Sacubitril/valsartan - Drug Monograph

Introduction

Sacubitril/valsartan (brand name Entresto®) is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) combination medication approved for the treatment of heart failure. This fixed-dose combination represents a significant advancement in heart failure management, demonstrating superior outcomes compared to traditional ACE inhibitor therapy in clinical trials.

Mechanism of Action

Sacubitril/valsartan exerts its effects through dual mechanisms:

• Valsartan component: Blocks the angiotensin II type-1 receptor, inhibiting the effects of angiotensin II (vasoconstriction, sodium retention, cardiac remodeling)
• Sacubitril component: A prodrug that is converted to sacubitrilat, which inhibits neprilysin enzyme activity. Neprilysin degradation leads to increased levels of vasoactive peptides including:

- Natriuretic peptides (ANP, BNP) - promote diuresis, natriuresis, and vasodilation - Bradykinin - causes vasodilation - Adrenomedullin - induces vasodilation and natriuresis

This dual mechanism provides complementary cardiovascular effects by simultaneously inhibiting the harmful renin-angiotensin-aldosterone system while enhancing protective natriuretic peptide systems.

Indications

• Heart failure with reduced ejection fraction (HFrEF): For reduction of cardiovascular death and hospitalization in patients with chronic heart failure (NYHA Class II-IV) and left ventricular ejection fraction ≤40%
• Pediatric heart failure: For children ≥1 year old with symptomatic HFrEF

Dosage and Administration

• Initial dose: 49/51 mg (sacubitril/valsartan) twice daily
• Target maintenance dose: 97/103 mg twice daily after 2-4 weeks
• Titration: Double the dose every 2-4 weeks as tolerated

• Renal impairment:

- Mild (eGFR 60-90 mL/min/1.73m²): No adjustment needed - Moderate (eGFR 30-60 mL/min/1.73m²): Initial dose 24/26 mg twice daily - Severe (eGFR <30 mL/min/1.73m²): Use not recommended

• Hepatic impairment:

- Mild: No adjustment needed - Moderate (Child-Pugh B): Initial dose 24/26 mg twice daily - Severe (Child-Pugh C): Contraindicated

• Elderly: No dosage adjustment based on age alone

• Take twice daily with or without food
• If switching from ACE inhibitor: Allow 36-hour washout period before initiation
• Tablets should be swallowed whole; not recommended for splitting or crushing

Pharmacokinetics

• Sacubitril: Rapidly absorbed (Tmax ~0.5 hours)
• Valsartan: Moderately absorbed (Tmax ~1.5 hours)
• Food does not significantly affect bioavailability

• Sacubitrilat: ~97% protein bound
• Valsartan: ~94-97% protein bound
• Steady state reached in 3 days

• Sacubitril: Converted to active metabolite sacubitrilat via esterases
• Valsartan: Minimally metabolized via CYP450 2C9
• Neither component inhibits or induces major CYP450 enzymes

• Sacubitrilat: Renal (52-68%) and fecal (37-48%) excretion
• Valsartan: Primarily fecal (83%) and renal (13%) excretion
• Half-life: Sacubitrilat ~11.5 hours; Valsartan ~9.9 hours

Contraindications

• History of angioedema related to previous ACE inhibitor or ARB therapy
• Concomitant use with ACE inhibitors (require 36-hour washout period)
• Concomitant use with aliskiren in patients with diabetes
• Severe hepatic impairment (Child-Pugh C)
• Pregnancy (second and third trimester)
• Hypersensitivity to any component

Warnings and Precautions

• Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus
• Discontinue when pregnancy is detected

• Black patients and those with prior ACE inhibitor-associated angioedema at higher risk
• Discontinue immediately if angioedema occurs

• May cause symptomatic hypotension; more common in volume-depleted patients
• Correct volume depletion prior to initiation

• May cause increases in serum creatinine and BUN
• Monitor renal function during therapy

• May increase serum potassium
• Monitor potassium levels, especially in patients with renal impairment or diabetes

Drug Interactions

• ACE inhibitors: Increased risk of angioedema (absolute contraindication)
• Potassium-sparing diuretics, potassium supplements: Increased risk of hyperkalemia
• NSAIDs: May reduce antihypertensive effect and worsen renal function
• Lithium: Increased lithium concentrations and toxicity
• Aliskiren: Contraindicated in diabetic patients

• Other antihypertensive agents: Additive hypotensive effects
• Dual CYP2C9 and CYP3A4 inhibitors: May increase valsartan exposure

Adverse Effects

• Hypotension (18%)
• Hyperkalemia (12%)
• Cough (9%)
• Dizziness (6%)
• Renal impairment (5%)

• Angioedema (<1%)
• Symptomatic hypotension
• Acute renal failure
• Elevated liver enzymes

Monitoring Parameters

• Blood pressure (sitting and standing)
• Renal function (serum creatinine, eGFR)
• Serum electrolytes (potassium, sodium)
• Liver function tests
• Pregnancy test in women of childbearing potential

• Blood pressure at each dose titration and periodically thereafter
• Renal function and potassium within 1-2 weeks of initiation and after dose changes
• Regular assessment of volume status
• Monitor for signs of angioedema

Patient Education

• Take medication exactly as prescribed, twice daily with or without food
• Do not stop taking suddenly without medical supervision
• Report any signs of allergic reaction (swelling of face, lips, throat, difficulty breathing)
• Report dizziness, lightheadedness, or fainting, especially when standing up
• Regular blood pressure monitoring is important
• Avoid pregnancy while taking this medication; use effective contraception
• Inform all healthcare providers about all medications being taken
• Report any persistent dry cough
• Maintain regular follow-up appointments for monitoring

• Limit alcohol consumption
• Maintain consistent salt intake unless otherwise directed
• Stay well-hydrated but avoid excessive fluid intake
• Report any changes in weight or swelling

References

1. McMurray JJV, et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014;371(11):993-1004. 2. Entresto® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 3. Yancy CW, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017;70(6):776-803. 4. Ponikowski P, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37(27):2129-2200. 5. Packer M, et al. Angiotensin Receptor Neprilysin Inhibition Compared with Enalapril on the Risk of Clinical Progression in Surviving Patients with Heart Failure. Circulation. 2015;131(1):54-61.