TABUVAN

(sacubitril and valsartan) is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker.

ENTRESTO contains a complex comprised of anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively.

Following oral administration, the complex dissociates into sacubitril (which is further metabolized to LBQ657) and valsartan.

The complex is chemically described as

Octadecasodiumhexakis(4-{[(1 S,3 R )-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)hexakis( N -pentanoyl - N -{[2´-(1 H -tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)—water (1/15).

Its empirical formula (hemipentahydrate) is C 48 H 55 N 6 O 8 Na 3 2.5 H 2 O. Its molecular mass is 957.99 g/mol and its schematic structural formula is: ENTRESTO is available as film-coated tablets for oral administration, containing 24 mg of sacubitril and 26 mg of valsartan; 49 mg of sacubitril and 51 mg of valsartan; and 97 mg of sacubitril and 103 mg of valsartan.

The tablet inactive ingredients are colloidal silicon dioxide, crospovidone, low-substituted hydroxypropylcellulose, magnesium stearate (vegetable origin), microcrystalline cellulose, and talc.

The film-coat inactive ingredients are hypromellose, iron oxide red (E172), polyethylene glycol 4000, talc, and titanium dioxide (E171).

The film-coat for the 24 mg of sacubitril and 26 mg of valsartan tablet and the 97 mg of sacubitril and 103 mg of valsartan tablet also contains iron oxide black (E172).

The film-coat for the 49 mg of sacubitril and 51 mg of valsartan tablet contains iron oxide yellow (E172).

SPRINKLE is available as film-coated oral pellets within capsules for oral administration, containing 6 mg of sacubitril and 6 mg of valsartan; and 15 mg of sacubitril and 16 mg of valsartan.

The oral pellet inactive ingredients are colloidal silicon dioxide, hydroxypropylcellulose, magnesium stearate (vegetable origin), microcrystalline cellulose, and talc.

The film-coat inactive ingredients are basic butylated methacrylate copolymer, sodium lauryl sulfate, stearic acid, and talc.

The capsule shell inactive ingredients are hypromellose and titanium dioxide (E171).

The capsule shell for the 15 mg of sacubitril and 16 mg of valsartan oral pellets also contains iron oxide yellow (E172).

The printing ink contains shellac, propylene glycol, iron oxide red (E172), ammonia solution (concentrated), and potassium hydroxide.

Valsartan structural formula.

Saran, in the post-heart attack treatment plan, uses Saran to reduce the patient's death rate after a heart attack, or to reduce the mortality rate of the left abdominal patients with left ventricular disorders after the infarction of the heart muscle.

Saran, for the treatment of cardiac deficiency, may use Saratan to reduce the patient's need for hospital care due to heart failure, can be fed by the heart failure patient's maximum dose of Valsartan, which is 320 mg per day on split doses.

This drug may cause kidney function decline or increase in kryatin, especially in patients with low kidney blood flow (clerosis, heart failure).

In patients with apparent aorta constriction, heart failure, liver function disruption, hypothermia.

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 (AT 1 ) 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 AT 1 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

AT 1 -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.

In PARAMOUNT, a randomized, double-blind, 36-week study in patients with heart failure with LVEF greater than or equal to 45% comparing 97/103 mg of ENTRESTO (n=149) to 160 mg of valsartan (n =152) twice-daily, ENTRESTO decreased NT-proBNP by 17% while valsartan increased NT-proBNP by 8% at Week 12 (p = 0.005).

In PARAGON-HF, ENTRESTO decreased NT-proBNP by 24% (Week 16) and 19% (Week 48) compared to 6% and 3% reductions on valsartan, respectively.

In PANORAMA-HF, a reduction in NT-proBNP was observed at Weeks and 12 for ENTRESTO (40% and 50%) compared to baseline.

NT-proBNP levels continued to decrease over the duration of the study with a reduction of 65% for ENTRESTO at Week 52 compared to baseline.

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 Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 or CSF Aβ 1-42.

The clinical relevance of this finding is unknown.

Addition of a 50 mg single dose of sildenafil to ENTRESTO at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (approximately 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. 12.3 Pharmacokinetics Absorption Following oral administration, ENTRESTO dissociates into sacubitril and valsartan.

Sacubitril is further metabolized to

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 greater than or equal to 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.

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 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 has been identified in plasma at low concentrations (less than 10%).

Following oral administration, 52% to 68% of sacubitril (primarily as LBQ657) and approximately 13% of valsartan and its metabolites are excreted in urine; 37% to 48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces.

Sacubitril, LBQ657, and valsartan are eliminated from plasma with a mean elimination half-life (T 1/2 ) of approximately 1.4 hours, 11.5 hours, and 9.9 hours, respectively.

Linearity/Nonlinearity The pharmacokinetics of sacubitril, LBQ657, and valsartan were linear over an ENTRESTO dose range of 24 mg sacubitril/26 mg valsartan to 194 mg sacubitril/206 mg valsartan.

Effect of Co-administered Drugs on ENTRESTO: Because CYP450 enzyme-mediated metabolism of sacubitril and valsartan is minimal, coadministration with drugs that impact CYP450 enzymes is not expected to affect the pharmacokinetics of ENTRESTO.

Dedicated drug interaction studies demonstrated that coadministration of furosemide, warfarin, digoxin, carvedilol, a combination of levonorgestrel/ethinyl estradiol, amlodipine, omeprazole, hydrochlorothiazide (HCTZ), metformin, atorvastatin, and sildenafil, did not alter the systemic exposure to sacubitril, LBQ657 or valsartan.

In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters.

The effects of

ENTRESTO on the pharmacokinetics of coadministered drugs are summarized in Figure 1.

Figure 1: Effect of ENTRESTO on Pharmacokinetics of Coadministered Drugs Specific Populations Effect of specific populations on the pharmacokinetics of LBQ657 and valsartan are shown in Figure 2.

Figure 2: Pharmacokinetics of ENTRESTO in Specific Populations Note: Child-Pugh Classification was used for hepatic impairment.

The pharmacokinetics of ENTRESTO were evaluated in pediatric heart failure patients to less than 18 years old administered oral doses of 0.8 mg/kg and 3.1 mg/kg of ENTRESTO.

Pharmacokinetic data indicated that exposure to

ENTRESTO in pediatric and adult patients is similar.

Figure 1: Effect of ENTRESTO on Pharmacokinetics of Coadministered Drugs Figure 2: Pharmacokinetics of ENTRESTO in Specific Populations.

The low effect of blood pressure is caused by the ban on angiotencin receptors, because angiotensine causes blood pressure, the release of dosterone that causes water and sodium absorption and hypertension, and the release of katycolamine, Argenin vosiprisen, so the receptors of angiotencin are reversible and cause lower blood pressure, and have fewer side effects than the enzyme inhibitors of negotin.

Clinically significant adverse reactions that appear in other sections of the labeling include: Angioedema Hypotension Impaired Renal Function Hyperkalemia Adverse reactions occurring greater than or equal to 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure.fda.gov/medwatch. 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.

PARADIGM-HF, patients were required to complete sequential enalapril and ENTRESTO run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing ENTRESTO and enalapril.

During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%).

During the

ENTRESTO run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%).

Because of this run-in design, the adverse reaction rates described below are lower than expected in practice.

In the double-blind period, safety was evaluated in 4,203 patients treated with ENTRESTO and 4,229 treated with enalapril.

In PARADIGM-HF, patients randomized to ENTRESTO received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3,271 patients were treated for more than one year.

Discontinuation of therapy because of an adverse event during the double-blind period occurred in 450 (10.7%) of ENTRESTO-treated patients and 516 (12.2%) of patients receiving enalapril.

Adverse reactions occurring at an incidence of greater than or equal to 5% in patients who were treated with ENTRESTO in the double-blind period of PARADIGM-HF are shown in Table 3.

In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and ENTRESTO run-in periods.

In the double-blind period, the incidence of angioedema was higher in patients treated with ENTRESTO than enalapril (0.5% and 0.2%, respectively).

The incidence of angioedema in

Black patients was 2.4% with ENTRESTO and 0.5% with enalapril.

Orthostasis was reported in 2.1% of patients treated with ENTRESTO compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF.

Falls were reported in 1.9% of patients treated with ENTRESTO compared to 1.3% of patients treated with enalapril.

Table 3: Adverse Reactions Reported in greater than or equal to 5% of Patients Treated with ENTRESTO in the Double-Blind Period of PARADIGM-HF ENTRESTO (n = 4,203) % Enalapril (n = 4,229) % Hypotension 18 12 Hyperkalemia 12 14 Cough 9 13 Dizziness 6 5 Renal failure/acute renal failure 5 5 In PARAGON-HF, no new adverse reactions were identified.

The adverse reactions observed in pediatric patients 1 year to less than 18 years old who received treatment with ENTRESTO were consistent with those observed in adult patients.

Laboratory Abnormalities Hemoglobin and Hematocrit

Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 5% of both ENTRESTO.

• and enalapril-treated patients in the double-blind period in PARADIGM-HF.

Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 7% of ENTRESTO-treated patients and 9% of valsartan-treated patients in the double-blind period in PARAGON-HF.

Serum Creatinine During the double-blind period in PARADIGM-HF, approximately 16% of both ENTRESTO.

• and enalapril-treated patients had increases in serum creatinine of greater than 50%.

During the double-blind period in

PARAGON-HF, approximately 17% of ENTRESTO-treated patients and 21% of valsartan-treated patients had increases in serum creatinine of greater than 50%.

Serum Potassium During the double-blind period of PARADIGM-HF, approximately 16% of both ENTRESTO.

• and enalapril-treated patients had potassium concentrations greater than 5.5 mEq/L. During the double-blind period of PARAGON-HF, approximately 18% of ENTRESTO-treated patients and 20% of valsartan-treated patients had potassium concentrations greater than 5.5 mEq/L. 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.

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.

is contraindicated: in patients with hypersensitivity to any component in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy with concomitant use of ACE inhibitors.

Do not administer within 36 hours of switching from or to an ACE inhibitor with concomitant use of aliskiren in patients with diabetes Hypersensitivity to any component.

History of angioedema related to previous ACEi or ARB therapy.

Concomitant use with

ACE inhibitors.

Concomitant use with aliskiren in patients with diabetes.

The recommended starting dosage for adults is 49 mg/51 mg orally twice daily.

The target maintenance dose is 97 mg/103mg orally twice daily.

Adjust adult doses every to 4 weeks to the target maintenance dose, as tolerated by the patient.

For pediatric patients, see the Full Prescribing Information for recommended dosage, titrations, preparation and administration instructions.

Reduce starting dose to half the usually recommended starting dosage for: patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents. patients with severe renal impairment. patients with moderate hepatic impairment. 2.1 General Considerations ENTRESTO is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor.

If switching from an ACE inhibitor to ENTRESTO allow a washout period of 36 hours between administration of the two drugs. 2.2 Adult Heart Failure The recommended starting dose of ENTRESTO is 49/51 mg orally twice-daily.

Double the dose of

ENTRESTO after to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient. 2.3 Pediatric Heart Failure For the recommended dosage for pediatric patients aged 1 year and older, refer to Table 1 if using the tablets, or Table 2 if using the oral pellets.

Take the recommended dose orally twice daily.

Adjust pediatric patient doses every 2 weeks, as tolerated by the patient.

Table 1: Recommended Dose and Titration for Pediatric Patients Using Tablets † Use of the oral suspension or oral pellets is recommended in these patients.

Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan. ‡ Doses of 72 mg/78 mg can be achieved using three 24 mg/26 mg tablets.

Dose (twice daily) Weight (kg) Starting Second Final Less than 40 kg † 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg At least 40 kg, less than 50 kg 24 mg/26 mg 49 mg/51 mg 72 mg/78 mg ‡ At least 50 kg 49 mg/51 mg 72 mg/78 mg ‡ 97 mg/103 mg Table 2: Recommended Dose and Titration for Pediatric Patients using ENTRESTO SPRINKLE † † When using capsules, more than one capsule may be needed to achieve recommended doses.

Oral pellets are contained within each capsule.

Use the entire contents of the capsules to achieve the dose. ‡ Recommended mg/kg doses are of the combined amount of sacubitril and valsartan. * For patients 50 kg or more, see Table 1.

Dose (twice daily) Weight (kg) Starting Second Final Less than 13 (use oral suspension ‡ ) 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg to less than 19 12 mg/12 mg (Two 6 mg/6 mg capsules) 18 mg/18 mg (Three 6 mg/6 mg capsules) 24 mg/24 mg (Four 6 mg/6 mg capsules) 19 to less than 26 18 mg/18 mg (Three 6 mg/6 mg capsules) 24 mg/24 mg (Four 6 mg/6 mg capsules) 30 mg/32 mg (Two 15 mg/16 mg capsules) 26 to less than 34 24 mg/24 mg (Four 6 mg/6 mg capsules) 30 mg/32 mg (Two 15 mg/16 mg capsules) 45 mg/48 mg (Three 15 mg/16 mg capsules) 34 to less than 50 30 mg/32 mg (Two 15 mg/16 mg capsules) 45 mg/48 mg (Three 15 mg/16 mg capsules) 60 mg/64 mg (Four 15 mg/16 mg capsules) 2.4 Preparation of Oral Suspension Using Tablets ENTRESTO oral suspension can be substituted at the recommended tablet dosage in patients unable to swallow tablets.

ENTRESTO 800 mg/200 mL oral suspension can be prepared in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL).

ENTRESTO 49/51 mg tablets in the preparation of the suspension.

To make an 800 mg/200 mL (4 mg/mL) oral suspension, transfer eight tablets of ENTRESTO 49/51 mg film-coated tablets into a mortar.

Crush the tablets into a fine powder using a pestle.

Add 60 mL of Ora-Plus ® into the mortar and triturate gently with pestle for 10 minutes, to form a uniform suspension.

Add 140 mL of Ora-Sweet ® SF into mortar and triturate with pestle for another 10 minutes, to form a uniform suspension.

Transfer the entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle.

Place a press-in bottle adapter and close the bottle with a child resistant cap.

The oral suspension can be stored for up to 15 days.

Do not store above 25°C (77°F) and do not refrigerate.

Shake before each use. * Ora-Sweet SF ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc. 2.5 Preparation and Administration of Oral Pellets ENTRESTO SPRINKLE are oral pellets contained within capsules.

Do not swallow the capsules.

Do not chew or crush the oral pellets.

SPRINKLE can also be substituted in patients unable to swallow tablets.

Use the entire contents of the capsules to achieve the dose.

To administer

ENTRESTO oral pellets, open the capsule and sprinkle the full content onto to 2 teaspoons of soft food.

Consume the food containing the oral pellets immediately after adding them.

Empty capsule shells must be discarded after use and not swallowed.

Do not administer

ENTRESTO oral pellets via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction of enteral tubes. 2.6 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 to 4 weeks in adults and every 2 weeks in pediatric patients to follow the recommended dose escalation thereafter.

Initiate pediatric patients weighing to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets. 2.7 Dose Adjustment for Severe Renal Impairment In adults and pediatric patients with severe renal impairment estimated glomerular filtration rate (eGFR less than 30 mL/min/1.73 m 2 ), start ENTRESTO at half the usually recommended starting dose.

After initiation, increase the dose to follow the recommended dose escalation thereafter.

Initiate pediatric patients weighing to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension or oral pellets.

No starting dose adjustment is needed for mild or moderate renal impairment. 2.8 Dose Adjustment for Hepatic Impairment In adults and pediatric patients with moderate hepatic impairment (Child-Pugh B classification), start ENTRESTO at half the usually recommended starting dose.

No starting dose adjustment is needed for mild hepatic impairment.

Use in patients with severe hepatic impairment is not recommended.

(sacubitril/valsartan) tablets are unscored, ovaloid, biconvex, and film-coated.

ENTRESTO film-coated oral pellets are round, biconvex in shape, and provided in a hard capsule.

All strengths are packaged in bottles as described below.

Sacubitril/valsartan mg/mg Color Debossment Side 1/side 2 NDC 0078-XXXX-XX Bottle of 60 Bottle of 180 24/26 Violet white NVR/LZ 0659-20 0659-67 49/51 Pale yellow NVR/L1 0777-20 0777-67 97/103 Light pink NVR/L11 0696-20 0696-67 ENTRESTO SPRINKLE Sacubitril/valsartan mg/mg Color Print NDC 0078-XXXX-XX Bottle of 60 6/6 White cap and transparent body “NVR” and both parts with arrows and “04” 1231-20 15/16 Yellow cap and transparent body “NVR” and both parts with arrows and “10” 1238-20 Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) .

Protect from moisture.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) .

Protect from moisture.

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 background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

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.

ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [LBQ657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively).

ENTRESTO is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an ENTRESTO dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of ENTRESTO are attributed to the angiotensin receptor antagonist activity.

• and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-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.

The safety and effectiveness of

ENTRESTO have been established for the treatment of heart failure in pediatric patients 1 year to less than 18 years.

Use of

ENTRESTO was evaluated in a multinational, randomized, double-blind trial comparing ENTRESTO and enalapril in 375 patients aged 1 month to less than 18 years (ENTRESTO n = 187; Enalapril n = 188) (PANORAMA-HF) .

The safety profile in pediatric patients (1 year to less than 18 years) receiving ENTRESTO was similar to that seen in adult patients.

Limited safety and efficacy data in patients aged 1 month to less than 1 year were inadequate to support conclusions on safety and efficacy in this.

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 greater than or equal to 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 to PND 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 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.

This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans.

In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age.

It is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney.

There were and 3,971 heart failure patients 65 years of age and older in PARADIGM-HF and PARAGON-HF, respectively.

Of the total number of

ENTRESTO-treated patients, 2,087 (49.6%) and 1,995 (82.9%) were 65 years of age and older, while 786 (18.7%) and 1,100 (45.7%) were 75 years of age and older in PARADIGM-HF and PARAGON-HF, respectively.

No overall differences in safety or effectiveness of ENTRESTO have been observed between patients 65 years of age and older and younger adult patients in either study.

No relevant pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population.