Sacubitril is only available in combination with valsartan. This combined drug is known as sacubitril/valsartan. Therefore, the information provided below pertains to the combined drug sacubitril/valsartan.
Usage
- Medical Conditions: Sacubitril/valsartan is prescribed for chronic heart failure with reduced ejection fraction (HFrEF). It is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic HFrEF (NYHA Class II-IV). It is usually administered in conjunction with other heart failure therapies, replacing ACE inhibitors or ARBs.
- Pharmacological Classification: Angiotensin receptor-neprilysin inhibitor (ARNI). Sacubitril is a neprilysin inhibitor and valsartan is an angiotensin II receptor blocker (ARB).
- Mechanism of Action: Sacubitril/valsartan has a dual mechanism: Sacubitril inhibits neprilysin, a neutral endopeptidase that degrades vasoactive peptides including natriuretic peptides. Valsartan blocks the angiotensin II type-1 receptor, preventing vasoconstriction and aldosterone release. The combined effect leads to increased levels of natriuretic peptides, promoting vasodilation, natriuresis, and diuresis, thereby reducing cardiac workload and improving hemodynamics in heart failure.
Alternate Names
- International Nonproprietary Name (INN): Sacubitril/valsartan
- Brand Names: Entresto, Vymada
How It Works
- Pharmacodynamics: Sacubitril increases levels of vasoactive peptides like natriuretic peptides, resulting in vasodilation, natriuresis, and diuresis. Valsartan blocks the effects of angiotensin II, leading to vasodilation and reduced aldosterone secretion.
- Pharmacokinetics: Both sacubitril and valsartan are orally administered. Sacubitril is rapidly metabolised to the active metabolite LBQ657. Valsartan is also metabolized, but to a lesser extent. Both LBQ657 and valsartan are primarily eliminated through biliary excretion, with a smaller portion undergoing renal excretion. They have a half-life of approximately 12 hours.
- Mode of Action: Sacubitril inhibits neprilysin, preventing the breakdown of natriuretic peptides. Valsartan blocks the AT1 receptor, preventing angiotensin II from binding and exerting its effects.
- Receptor Binding/Enzyme Inhibition: Sacubitril inhibits neprilysin. Valsartan blocks AT1 receptors.
- Elimination Pathways: Primarily biliary excretion; some renal excretion.
Dosage
Standard Dosage
Adults:
- Starting Dose: 49 mg sacubitril/51 mg valsartan twice daily.
- Target Maintenance Dose: 97 mg sacubitril/103 mg valsartan twice daily.
- Titration: Double the dose every 2-4 weeks as tolerated, aiming for the target maintenance dose.
- Patients not currently taking an ACE inhibitor or an ARB or taking low doses: Starting dose of 24 mg/26 mg twice daily, doubling every 3–4 weeks as tolerated, up to the target maintenance dose.
- Patients with SBP ≥100 to 110 mmHg: A starting dose of 24 mg/26 mg twice daily should be considered.
Children (1 year and older): Dosing based on body weight. See detailed dosing information in sources.
Special Cases:
- Elderly Patients: Start with the lowest dose and titrate cautiously. Close monitoring of renal function and blood pressure is important.
- Patients with Renal Impairment (eGFR < 30 mL/min/1.73 m2): Start at half the usual recommended starting dose.
- Patients with Hepatic Dysfunction (Child-Pugh B): Start at half the usual recommended starting dose. Severe hepatic impairment (Child-Pugh C) is a contraindication.
- Patients with Comorbid Conditions: Careful monitoring is recommended. Dose adjustments may be necessary based on individual patient characteristics and response to therapy.
Clinical Use Cases
Sacubitril/valsartan is specifically indicated for chronic HFrEF. Its use in acute settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations is not established and generally not recommended.
Dosage Adjustments
Adjustments based on tolerability and the presence of renal or hepatic impairment are outlined above and in the source documents.
Side Effects
Common Side Effects:
Hypotension, dizziness, cough, hyperkalemia, renal impairment.
Rare but Serious Side Effects:
Angioedema, severe hypotension, worsening renal function (including acute renal failure), hyperkalemia.
Long-Term Effects:
Long-term side effects are still being investigated. Regular monitoring of renal function, potassium levels and blood pressure are crucial.
Adverse Drug Reactions (ADR):
Angioedema, severe hypotension, acute renal failure, hyperkalemia.
Contraindications
- Hypersensitivity to sacubitril, valsartan, or any component of the formulation.
- History of angioedema related to previous ACE inhibitor or ARB therapy.
- Concomitant use of ACE inhibitors.
- Concomitant use of aliskiren in patients with diabetes.
- Severe hepatic impairment (Child-Pugh C), biliary cirrhosis, or cholestasis.
- Pregnancy (second and third trimesters). Not recommended during the first trimester.
Drug Interactions
- ACE Inhibitors: Contraindicated. Do not administer within 36 hours of switching to or from an ACE inhibitor.
- ARBs: Avoid concomitant use.
- Aliskiren: Contraindicated in patients with diabetes or renal impairment. Not recommended in other patients.
- NSAIDs (including COX-2 inhibitors): Can worsen renal function, especially in patients who are elderly, volume-depleted, or with compromised renal function.
- Lithium: Can increase serum lithium levels and lithium toxicity.
- OATP1B1 and OATP1B3 substrates (e.g. statins): Sacubitril/valsartan can increase systemic exposure to these substrates. Exercise caution when co-administering.
- Metformin: Sacubitril/valsartan can reduce Cmax and AUC of metformin.
- Potassium-sparing diuretics and potassium supplements: Can increase risk of hyperkalemia.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Contraindicated during the second and third trimesters. Use not recommended during the first trimester due to the potential for fetal harm (renal toxicity).
- Breastfeeding: Not recommended due to potential for adverse effects in infants from exposure to sacubitril/valsartan.
Drug Profile Summary
- Mechanism of Action: ARNI; sacubitril inhibits neprilysin, increasing natriuretic peptides; valsartan blocks AT1 receptors.
- Side Effects: Hypotension, hyperkalemia, cough, dizziness, renal impairment, angioedema.
- Contraindications: Hypersensitivity, angioedema history with ACEi/ARB, concomitant ACEi/aliskiren (in diabetics), severe hepatic impairment, pregnancy (2nd/3rd trimesters).
- Drug Interactions: ACE inhibitors, ARBs, aliskiren, NSAIDs, lithium, OATP substrates, metformin.
- Pregnancy & Breastfeeding: Contraindicated in 2nd/3rd trimesters, not recommended in 1st trimester or during breastfeeding.
- Dosage: Adults: Start 49/51 mg BID, target 97/103 mg BID. Pediatric: Weight-based dosing. Adjustments for renal/hepatic impairment.
- Monitoring Parameters: Blood pressure, renal function, potassium levels.
Popular Combinations
Sacubitril/valsartan is often used in combination with beta-blockers, mineralocorticoid receptor antagonists (MRAs), and diuretics in the management of heart failure.
Precautions
- General Precautions: Monitor renal function, potassium levels, and blood pressure regularly.
- Pregnant Women: Avoid use. Contraindicated in 2nd/3rd trimesters.
- Breastfeeding Mothers: Avoid use.
- Children & Elderly: Start with lower doses and titrate carefully.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Sacubitril/valsartan?
A: Adults: Initial dose is 49/51 mg twice daily, titrated to a target maintenance dose of 97/103 mg twice daily as tolerated. Pediatric dosing is weight-based.
Q2: What are the most common side effects of Sacubitril/valsartan?
A: The most common side effects are hypotension, dizziness, cough, and hyperkalemia.
Q3: Can Sacubitril/valsartan be used with ACE inhibitors?
A: No, concomitant use with ACE inhibitors is contraindicated due to increased risk of angioedema.
Q4: What is the mechanism of action of Sacubitril/valsartan?
A: Sacubitril/valsartan is an ARNI. Sacubitril inhibits neprilysin, increasing levels of natriuretic peptides. Valsartan blocks AT1 receptors, inhibiting the effects of angiotensin II.
Q5: Is Sacubitril/valsartan safe in pregnancy?
A: No, it is contraindicated during the second and third trimesters of pregnancy and is not recommended in the first trimester.
Q6: What monitoring parameters are important for patients on Sacubitril/valsartan?
A: Blood pressure, renal function, and potassium levels should be monitored regularly.
Q7: What should be done if a patient experiences hypotension while taking Sacubitril/valsartan?
A: If hypotension occurs, consider adjusting concomitant medications (like diuretics), temporarily down-titrating, or discontinuing Sacubitril/valsartan.
Q8: Can Sacubitril/valsartan be used in patients with hepatic impairment?
A: Use with caution in patients with moderate hepatic impairment. It is contraindicated in severe hepatic impairment.
Q9: What are the contraindications to using Sacubitril/valsartan?
A: Contraindications include hypersensitivity, history of angioedema related to ACEi/ARB therapy, concomitant use of ACE inhibitors or aliskiren (in patients with diabetes), severe hepatic impairment, and pregnancy (second and third trimesters).
Q10: What patient education should be provided when prescribing Sacubitril/valsartan?
A: Counsel patients on the importance of adhering to the prescribed dose, potential side effects (including hypotension, cough, and hyperkalemia), and the need for regular monitoring of blood pressure, renal function, and potassium levels. Emphasize the contraindication with ACE inhibitors.
