This combination is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.This combination is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.Therapeutic ClassCombined antihypertensive preparationsPharmacologySacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin.Valsartan is an oral medication that belongs to a class of drugs called angiotensin receptor blockers (ARBs). It is orally active and specific angiotensin II antagonist acting on the AT1 subtype. Angiotensin's attachment to the receptors cause the blood vessels to narrow (vasoconstrict) which leads to an increase in blood pressure (hypertension). Valsartan blocks the angiotensin II receptor. By blocking the action of angiotensin, Valsartan dilates blood vessels and reduces blood pressure without affecting pulse rate. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. It does not bind or block other hormone receptors or ion channels known to be important in cardiovascular regulation.Dosage & AdministrationThe recommended starting dose of this combination is 49/51 mg twice-daily.Double the dose of this combination after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.Dose Adjustment For Patients Not Taking An ACE inhibitor Or ARB Or Previously Taking Low Doses Of These Agents.A starting dose of 24/26 mg twice-daily is recommended for patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents. Double the dose of this combination every 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.Sacubitril & Valsartan is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to Sacubitril & Valsartan allow a washout period of 36 hours between administration of the two drugs.ContraindicationsThis combination is contraindicated:In patients with hypersensitivity to any componentIn patients with a history of angioedema related to previous ACE inhibitor or ARB therapy With concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor With concomitant use of aliskiren in patients with diabetesSide EffectsClinically significant adverse reactions that appear in other sections of the labeling include: Angioedema, Hypotension, Impaired Renal Function, HyperkalemiaPregnancy & LactationPregnancy: Advise female patients of childbearing age about the consequences of exposure to this combination during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possibleLactation: 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 sacubitril/valsartan.Use in Special PopulationsPediatric Use: Safety and effectiveness in pediatric patients have not been established.Geriatric Use: No relevant pharmacokinetic differences have been observed in elderly ( ≥ 65 years) or very elderly ( ≥ 75 years) patients compared to the overall populationRenal Impairment:Severe: A starting dose of 24/26 mg twice-daily is recommended for patients with severe renal impairment (eGFR <..