Entrovas

Approved Indications:

• Chronic Heart Failure with Reduced Ejection Fraction (HFrEF):
  Indicated in adult patients with NYHA Class II–IV chronic heart failure and left ventricular ejection fraction (LVEF) ≤40% to reduce the risk of cardiovascular death and heart failure hospitalizations.
• Pediatric Heart Failure (≥1 year of age):
  Indicated for children aged 1 year and older with symptomatic heart failure and systemic left ventricular systolic dysfunction.

Clinically Accepted (Off-label) Uses:

• Heart Failure with Preserved Ejection Fraction (HFpEF):
  Studied in the PARAGON-HF trial; although not FDA-approved, Sacubitril + Valsartan may be considered in select patients based on individual clinical judgment and evolving guidelines.

Formulation: Oral tablet (film-coated)

Initial Dosing (Adults):

• Standard initiation: 49 mg sacubitril / 51 mg valsartan twice daily
• Low-dose initiation (e.g., in patients naïve to ACEI/ARB, elderly, renal/hepatic impairment): 24 mg sacubitril / 26 mg valsartan twice daily

Target Maintenance Dose:

• 97 mg sacubitril / 103 mg valsartan twice daily

Titration:
Increase dose every 2–4 weeks to the target dose as tolerated.

Pediatric Dosing (≥1 year):

• Initial dose: 1.6 mg/kg (of combined drug) twice daily, rounded to nearest tablet strength
• Max dose (≥40 kg): 97/103 mg twice daily

Renal Impairment:

• Mild to moderate (eGFR ≥30 mL/min/1.73 m²): No adjustment initially
• Severe (eGFR <30 mL/min/1.73 m²): Start at 24/26 mg twice daily; titrate cautiously

Hepatic Impairment:

• Mild (Child-Pugh A): No adjustment
• Moderate (Child-Pugh B): Start at reduced dose
• Severe (Child-Pugh C): Contraindicated

Administration Instructions:

• Administer orally, twice daily, with or without food.
• Avoid use within 36 hours of last dose of an ACE inhibitor due to angioedema risk.

Sacubitril + Valsartan is a dual-action agent that combines sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB). Sacubitril is a prodrug metabolized to LBQ657, which inhibits neprilysin, preventing the degradation of beneficial natriuretic peptides such as ANP and BNP. This enhances natriuresis, diuresis, vasodilation, and inhibition of fibrosis. Valsartan selectively blocks the angiotensin II type 1 (AT₁) receptor, reducing vasoconstriction, aldosterone secretion, and cardiac remodeling. The synergistic effect of neprilysin inhibition and RAAS blockade leads to improved cardiac function and reduced morbidity and mortality in heart failure patients.

• Absorption:
  Rapidly absorbed; peak plasma concentrations reached in 1.5 to 3 hours
  Oral bioavailability: Sacubitril ~60%, Valsartan ~60%
• Distribution:
  Protein binding: ~94% (Sacubitril), ~97% (Valsartan)
  Volume of distribution: Sacubitril ~103 L, Valsartan ~75 L
• Metabolism:
  Sacubitril is converted by esterases to LBQ657 (active).
  Valsartan is minimally metabolized (non-CYP dependent, minor CYP2C9 involvement).
• Elimination:
  Half-life:
• LBQ657: ~11.5 hours
• Valsartan: ~9.9 hours
  Excretion:
• 52–68% feces
• 27–38% urine

• Contraindicated during pregnancy
• Associated with fetal harm (renal dysfunction, oligohydramnios, skull hypoplasia, fetal death), especially during the second and third trimesters
• Boxed Warning: Discontinue immediately upon detection of pregnancy

Lactation:

• Not recommended during breastfeeding
• Animal studies show valsartan and LBQ657 are excreted in milk
• Risk to human infants is unknown; avoid if breastfeeding

• Primary Class: ARNI (Angiotensin Receptor–Neprilysin Inhibitor)
• Subclasses:
• ARB (Valsartan component)
• Neprilysin Inhibitor (Sacubitril component)

• Hypersensitivity to sacubitril, valsartan, or any excipient
• History of angioedema related to ACE inhibitors or ARBs
• Concomitant use with ACE inhibitors or within 36 hours of last ACE inhibitor dose
• Concomitant use with aliskiren in patients with diabetes
• Severe hepatic impairment (Child-Pugh C)
• Pregnancy

• Angioedema Risk: Higher in Black patients or those with prior ACEI-induced angioedema
• Hypotension: Especially in volume-depleted, elderly, or renal-impaired patients
• Renal Function Deterioration: Monitor serum creatinine and eGFR
• Hyperkalemia: Monitor potassium, especially in patients taking potassium-sparing agents
• Cognitive Impairment (Theoretical): Neprilysin degrades amyloid-β; long-term effects under investigation
• Hepatic Dysfunction: Avoid use in Child-Pugh Class C

Common (≥1%):

• Cardiovascular: Hypotension, orthostatic symptoms
• Renal: Increased creatinine, decreased eGFR
• Metabolic: Hyperkalemia
• General: Fatigue, dizziness

Serious and Rare:

• Angioedema (potentially life-threatening)
• Acute kidney injury
• Severe hyperkalemia
• Liver enzyme elevations

Onset & Severity:

• Most adverse events occur during initial weeks of treatment or dose escalation
• Severity is often dose-related and reversible with dose adjustment or discontinuation

Major Drug Interactions:

• ACE inhibitors: Increased angioedema risk; contraindicated within 36 hours
• Aliskiren: Avoid in diabetic patients
• Potassium supplements & potassium-sparing diuretics: Risk of severe hyperkalemia
• NSAIDs: May worsen renal function, especially in elderly
• Lithium: Risk of lithium toxicity—monitor levels
• OATP1B1/B3 substrates (e.g., statins): May increase exposure to certain drugs

Food Interaction:

• Food may slow absorption, but does not affect total exposure—may be taken with or without food

CYP450 Interactions:

• Not significantly metabolized via CYP450—minimal CYP-mediated interactions

• FDA Update (2022):
• Approved use in pediatric patients ≥1 year with symptomatic heart failure
• ESC & ACC/AHA Guidelines:
• Recommended as first-line therapy for HFrEF in place of ACEI/ARB in symptomatic patients
• PARAGON-HF Trial:
• Did not meet primary endpoint in HFpEF but showed potential benefit in patients with LVEF on lower end of the preserved spectrum

• Storage Temperature: Below 30°C (86°F)
• Humidity: Store in a dry place, protect from moisture
• Light Protection: Store in original blister packaging to avoid light degradation
• Handling:
• Do not remove tablets until time of administration
• Keep tightly closed
• Do not refrigerate or freeze