sacubitril/valsartan

REMS

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);
Rep: 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.
Potassium-sparing diuretics, potassium-containing salt substitutes, or potassium supplements may ↑ risk of hyperkalemia.
↑risk of hyperkalemia, renal dysfunction, hypotension, and syncope with 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 ↑ levels and risk of toxicity of lithium.

(Generic available)

Tablets: sacubitril 24 mg/valsartan 26 mg; sacubitril 49 mg/valsartan 51 mg; sacubitril 97 mg/valsartan 103 mg
Oral pellets (sprinkle): sacubitril 6 mg/valsartan 6 mg; sacubitril 15 mg/valsartan 16 mg

Tablets or Oral Suspension (suspension indicated where applicable)

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 ACE 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 amount of sacubitril and valsartan) of oral suspension twice daily initially; ↑ dose in 2 wk to 1.6 mg/kg (represents combined amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated; then ↑ dose in 2 wk to 2.3 mg/kg (represents combined amount 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 amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated.
PO (Children ≥1 yr and <40 kg): 1.6 mg/kg (represents combined amount of sacubitril and valsartan) of oral suspension twice daily initially; then ↑ dose in 2 wk to 2.3 mg/kg (represents combined amount 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 amount 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 amount of sacubitril and valsartan) of oral suspension twice daily initially; ↑ dose in 2 wk to 1.6 mg/kg (represents combined amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated; then ↑ dose in 2 wk to 2.3 mg/kg (represents combined amount 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 amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated.

Hepatic/Renal Impairment

PO (Adults ): Severe renal impairment (CCr <30 mL/min/1.73 m²) or moderate hepatic impairment: 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.

Hepatic/Renal Impairment

PO (Children ≥1 yr and ≥50 kg): Severe renal impairment (CCr <30 mL/min/1.73 m²) or moderate hepatic impairment: 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.

Hepatic/Renal Impairment

PO (Children ≥1 yr and 40–<50 kg): Severe renal impairment (CCr <30 mL/min/1.73 m²) or moderate hepatic impairment: 0.8 mg/kg (represents combined amount of sacubitril and valsartan) of oral suspension twice daily initially; ↑ dose in 2 wk to 1.6 mg/kg (represents combined amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated; then ↑ dose in 2 wk to 2.3 mg/kg (represents combined amount 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 amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated.

Hepatic/Renal Impairment

PO (Children ≥1 yr and <40 kg): Severe renal impairment (CCr <30 mL/min/1.73 m²) or moderate hepatic impairment: 0.8 mg/kg (represents combined amount of sacubitril and valsartan) of oral suspension twice daily initially; ↑ dose in 2 wk to 1.6 mg/kg (represents combined amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated; then ↑ dose in 2 wk to 2.3 mg/kg (represents combined amount 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 amount of sacubitril and valsartan) of oral suspension twice daily, as tolerated.

Oral Pellets

PO (Children ≥1 yr and 34–<50 kg): Sacubitril 30 mg/valsartan 32 mg (using two sacubitril 15 mg/valsartan 16 mg capsules) twice daily initially; ↑ dose in 2 wk to sacubitril 45 mg/valsartan 48 mg (using three sacubitril 15 mg/valsartan 16 mg capsules) twice daily, as tolerated; then ↑ dose again in 2 wk to target dose of sacubitril 60 mg/valsartan 64 mg (using four sacubitril 15 mg/valsartan 16 mg capsules) twice daily, as tolerated. Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: Use oral suspension (see above for dosing information).
PO (Children ≥1 yr and 26–<34 kg): Sacubitril 24 mg/valsartan 24 mg (using four sacubitril 6 mg/valsartan 6 mg capsules) twice daily initially; ↑ dose in 2 wk to sacubitril 30 mg/valsartan 32 mg (using two sacubitril 15 mg/valsartan 16 mg capsules) twice daily, as tolerated; then ↑ dose again in 2 wk to target dose of sacubitril 45 mg/valsartan 48 mg (using three sacubitril 15 mg/valsartan 16 mg capsules) twice daily, as tolerated. Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: Use oral suspension (see above for dosing information).
PO (Children ≥1 yr and 19–<26 kg): Sacubitril 18 mg/valsartan 18 mg (using three sacubitril 6 mg/valsartan 6 mg capsules) twice daily initially; ↑ dose in 2 wk to sacubitril 24 mg/valsartan 24 mg (using four sacubitril 6 mg/valsartan 6 mg capsules) twice daily, as tolerated; then ↑ dose again in 2 wk to target dose of sacubitril 30 mg/valsartan 32 mg (using two sacubitril 15 mg/valsartan 16 mg capsules) twice daily, as tolerated. Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: Use oral suspension (see above for dosing information).
PO (Children ≥1 yr and 13–<19 kg): Sacubitril 12 mg/valsartan 12 mg (using two sacubitril 6 mg/valsartan 6 mg capsules) twice daily initially; ↑ dose in 2 wk to sacubitril 18 mg/valsartan 18 mg (using three sacubitril 6 mg/valsartan 6 mg capsules) twice daily, as tolerated; then ↑ dose again in 2 wk to target dose of sacubitril 24 mg/valsartan 24 mg (using four sacubitril 6 mg/valsartan 6 mg capsules) twice daily, as tolerated. Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: Use oral suspension (see above for dosing information).
PO (Children ≥1 yr and <13 kg): Use oral suspension (see above for dosing information). Patients not currently receiving ACE inhibitors or angiotensin II receptor blockers or receiving low doses of these agents: Use oral suspension (see above for dosing information).

Entresto, Entresto Sprinkle

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.

Therapeutic effects:

Reduction in cardiovascular death and hospitalizations due to HF in adults.
Reduction in NT-proBNP concentrations and improvement in cardiovascular outcomes 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 more compared to 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)

ROUTE		ONSET		PEAK		DURATION
Sacubitril (PO)		unknown		0.5 hr		12 hr
Valsartan (PO)		unknown		1.5 hr		12 hr

Explain the purpose and side effects of sacubitril/valsartan to patient. Instruct patient to take 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. Do not swallow Entresto Sprinkle capsules or crush the oral pellets. Open the capsule and sprinkle the entire contents onto 1–2 teaspoons of soft food. Consume food containing the oral pellets immediately after adding them. Empty capsule shells must be discarded after use. Warn patient not to discontinue therapy unless directed by health care provider. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
Emphasize the importance of follow-up exams to evaluate effectiveness of medication.
Caution patient to avoid salt substitutes containing potassium or foods containing high levels of potassium or sodium unless directed by health care provider. See Food Sources for Specific Nutrients.
Instruct patient to notify health care provider and immediately seek treatment 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 provider 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, salt substitutes, ACE inhibitors, ARBs, lithium, or aliskiren, without consulting health care provider.
Instruct patient to notify health care provider of medication regimen before treatment or surgery.
Rep: May cause fetal harm. Advise women of reproductive potential to use contraception and avoid breastfeeding during therapy. Notify health care provider if pregnancy is planned or suspected. Sacubitril/valsartan should be discontinued as soon as possible when pregnancy is detected.

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

section name header

Indications ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Availability ⬆ ⬇

Route/Dosage ⬆ ⬇

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Classifications ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Pronunciation ⬆