Genetic Implications: Genetic Implications


Trade Name(s)

  • Entresto

Ther. Class.

Pharm. Class.
angiotensin II receptor antagonists
neprilysin inhibitors


To ↓ risk of cardiovascular death and hospitalization for chronic heart failure patients (NYHA Class II-IV and ↓ ejection fraction).


  •  sacubitril– a pro-drug converted to LBQ657, its active moeity. LBQ657 inhibits the enzyme neprilysin. Neprilysin degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin resulting in ↑ levels of these peptides, causing vasodilation and ↓ ECF 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 Effect(s):

Reduced cardiovascular death and hospitalizations due to HF.


Absorption:  Sacubitril– ≥60% absorbed following oral administration; rapidly converted to LBQ657, its active form.  valsartan– Absorption in combinations with sacubitril is greater than 10–35% absorbed following oral administration of single-entity formulation.

Distribution:  Sacubitril– small amounts cross the blood-brain barrier.  valsartan– crosses the placenta.

Protein Binding:  Sacubitril, valsartan– 94–97%.

Metabolism and Excretion:  Sacubitril– following conversion to LBQ657 metabolism is minimal; 52–68% excreted in urine.  valsartan– Minor metabolism by the liver; 13% excreted in urine, 83% in feces.

Half-life:  Sacubitril– 1.4 hr.  LBQ657– 11.5 hr.  valsartan– 9.9 hr.

TIME/ACTION PROFILE (blood levels)

sacubitrilunknown0.5 hr12 hr
LBQ657unknown2 hr12 hr
Valsartanunknown1.5 hr12 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:  Can cause injury or death of fetus–if pregnancy occurs, discontinue immediately;
  • Lactation: Discontinue drug or use formula.

Use Cautiously in:

  • HF (may result in azotemia, oliguria, acute renal failure and/or death);
  • Volume- or salt-depleted patients or patients receiving high doses of diuretics (correct deficits before initiating therapy or initiate at lower doses);
  • Genetic implication  Black patients (may not be effective);
  • Impaired renal function due to primary renal disease or HF (may worsen renal function);
  • Rep:   Women of reproductive potential;
  • Pedi:  Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: dizziness

CV: hypotension

F and E: hyperkalemia

Resp: cough


* CAPITALS indicate life-threatening.
Underline indicate most frequent.



  •  NSAIDs  and selective  COX-2 inhibitors  may ↑ the risk of renal dysfunction.
  • ↑ 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.


PO (Adults): Sacubitril 49 mg/valsartan 51 mg twice daily initially; may double dose every 2–4 wk to target dose of sacubitril 97 mg/valsartan 103 mg as tolerated.  Patients not currently receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or receiving low doses– Sacubitril 24 mg/valsartan 26 mg twice daily initially; may double dose every 2–4 wk to target dose of sacubitril 97 mg/valsartan 103 mg as tolerated.

Hepatic Renal Impairment  
PO (Adults):  Severe renal impairment (CCr <30 mL/min/1.73 m2  or moderate hepatic impairment (Child-Pugh class B)– Sacubitril 24 mg/valsartan 26 mg twice daily initially; may double dose every 2–4 wk to target dose of sacubitril 97 mg/valsartan 103 mg as tolerated.


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


  • Assess BP (lying, sitting, standing) and pulse frequently during initial dose adjustment and periodically throughout therapy. Correct volume or salt depletion prior to administration of therapy. If hypotension occurs, consider reducing dose of diuretics, concomitant antihypertensive agents, and treatment of other causes of hypotension (hypovolemia). If hypotension persist, reduce 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 frequency of prescription refills to determine compliance.
  • 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: Monitor renal function. May cause increase in BUN and serum creatinine. May require ↓ dose.

  • May cause hyperkalemia. May require ↓ dose.
  • May cause ↓ in hemoglobin and hematocrit.

Potential Diagnoses


  • PO Administer twice daily.
    • If switching from an ACE inhibitor to  Entresto , allow 36 hrs between last ACE inhibitor dose and starting  Entresto. For patients unable to swallow pills a suspension can be made by a pharmacist.

Patient/Family Teaching

  • 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 food sources for specific nutrients.
  • 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.
  • Rep:  May be teratogenic. Advise females of reproductive potential to use contraception and avoid breast feeding 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.

Evaluation/Desired Outcomes

Decreased heart-failure-related hospitalizations in patients with heart failure.

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