ENTRESTO Sacubitril and Valsartan 97 mg; 103 mg Tablet, Film Coated, 60-count

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 ) Severe Hepatic Impairment: Use not recommended. ( 2.8 , 8.6 )

8.1Pregnancy 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 ( see Clinical Considerations ). 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 ( see Data ). 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 2 to 4% and 15 to 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 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. 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.

8.2 Lactation Risk Summary There is no information regarding the p…

8.1Pregnancy 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 ( see Clinical Considerations ). 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 ( see Data ). 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 2 to 4% and 15 to 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 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. 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.

8.4Pediatric Use 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) [see Clinical Studies (14.2)] . 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 age group. Juvenile Animal Toxicity 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 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 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.

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.

8.5Geriatric Use There were 4,143 and 3,971 heart failure patients 65 years of age and older in PARADIGM-HF and PARAGON-HF, respectively [see Clinical Studies (14)] . 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 [see Clinical Pharmacology (12.3)] .