`8.7
`Renal Impairment
`No dose adjustment is required in patients with mild (eGFR 60 to 90 mL/min/1.73 m2) to moderate (eGFR 30 to 60
`mL/min/1.73 m2) renal impairment. The recommended starting dose in patients with severe renal impairment (eGFR <30
`mL/min/1.73 m2) is 24/26 mg twice daily [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and
`Clinical Pharmacology (12.3)].
`
`
`10
`OVERDOSAGE
`Limited data are available with regard to overdosage in human subjects with ENTRESTO. In healthy volunteers, a single
`dose of ENTRESTO 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14
`
`days) have been studied and were well tolerated.
`Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of ENTRESTO.
`Symptomatic treatment should be provided.
`
`ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding.
`
`DESCRIPTION
`11
`ENTRESTO (sacubitril and valsartan) is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker.
`ENTRESTO contains a complex comprised of anionic forms of sacubitril and valsartan, sodium cations, and water
`molecules in the molar ratio of 1:1:3:2.5, respectively. Following oral administration, the complex dissociates into
`sacubitril (which is further metabolized to LBQ657) and valsartan. The complex is chemically described as
`
`Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4­
`oxobutanoate)hexakis(N-pentanoyl-N-{[2´-(1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)—water
`(1/15).
`Its empirical formula (hemipentahydrate) is C48H55N6O8Na3 2.5 H2O. Its molecular mass is 957.99 and its schematic
`structural formula is:
`
`Reference ID: 3788834
`
`

`

`
`
`
`ENTRESTO is available as film-coated tablets for oral administration, containing 24 mg of sacubitril and 26 mg of
`valsartan; 49 mg of sacubitril and 51 mg of valsartan; and 97 mg of sacubitril and 103 mg of valsartan. The tablet inactive
`
`ingredients are microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate
`
`(vegetable origin), talc, and colloidal silicon dioxide. The film-coat inactive ingredients are hypromellose, titanium
`
`dioxide (E 171), Macrogol 4000, talc, and iron oxide red (E 172). The film-coat for the 24 mg of sacubitril and 26 mg of
`
`valsartan tablet and the 97 mg of sacubitril and 103 mg of valsartan tablet also contains iron oxide black (E 172). The
`film-coat for the 49 mg of sacubitril and 51 mg of valsartan tablet contains iron oxide yellow (E 172).
`
`
`
`
`CLINICAL PHARMACOLOGY
`12
`
`12.1 Mechanism of Action
`
`ENTRESTO contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. ENTRESTO
`inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks
`the angiotensin II type-1 (AT1) receptor via valsartan. The cardiovascular and renal effects of ENTRESTO in heart failure
`patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by
`
`
`LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan. Valsartan inhibits the effects of
`
`angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
`12.2
`Pharmacodynamics
`The pharmacodynamic effects of ENTRESTO were evaluated after single and multiple dose administrations in healthy
`
`subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin
`system blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration
`of ENTRESTO resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased
`plasma MR-proANP and NT-proBNP compared to valsartan.
`In a 21-day study in HFrEF patients, ENTRESTO significantly increased urine ANP and cGMP and plasma cGMP, and
`decreased plasma NT-proBNP, aldosterone and endothelin-1. ENTRESTO also blocked the AT1-receptor as evidenced by
`
`
`increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, ENTRESTO decreased plasma NT­
`proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with
`enalapril.
`
`QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of ENTRESTO 194 mg
`
`sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization.
`
`Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and
`cerebrospinal fluid (CSF). Administration of ENTRESTO 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to
`healthy subjects was associated with an increase in CSF Aβ1-38 compared to placebo; there were no changes in
`concentrations of CSF Aβ1-40 or CSF Aβ1-42. The clinical relevance of this finding is unknown [see Nonclinical Toxicology
`
`(13)].
`
`
`Blood Pressure: Addition of a 50 mg single dose of sildenafil to ENTRESTO at steady state (194 mg sacubitril/206 mg
`
`valsartan mg once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP)
`
`reduction (~5/4 mmHg, systolic/diastolic BP) compared to administration of ENTRESTO alone.
`Co-administration of ENTRESTO did not significantly alter the BP effect of intravenous nitroglycerin.
`
`
`Reference ID: 3788834
`
`

`

`
`Pharmacokinetics
`12.3
`Absorption
`Following oral administration, ENTRESTO dissociates into sacubitril and valsartan. Sacubitril is further metabolized to
`LBQ657. The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5 hours, 2 hours, and 1.5
`
`hours, respectively. The oral absolute bioavailability of sacubitril is estimated to be ≥ 60%. The valsartan in ENTRESTO
`
`is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in
`ENTRESTO is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively.
`
`Following twice-daily dosing of ENTRESTO, steady state levels of sacubitril, LBQ657, and valsartan are reached in 3
`
`days. At steady state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold.
`ENTRESTO administration with food has no clinically significant effect on the systemic exposures of sacubitril, LBQ657,
`or valsartan. Although there is a decrease in exposure to valsartan when ENTRESTO is administered with food, this
`decrease is not accompanied by a clinically significant reduction in the therapeutic effect. ENTRESTO can therefore be
`administered with or without food.
`Distribution
`
`Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94% to 97%). Based on the comparison of plasma
`and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent (0.28%). The average apparent volumes of
`distribution of valsartan and sacubitril are 75 and 103 L, respectively.
`
`Metabolism
`
`Sacubitril is readily converted to LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent.
`Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite