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 .

Data Following an oral dose ( 15 mg sacubitril / 15 mg valsartan / kg ) of [ 14 C ] ENTRESTO to lactating rats , transfer of LBQ657 into milk was observed . After a single oral administration of 3 mg / kg [ 14 C ] 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 ) in the full prescribing information ].

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 ) in the full prescribing information , Clinical Pharmacology ( 12.3 ) in the full prescribing information ].

8.7 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 ( 2.3 ) in the full prescribing information , Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 ) in the full prescribing information ].

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 .

Distributed by : Novartis Pharmaceuticals Corporation East Hanover , New Jersey 07936

© Novartis T2015-100 ENTRESTO is a trademark of Novartis AG

Issued : July / 2015

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