Sacubitril + Valsartan

Usage

• Sacubitril + Valsartan is prescribed to reduce the risk of cardiovascular death and hospitalization for adults with chronic heart failure (CHF) and children aged 1 year and older with symptomatic heart failure with systemic left ventricular systolic dysfunction. It is most effective in patients with a left ventricular ejection fraction (LVEF) below normal.
• Pharmacological Classification: Angiotensin receptor-neprilysin inhibitor (ARNI).
• Mechanism of Action: Sacubitril + Valsartan has a dual mechanism: Sacubitril inhibits neprilysin, which increases the levels of natriuretic peptides (NPs). NPs have vasodilatory, natriuretic, and diuretic effects. Valsartan blocks the angiotensin II receptor, preventing vasoconstriction and reducing aldosterone secretion.

Alternate Names

• International Nonproprietary Name (INN): Sacubitril/Valsartan.
• Brand Name: Entresto, Entresto Sprinkle.

How It Works

• Pharmacodynamics: Sacubitril increases the levels of vasoactive peptides, promoting vasodilation and diuresis. Valsartan blocks the deleterious effects of angiotensin II, preventing vasoconstriction and reducing aldosterone release. This dual action decreases cardiac workload and improves hemodynamics.
• Pharmacokinetics:
  • Absorption: Both sacubitril and valsartan are orally absorbed, with peak plasma concentrations reached within 0.5-2 hours for sacubitril and its active metabolite (LBQ657), and 1.5 hours for valsartan. Food doesn’t significantly affect absorption.
  • Metabolism: Sacubitril is metabolized to LBQ657, its active metabolite. Valsartan is minimally metabolized.
  • Elimination: Primarily renal excretion for LBQ657 and a combination of hepatic metabolism and renal excretion for valsartan.

Dosage

Standard Dosage

Adults:

• Initial Dose: 49 mg sacubitril/51 mg valsartan orally twice daily.
• Target Maintenance Dose: After 2-4 weeks, increase to 97 mg sacubitril/103 mg valsartan twice daily, as tolerated.

Children (≥1 year):

• Dose based on body weight, administered orally twice daily. Titration every 2-4 weeks, as tolerated.
• <40 kg: Recommended mg/kg doses of combined sacubitril and valsartan. An extemporaneously compounded oral suspension (4 mg/mL sacubitril/valsartan, 1.96 mg/mL sacubitril and 2.04mg/mL valsartan) is available.
  • Starting dose: 1.6 mg/kg BID.
  • Second titration: 2.3 mg/kg BID.
  • Maximum dose: 3.1 mg/kg BID.
• ≥40 kg and <50 kg:
  • Starting dose: 24 mg/26 mg BID.
  • Second titration: 49 mg/51 mg BID.
  • Maximum dose: 72 mg/78 mg BID.
• ≥50 kg:
  • Starting dose: 49 mg/51 mg BID.
  • Second titration: 72 mg/78 mg BID.
  • Maximum dose: 97 mg/103 mg BID.

Special Cases:

• Elderly Patients (≥75 years): Consider a lower starting dose (24/26 mg twice daily).
• Renal Impairment:
  • Mild-to-moderate (eGFR ≥30 mL/min/1.73 m²): No initial dose adjustment.
  • Severe (eGFR <30 mL/min/1.73 m²): Reduce starting dose to 24/26 mg BID, titrate as tolerated.
• Hepatic Impairment:
  • Mild (Child-Pugh A): No initial dose adjustment.
  • Moderate (Child-Pugh B): Reduce starting dose to 24/26 mg BID, titrate as tolerated.
  • Severe (Child-Pugh C): Not recommended.

Clinical Use Cases

• Dosages for specific medical settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations are not specifically defined for sacubitril/valsartan. Treat CHF according to standard guidelines based on the patient’s clinical status and the provided dosage adjustments.

Side Effects

Common Side Effects:

• Hypotension, dizziness, lightheadedness
• Cough
• Hyperkalemia
• Renal impairment

Rare but Serious Side Effects:

• Angioedema
• Renal failure

Adverse Drug Reactions (ADR):

• Angioedema requires immediate discontinuation of the drug and appropriate medical intervention.

Contraindications

• Hypersensitivity to sacubitril or valsartan.
• History of angioedema related to ACE inhibitor or ARB therapy.
• Concomitant use of ACE inhibitors.
• Concomitant use of aliskiren in patients with diabetes or renal impairment (eGFR <60 mL/min/1.73 m²).
• Severe hepatic impairment, biliary cirrhosis, cholestasis (Child-Pugh C).
• Pregnancy (second and third trimesters).

Drug Interactions

• ACE Inhibitors: Contraindicated due to increased risk of angioedema. A 36-hour washout period is required when switching between ACE inhibitors and sacubitril/valsartan.
• ARBs: Avoid concomitant use as valsartan is an ARB.
• Aliskiren: Contraindicated in patients with diabetes or renal impairment.
• Potassium-sparing diuretics: May increase the risk of hyperkalemia.
• Statins: Sacubitril can inhibit OATP transporters, potentially increasing statin exposure. Monitor cholesterol levels and adjust statin dose as needed.
• PDE5 inhibitors (e.g., sildenafil): May increase the risk of hypotension.
• OATP1B1, OATP1B3, OAT1, OAT3, and MRP2 substrates: Concomitant use with inhibitors of these transporters may increase exposure to LBQ657 or valsartan.
• Lithium: Increased lithium levels may occur. Monitor lithium levels closely.

Pregnancy and Breastfeeding

• Pregnancy: Contraindicated during the second and third trimesters due to the risk of fetal harm. Not recommended during the first trimester.
• Breastfeeding: Not recommended due to potential risk to the newborn.

Drug Profile Summary

• Mechanism of Action: ARNI - increases natriuretic peptides, blocks angiotensin II receptors.
• Side Effects: Hypotension, cough, hyperkalemia, angioedema, renal impairment.
• Contraindications: Hypersensitivity, history of angioedema with ACEi/ARB, concomitant ACEi/aliskiren, severe hepatic impairment, pregnancy (2nd/3rd trimesters).
• Drug Interactions: ACE inhibitors, ARBs, aliskiren, potassium-sparing diuretics, statins, PDE5 inhibitors.
• Pregnancy & Breastfeeding: Contraindicated in 2nd and 3rd trimesters of pregnancy; breastfeeding not recommended.
• Dosage: Adults: Initial 49/51 mg BID, target 97/103 mg BID; children 1 year or older: weight based dose. See dosage section for detailed recommendations and adjustments.
• Monitoring Parameters: Blood pressure, potassium levels, renal function (serum creatinine, eGFR).

Popular Combinations

• Sacubitril/valsartan is often used in combination with beta-blockers and mineralocorticoid receptor antagonists (MRAs) in patients with heart failure, as part of guideline-directed medical therapy.

Precautions

• Monitor renal function and potassium levels during treatment.
• Angioedema: Be vigilant, especially in Black patients and those with a history of angioedema.
• Renal artery stenosis: May increase blood urea and serum creatinine levels.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Sacubitril + Valsartan in adults?

A: Initial dose is 49 mg sacubitril/51 mg valsartan twice daily, increasing to 97/103 mg twice daily after 2-4 weeks as tolerated.

Q2: How should I transition a patient from an ACE inhibitor to Sacubitril + Valsartan?

A: Discontinue the ACE inhibitor and wait 36 hours before starting sacubitril/valsartan.

Q3: Can Sacubitril + Valsartan be used in patients with renal impairment?

A: Yes, but dose adjustments are needed for severe renal impairment (eGFR <30 mL/min/1.73 m²).

Q4: What are the most common side effects of Sacubitril + Valsartan?

A: Hypotension, dizziness, cough, and hyperkalemia.

Q5: What is the most serious side effect of Sacubitril + Valsartan?

A: Angioedema, which can be life-threatening.

Q6: Can Sacubitril + Valsartan be used during pregnancy?

A: Contraindicated during the second and third trimesters and not recommended during the first trimester.

Q7: Is it safe to breastfeed while taking Sacubitril + Valsartan?

A: Breastfeeding is not recommended while taking this medication.

Q8: What other medications should be avoided while taking Sacubitril + Valsartan?

A: ACE inhibitors, aliskiren (especially in patients with diabetes or renal impairment), and ARBs. Caution should be used when co-administering with statins, potassium sparing diuretics, and PDE5 inhibitors.

Q9: What monitoring parameters are important for patients on Sacubitril/Valsartan?

A: Blood pressure, potassium levels, and renal function (eGFR and creatinine).