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 [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.
8.6 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 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) 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.
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