• Chronic HF in adults.
• Symptomatic HF in children 1 yr with systemic left ventricular systolic dysfunction.

Contraindicated in:

• Hypersensitivity, hereditary angioedema, or history of angioedema from previous ACE inhibitors or ARBs
• Concurrent use of ACE inhibitors during or for 36 hr before or after
• Concurrent use with aliskiren in patients with diabetes or moderate to severe renal impairment (CCr <60 mL/min)
• Severe hepatic impairment
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• Volume- or salt-depleted patients or patients receiving high doses of diuretics (correct deficits before initiating therapy or initiate at lower doses)
• Black patients (may not be effective)
• Renal impairment due to primary renal disease or HF (may worsen renal function)
• Women of reproductive potential
• Pedi: Children <1 yr (safety and effectiveness not established).

CV: hypotension.

F and E: hyperkalemia.

Neuro: dizziness.

Resp: cough.
Misc: ANGIOEDEMA.

Drug-Drug:

• NSAIDs and selective COX-2 inhibitors may ↑ the risk of renal impairment.
• ↑risk of hypotension with other antihypertensives and diuretics.
• Concurrent use of potassium-sparing diuretics, potassium-containing salt substitutes, or potassium supplements may ↑ risk of hyperkalemia.
• ↑risk of hyperkalemia, renal dysfunction, hypotension, and syncope with concurrent use of ACE inhibitors or aliskiren; avoid concurrent use with aliskiren in patients with diabetes or CCr <60 mL/min; avoid concurrent use with ACE inhibitors.
• May ↑ lithium levels and risk of toxicity.

• Tablets: sacubitril 24 mg/valsartan 26 mg; sacubitril 49 mg/valsartan 51 mg; sacubitril 97 mg/valsartan 103 mg;

• PO (Adults): Sacubitril 49 mg/valsartan 51 mg twice daily initially; double dose in 2–4 wk to target dose of sacubitril 97 mg/valsartan 103 mg as tolerated. Patients not currently receiving ARBs inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: Sacubitril 24 mg/valsartan 26 mg twice daily initially; double dose every 2–4 wk to target dose of sacubitril 97 mg/valsartan 103 mg as tolerated.
• PO (Children 1 yr and 50 kg): Sacubitril 49 mg/valsartan 51 mg twice daily initially; ↑ dose in 2 wk to sacubitril 72 mg/valsartan 78 mg twice daily as tolerated, then ↑ dose again in 2 wk to target dose of sacubitril 97 mg/valsartan 103 mg twice daily as tolerated. Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: Sacubitril 24 mg/valsartan 26 mg twice daily initially; ↑ dose in 2 wk to sacubitril 49 mg/valsartan 51 mg twice daily as tolerated, then ↑ dose again in 2 wk to sacubitril 72 mg/valsartan 78 mg twice daily as tolerated, then ↑ dose again in 2 wk to target dose of sacubitril 97 mg/valsartan 103 mg twice daily as tolerated.
• PO (Children 1 yr and 40–<50 kg): Sacubitril 24 mg/valsartan 26 mg twice daily initially; ↑ dose in 2 wk to sacubitril 49 mg/valsartan 51 mg twice daily as tolerated, then ↑ dose again in 2 wk to target dose of sacubitril 72 mg/valsartan 78 mg twice daily as tolerated. Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: 0.8 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily initially; ↑ dose in 2 wk to 1.6 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated, then ↑ dose in 2 wk to 2.3 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated, then ↑ dose again in 2 wk to target dose of 3.1 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated.
• PO (Children 1 yr and <40 kg): 1.6 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily initially, then ↑ dose in 2 wk to 2.3 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated, then ↑ dose again in 2 wk to target dose of 3.1 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated. Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: 0.8 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily initially; ↑ dose in 2 wk to 1.6 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated, then ↑ dose in 2 wk to 2.3 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated, then ↑ dose again in 2 wk to target dose of 3.1 mg/kg (represents combined mg dose of sacubitril and valsartan) of oral suspension twice daily as tolerated.

Entresto

• Sacubitril: a pro-drug converted to LBQ657, its active moiety. LBQ657 inhibits the enzyme neprilysin. Neprilysin degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin resulting in ↑ levels of these peptides, causing vasodilation and ↓ extracellular fluid volume via sodium excretion.
• Valsartan: Blocks vasoconstrictor and aldosterone-producing effects of angiotensin II at receptor sites, including vascular smooth muscle and the adrenal glands.

• Reduction in cardiovascular death and hospitalizations due to HF in adults.
• Reduction in NT-proBNP concentrations in children.

Therapeutic Classification: vasodilators, heart failure agents

Pharmacologic Classification: angiotensin II receptor antagonists, neprilysin inhibitors

Sacubitril

Absorption: 60% absorbed following oral administration.

Distribution: Widely distributed to tissues.

Protein Binding: 94–97%.

Metabolism/Excretion: Rapidly converted to LBQ657, its active form. LBQ657 is not significantly metabolized; 52–68% excreted in urine, primarily as LBQ657; 37–48% excreted in feces, primarily as LBQ657.

Half-life: Sacubitril: 1.4 hr. LBQ657: 11.5 hr.

Valsartan

Absorption: Absorption in combinations with sacubitril is greater than 10–35% absorbed following oral administration of single-entity formulation.

Distribution: Widely distributed to tissues.

Protein Binding: 94–97%.

Metabolism/Excretion: Minimally metabolized by the liver; 13% excreted in urine, 86% in feces.

Half-life: 9.9 hr.

(plasma concentrations)

• Instruct patient to take Entresto as directed, at the same time each day, even if feeling well. Take missed doses as soon as remembered if not almost time for next dose; do not double doses. Warn patient not to discontinue therapy unless directed by health care professional. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
• Caution patient to avoid salt substitutes containing potassium or foods containing high levels of potassium or sodium unless directed by health care professional. See Appendix M.
• Instruct patient to notify health care professional if swelling of face, eyes, lips, or tongue or if difficulty swallowing or breathing occur.
• May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to avoid concurrent use of Rx, OTC, and herbal products, especially NSAIDs, potassium supplements or salt substitute, ACE inhibitors, ARBs, lithium, or aliskiren, without consulting health care professional.
• Instruct patient to notify health care professional of medication regimen before treatment or surgery.
• May cause fetal harm. Advise females of reproductive potential to use contraception and avoid breastfeeding during therapy. Notify health care professional if pregnancy is planned or suspected. Entresto should be discontinued as soon as possible when pregnancy is detected.
• Emphasize the importance of follow-up exams to evaluate effectiveness of medication.

sa-KU-bi-tril/val-SAR-tan