sacubitril/valsartan

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

Therapeutic Classification: vasodilators, heart failure agents

Pharmacologic Classification: angiotensin II receptor antagonists, neprilysin inhibitors

REMS

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

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.

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)

ROUTE	ONSET	PEAK	DURATION
Sacubitril (PO)	unknown	0.5 hr	12 hr
LBQ657	unknown	2 hr	12 hr
Valsartan (PO)	unknown	1.5 hr	12 hr

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.
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 or Oral Suspension (suspension indicated where applicable)

Oral Pellets

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.
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.
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.
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.
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.
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).

(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

Assess BP (lying, sitting, standing) and HR frequently during initial dose adjustment and periodically throughout therapy. Correct volume or salt depletion prior to administration of therapy. If hypotension occurs, consider ↓ dose of diuretics or concomitant antihypertensive agents. If hypotension persists, ↓ the dose or temporarily discontinue therapy. Permanent discontinuation of therapy is usually not required.
Monitor daily weight and assess patient routinely for resolution of fluid overload (peripheral edema, rales/crackles, dyspnea, weight gain, jugular venous distention).
Monitor for oliguria, progressive azotemia, and/or acute renal failure in patients with severe HF (renal function is dependent on the renin-angiotensin system).
Assess patients for signs of angioedema (dyspnea, orofacial swelling); may occur more frequently in Black patients. If signs occur, discontinue therapy, provide supportive therapy, and monitor for airway compromise.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
- Assess baseline hepatic function.
- Monitor renal function including BUN, serum creatinine, and eGFR. May cause ↑ BUN and serum creatinine. May require ↓ dose.
- May cause hyperkalemia. May require ↓ dose or temporary interruption of therapy.
- May cause ↓ in hemoglobin and hematocrit.

PO: Administer twice daily without regard to food.
- If switching from an ACE inhibitor to sacubitril/valsartan, allow 36 hr between last ACE inhibitor dose and starting sacubitril/valsartan. For patients unable to swallow pills, a suspension can be made by a pharmacist using the tablets. Store oral suspension at room temperature and use within 15 days. Shake oral suspension before each use.
- Entresto Sprinkle can be substituted in patients unable to swallow tablets. Capsules should not be swallowed.DNC: Do not chew or crush the oral pellets.Open the capsule and sprinkle the contents onto 1–2 teaspoons of soft food. Consume the food containing the oral pellets immediately after adding them. Empty capsule shells must be discarded after use. Use the entire contents of the capsules to achieve the dosage. Do not administer oral pellets via nasogastric, gastrostomy, or other enteral tubes because it may cause obstruction.

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 the 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 professional. 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 professional. See Food Sources for Specific Nutrients.
Instruct patient to notify health care professional 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 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, salt substitutes, 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.
Rep: 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. Sacubitril/valsartan should be discontinued as soon as possible when pregnancy is detected.

Decreased HF-related hospitalizations in adults with HF.
Decreased NT-proBNP concentrations and improvement in cardiovascular outcomes in children with HF.

Entresto, Entresto Sprinkle

section name header

Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆ ⬇

US Brand Names ⬆