Sacubitril And Valsartan

Introduction Overview

Generic Name

sacubitril and valsartan

Brand Name

Entresto, Entresto Sprinkle

Dosage Form

oral pellet (15 mg-16 mg; 6 mg-6 mg), oral tablet (24 mg-26 mg; 49 mg-51 mg; 97 mg-103 mg)

Drug Class

Angiotensin receptor blockers and neprilysin inhibitors

Pharmacokinetics

Sacubitril and valsartan is a combination of two active agents with complementary pharmacokinetic properties designed to improve clinical outcomes in heart failure patients.

Absorption:
Sacubitril and valsartan are administered orally; sacubitril is a prodrug that is rapidly absorbed and converted by esterases to the active neprilysin inhibitor, LBQ657. Valsartan is absorbed with moderate bioavailability, approximately 23–25% when dosed as the combination product, which is slightly lower compared to valsartan monotherapy due to formulation differences. Peak plasma concentrations of sacubitril, LBQ657, and valsartan occur within 0.5 to 2 hours post-dose. Food intake has minimal clinically significant impact on the absorption of the combination drug, allowing flexibility in administration with or without meals.

Distribution:
Both agents exhibit extensive distribution into body tissues. LBQ657 and valsartan are highly protein bound, predominantly to albumin (>95%), which impacts their pharmacodynamics and interaction potential. The volume of distribution for valsartan ranges from approximately 17 L to 30 L, indicating distribution beyond plasma but limited penetration into the central nervous system. LBQ657 distributes similarly, with a volume of distribution near 100 L, reflecting moderate tissue penetration but limited CNS crossing due to polarity and molecular weight.

Metabolism:
Sacubitril functions as a prodrug, rapidly metabolized by esterases in the cytosol to produce LBQ657, the active neprilysin inhibitor. This conversion is rapid and efficient, reaching peak levels within 1 hour. Valsartan undergoes minimal hepatic metabolism primarily via cytochrome P450 2C9 with less than 20% being metabolized, the majority is excreted unchanged. This limits the risk of extensive drug-drug metabolism interactions but necessitates caution in severe hepatic impairment.

Elimination:
Excretion of LBQ657 and valsartan occurs via renal and biliary routes. LBQ657 is primarily eliminated renally with a half-life of approximately 11.5 hours, whereas valsartan is cleared predominantly through biliary and fecal pathways with a half-life of 9.9 hours. The elimination half-lives support twice-daily dosing regimens. Patients with renal or hepatic impairment may exhibit altered clearance necessitating dose adjustment and monitoring. Clinical studies suggest that moderate renal impairment prolongs LBQ657 exposure, and severe hepatic impairment increases valsartan plasma concentrations.

Dosage Forms

Available Dosage Forms:
- Oral pellet capsule: 15 mg sacubitril and 16 mg valsartan; 6 mg sacubitril and 6 mg valsartan.
- Oral tablet: 24 mg sacubitril and 26 mg valsartan; 49 mg sacubitril and 51 mg valsartan; 97 mg sacubitril and 103 mg valsartan.

Dosages for Adults and Adolescents:
Sacubitril and valsartan is used primarily for the treatment of chronic heart failure with reduced ejection fraction in adults and symptomatic heart failure in children one year and older. The usual initial dose for adults is 49 mg sacubitril/51 mg valsartan twice daily, titrated upward to a target maintenance dose of 97 mg/103 mg twice daily as tolerated. Lower starting doses (24 mg/26 mg twice daily) are recommended for patients not previously treated with an ACE inhibitor or ARB, those with moderate hepatic impairment, or severe renal impairment. Dose adjustments may also consider blood pressure, renal function, and potassium levels during therapy.

Specific Patient Populations:
In pediatric patients (aged 1 year and above), dosing is weight-based and determined by clinical condition and response, frequently starting at conservative doses and titrating upward cautiously. In patients with moderate to severe renal impairment or moderate hepatic impairment, starting doses are reduced, with careful monitoring for adverse effects, particularly hyperkalemia and hypotension. Sacubitril and valsartan is contraindicated in patients with severe hepatic impairment. Administration instructions emphasize not taking the drug with concurrent ACE inhibitors or within 36 hours of ACE inhibitor therapy to avoid the risk of angioedema. For patients with difficulty swallowing tablets, oral suspension (prepared by pharmacist) and oral pellet forms provide alternatives. Oral pellets must be administered by opening the capsule and sprinkling contents over a small amount of soft food, not to be chewed or swallowed whole, nor administered via feeding tubes.

Mechanism Of Action

Sacubitril and valsartan combine two pharmacologically distinct mechanisms to produce a synergistic effect in managing heart failure. Sacubitril is a prodrug that is metabolized to LBQ657, an inhibitor of neprilysin, a neutral endopeptidase responsible for degrading natriuretic peptides. By inhibiting neprilysin, sacubitril increases the levels of biologically active natriuretic peptides including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These peptides promote vasodilation, natriuresis, diuresis, and inhibition of maladaptive fibrosis and hypertrophy, thereby reducing cardiac preload and afterload.

Valsartan is a selective antagonist of the angiotensin II type 1 (AT1) receptor, blocking the deleterious effects of angiotensin II such as vasoconstriction, aldosterone secretion, sodium retention, and sympathetic activation. This blockade results in reduced systemic vascular resistance and decreased myocardial workload.

The combination provides comprehensive neurohormonal modulation: sacubitril amplifies protective natriuretic peptide pathways, while valsartan suppresses detrimental renin-angiotensin-aldosterone system (RAAS) activation. This dual approach counters progressive cardiac remodeling and improves cardiac function.

Clinical trials, including the pivotal PARADIGM-HF study, demonstrate that sacubitril/valsartan significantly reduces mortality and heart failure hospitalization rates compared to ACE inhibitor therapy alone, correlating well with its dual biochemical and physiological effects. Compared to ACE inhibitors, sacubitril/valsartan reduces the risk of angioedema through the lack of bradykinin accumulation, while providing enhanced vasodilatory and natriuretic effects. Ongoing research also explores additional benefits in renal protection and metabolic effects mediated via neprilysin substrates.

Pharmacological Actions

Inhibition of neprilysin enzyme by sacubitril's active metabolite (LBQ657), increasing levels of natriuretic peptides.
Blockade of angiotensin II type 1 receptors by valsartan, preventing vasoconstriction and aldosterone-mediated sodium retention.
Enhanced vasodilation through increased cyclic GMP signaling from natriuretic peptides.
Promotion of natriuresis and diuresis reducing preload and pulmonary congestion.
Reduction of myocardial fibrosis and hypertrophy via natriuretic peptide mediated pathways.
Attenuation of sympathetic nervous system and renin-angiotensin-aldosterone system overactivation.
Decreased systemic vascular resistance decreasing afterload and cardiac workload.
Improved renal hemodynamics and reduction of renal fibrosis.
Improved cardiac remodeling and function in heart failure patients.
Lowered risk of hospitalization and mortality in chronic heart failure.
Complementary actions of neprilysin inhibition and angiotensin receptor blockade.
Potential metabolic benefits through modulation of vasoactive peptides.
Better safety profile regarding angioedema compared to ACE inhibitors.

Therapeutic Or Clinical Uses

Treatment of chronic heart failure with reduced ejection fraction in adults to reduce cardiovascular death and hospitalization.
Management of symptomatic heart failure in pediatric patients aged 1 year and older.
Reduction of hospitalization risk during episodes of worsening heart failure.
Alternative therapy in patients unable to tolerate ACE inhibitors due to cough or angioedema.
Combination therapy targeting neurohormonal pathways in heart failure management.
Potential off-label uses for improving cardiac remodeling in various heart failure etiologies.
Improvement of left ventricular ejection fraction as demonstrated in clinical trials.
Adjunct to optimize blood pressure control in patients with heart failure.
Renoprotective effects by modulating natriuretic peptide and RAAS systems.
Reduction of myocardial fibrosis and cardiac hypertrophy progression.
Part of multidrug regimen including beta-blockers, diuretics, and mineralocorticoid receptor antagonists for comprehensive heart failure care.
Therapeutic option in patients with previous inadequate response to ACE inhibitors or ARBs.
Improvement in quality of life measures in heart failure patients.
Potential use in patients with high risk for cardiovascular events due to heart failure.
Treatment approach in heart failure with persistent symptoms despite guideline directed medical therapy.

Side Or Adverse Effects

Kidney dysfunction or worsening renal function observed occasionally.
Hyperkalemia (elevated blood potassium), which may cause cardiac arrhythmias.
Symptomatic hypotension, including dizziness or lightheadedness, potentially leading to syncope.
Cough, although less frequent than with ACE inhibitors.
Angioedema, presenting as swelling of face, lips, tongue, or throat, requiring emergency care.
Fatigue or asthenia reported in some patients.
Nausea and gastrointestinal symptoms.
Increased serum creatinine indicating impaired renal function or dehydration risk.
Rare reports of hepatotoxicity or elevated liver enzymes.
Potential allergic reactions with rash or urticaria.
Electrolyte imbalances such as hyponatremia or hypokalemia in some cases.
Headache and dizziness due to blood pressure lowering effects.
Orthostatic hypotension particularly in elderly or volume-depleted patients.
Potential fetal toxicity if used during pregnancy.
Injection site reactions are not applicable as medication is oral.

Precautions

Avoid use during pregnancy due to risk of fetal injury or death; discontinue immediately if pregnancy detected.
Do not use concomitantly or within 36 hours of ACE inhibitors to reduce angioedema risk.
Use caution in patients with history of angioedema or hereditary angioedema.
Monitor renal function and potassium levels regularly, especially in patients with renal impairment or diabetes.
Adjust dose or discontinue in patients who develop symptomatic hypotension or worsening renal function.
Exercise caution in patients on potassium supplements, potassium-sparing diuretics, or high potassium diets.
Avoid use with aliskiren-containing drugs in diabetic or renal-compromised patients.
Use carefully in patients with severe hepatic impairment; generally contraindicated.
Evaluate volume status and correct dehydration before initiating therapy.
Do not use in patients allergic to sacubitril, valsartan, or related drugs (ACE inhibitors, ARBs).
Patients with low blood pressure should be monitored closely for symptoms of hypotension.
Special caution advised in elderly patients due to higher risk of hypotension and renal impairment.
Ensure patient education regarding symptom recognition of angioedema and electrolyte disturbances.
Avoid administration of oral pellets via feeding tubes to prevent tube blockage.
Dose adjustments required based on patient weight, especially in pediatric populations.

Warnings

Black box warning for fetal toxicity; discontinue immediately upon pregnancy detection.
Potential for life-threatening angioedema;seek emergency medical attention if swelling occurs.
Risk of severe hypotension especially in volume-depleted patients or those with impaired renal function.
Hyperkalemia risk necessitates periodic monitoring of serum potassium.
Do not administer within 36 hours of ACE inhibitors due to increased angioedema risk.
Concomitant use with aliskiren contraindicated in diabetic patients.
Use caution in patients with a history of hypersensitivity to angiotensin receptor blockers or neprilysin inhibitors.
Avoid abrupt discontinuation to prevent rebound heart failure exacerbations.
Combination therapy may increase risk of renal impairment in patients with bilateral renal artery stenosis.
Potential interaction with NSAIDs increasing risk of renal dysfunction.
Patients should be instructed not to take potassium supplements or salt substitutes containing potassium unless prescribed.
Monitoring is essential during dose titration to detect adverse hemodynamic effects early.
Careful consideration is required when switching from ACE inhibitors or ARBs to sacubitril/valsartan to avoid overlap.
Not recommended for use in patients with severe hepatic impairment or biliary obstruction.
Avoid use in patients with known hypersensitivity to either component.

Contraindication

Hypersensitivity to sacubitril, valsartan, or any component of the formulation.
History of angioedema related to previous ACE inhibitor or ARB therapy.
Concomitant use with ACE inhibitors or within 36 hours of ACE inhibitor use.
Concomitant use with aliskiren-containing drugs in patients with diabetes mellitus.
Pregnancy due to known fetal toxicity and risk of death.
Severe hepatic impairment (Child-Pugh Class C).
Unexplained bilateral renal artery stenosis.
Known hereditary or idiopathic angioedema.
Patients with a history of hypersensitivity to other ARBs or neprilysin inhibitors.
Use in patients with conditions predisposing to hyperkalemia without adequate monitoring.
Should not be administered via feeding tube (oral pellets form).
Severe hypotension or volume depletion without correction prior to treatment initiation.
Concomitant use with lithium due to risk of increased lithium toxicity.
Severe renal impairment without appropriate dose adjustments and monitoring.

Drug Interactions

Avoid concurrent use with ACE inhibitors to prevent angioedema; maintain a 36-hour washout period.
Concomitant use with aliskiren contraindicated in patients with diabetes or renal impairment.
Potential additive hyperkalemia risk when combined with potassium-sparing diuretics (spironolactone, triamterene, amiloride) or potassium supplements.
NSAIDs (including aspirin, ibuprofen, naproxen, celecoxib, diclofenac, indomethacin, meloxicam) may reduce the antihypertensive effect and increase risk of renal impairment.
Concomitant use with lithium may increase lithium serum levels and risk toxicity; monitoring recommended.
Potential interactions with other antihypertensive agents leading to excessive blood pressure reduction.
Drugs that affect renal function (e.g., diuretics) may enhance the risk of impaired renal clearance.
Caution with drugs metabolized by CYP2C9 as valsartan is partially metabolized through this pathway.
Concurrent use with other RAAS inhibitors requires close monitoring for hypotension, renal function, and electrolytes.
Use with other neprilysin inhibitors or drugs increasing natriuretic peptides not recommended.
Interactions with herbal supplements that may impact potassium or blood pressure levels.
Co-administration with drugs affecting plasma protein binding could alter valsartan pharmacokinetics.
Monitoring advised when used with cytochrome P450 inducers or inhibitors due to potential altered drug levels.
No significant interactions with food; however, concomitant medications may affect absorption.
Pharmacodynamic interactions with drugs affecting vascular tone or heart rate require careful assessment.

Preparations Of The Drug

Entresto oral tablets combining sacubitril and valsartan in strengths of 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg for twice daily administration.
Entresto Sprinkle oral pellets available in capsule form containing 15 mg sacubitril/16 mg valsartan or 6 mg sacubitril/6 mg valsartan.
Oral suspension (liquid) formulation may be compounded by a pharmacist for patients with swallowing difficulties; stable for up to 15 days at room temperature and not refrigerated.
Packaging includes capsules containing oral pellets intended to be sprinkled on soft foods such as applesauce, yogurt, or pudding just before administration.
Instructions clarify that pellets should not be chewed or swallowed whole, nor administered through feeding tubes to avoid clogging.
Tablets are film-coated for ease of swallowing and stability.
Supplied in blister packs or bottles with clear dosing instructions correlating to heart failure management protocols.
Commercial preparations include detailed patient information leaflets and dosing guides for adults and pediatric use.
Pharmaceutical-grade drug products undergo quality testing to ensure potency, stability, and bioavailability.
Storage recommendations specify keeping products at room temperature away from moisture and heat.
Prescriptions often include titration schedules based on clinical response and tolerance.
Drug packaging includes safety features to prevent medication errors given multiple strength options.
Distinct visual identifiers (imprints, colors, shapes) distinguish tablet strengths to minimize dosing errors.
Patient support programs may offer co-pay assistance or educational materials to improve adherence.
Preparation of oral suspension requires precise measurement with supplied devices, emphasizing the importance of pharmacist counseling.