Entresto

     Adult Heart Failure

ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)].

     Pediatric Heart Failure

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.

     General Considerations

ENTRESTO is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to ENTRESTO allow a washout period of 36 hours between administration of the two drugs [see Contraindications (4) and Drug Interactions (7.1)].

     Adult Heart Failure

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

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.

     Preparation of Oral Suspension

ENTRESTO oral suspension can be substituted at the recommended tablet dosage in patients unable to swallow tablets.

ENTRESTO 800 mg/200 mL oral suspension can be prepared in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL). Use ENTRESTO 49/51 mg tablets in the preparation of the suspension.

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.

     Dose Adjustment for Patients Not Taking an ACE inhibitor or ARB or Previously Taking Low Doses of These Agents

In patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents, start ENTRESTO at half the usually recommended starting dose. After initiation, increase the dose every 2 to 4 weeks in adults and every 2 weeks in pediatric patients to follow the recommended dose escalation thereafter [see Dosage and Administration (2.2, 2.3)].

Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension [see Dosage and Administration (2.3, 2.4)].

     Dose Adjustment for Severe Renal Impairment

In adults and pediatric patients with severe renal impairment (eGFR < 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 [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.

     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.

     Pregnancy

Risk Summary

ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. 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 uteroexposure to ENTRESTO for hypotension, oliguria, and hyperkalemia. In neonates with a history of in uteroexposure 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 (≤ 0.06 [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 ≥ 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 ≥ 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of ENTRESTO are attributed to the angiotensin receptor antagonist activity.

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

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.

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.

     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.

     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)].

     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 (2.6), Clinical Pharmacology (12.3)].

     Renal Impairment

No dose adjustment is required in patients with mild (eGFR 60 to 90 mL/min/1.73 m 2) to moderate (eGFR 30 to 60 mL/min/1.73 m 2) renal impairment. The recommended starting dose in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m 2) is 24/26 mg twice daily [see Dosage and Administration (2.5), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)].