CardioSource WorldNews October 2015 | Page 47
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.
Distributed by: Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
© Novartis
T2015-100
ENTRESTO is a trademark of Novartis AG
Issued: July/2015
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].
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patient-selection criteria from clinical definitions
by slowly peppering in and adding in some of
4C
change treatment of patients. This is how we’re
defining HFpEF out there. It’s very subjective,
To watch the full interview with
Tabloid Single-Page
so we try toConsumer
solidify it the Brief Summary
Jacob Kelly, MD, on the CSWN
YouTube channel, scan the QR code.
best we can so that we
can give that message to
clinicians, but also study it
in a rigorous way so that we
know if when we find that
therapy that works for these
patients—and we will—that
population and better choose the right patient
we can move that message to
population to treat.
clinicians and into practice.
I also think it’s very important to identify the
folks who have been so instrumental at CVCT,
as well as in mentoring fellows so that we can
With the methodologies
be the future clinical trialists. Without Robert
being all over the map, it’s
Mentz, MD, and Carolyn Lam, MBBS, along
no wonder that it’s hard to find treatments
with the leadership of Dr. Zannad and Pitt, the
that work. We really need a better underfuture of clinical trials would not be so strong. ■
standing of who these people are and then
By utilizing the actual definitions
that clinicians are using to define
their patients in clinical trials,
we’re going to inform clinicians of
how to treat these patients.
the omics data, some of these phenomapping
mapping techniques that Sanjeev Shah, MD, has
done, studied, demonstrated, and published in
JACC on how to use novel diagnostic techniques
to identify