function and is associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. If pregnancy occurs during therapy and the drug is considered lifesaving to the mother and there is no appropriate alternative therapy, advise the pregnant woman of the potential risk to the fetus. While it was previously thought that adverse effects do not result from first-trimester drug exposure, an observational study based on Tennessee Medicaid data reported that the risk of congenital malformations is significantly increased during first-trimester exposure to ACE inhibitors. However, a much larger observational study (n = 465,754) found that the risk of birth defects was similar in infants exposed to ACE inhibitors during the first trimester, in infants exposed to other antihypertensives during the first trimester, and in those whose mothers were hypertensive but were not treated. Ultrasound examination should be performed to assess the intra-amniotic environment, and fetal testing may be appropriate, based on week of gestation. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates and infants with histories of in utero exposure to sacubitril; valsartan for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, blood pressure and renal perfusion support may be required, as well as exchange transfusion or dialysis to reverse hypotension and/or support decreased renal function.
It is not known if sacubitril; valsartan is excreted in human milk, and there is no information on the effects of sacubitril; valsartan on a breastfed infant or the effects on milk production. Sacubitril; valsartan is present in rat milk. Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended during treatment with sacubitril; valsartan. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
MECHANISM OF ACTION
Sacubitril is a neprilysin inhibitor, and valsartan antagonizes angiotensin II at the AT1 receptor subtype. Neprilysin degrades endogenous vasoactive peptides, including natriuretic peptide, bradykinin, and adrenomedullin. Inhibition of neprilysin results in increases concentrations of these proteins and their activities, resulting in vasodilation, natriuresis, diuresis, and inhibition of pathologic growth and fibrosis. Inhibition of neprilysin occurs via the active metabolite of sacubitril, LBQ657. Angiotensin II is a potent vasoconstrictor and also stimulates the production and release of aldosterone. The cardiovascular and renal effects of sacubitril; valsartan in patients with heart failure are due to increased concentrations of peptides that are degraded by neprilysin and the simultaneous inhibition of angiotensin II and angiotensin II-dependent aldosterone release by valsartan.
PHARMACOKINETICS
Sacubitril; valsartan is administered orally. Sacubitril and valsartan and highly bound to plasma proteins (> 94%). Sacubitril is converted to its active metabolite, LBQ657, by plasma esterases and not further meta |
