Sacubitril, a neprilysin inhibitor, and Valsartan are combined to form Valsartan (Angiotensin receptor blocker) By blocking the enzyme neprilysin, sacubitril inhibits the breakdown of natriuretic peptides (atrial and brain natriuretic peptides), which has a diuretic effect. Patients with decreased ejection fraction and NYHA class II or higher symptomatic heart failure are eligible for it. It frequently co-administers medications for heart failure such as ACE inhibitors and angiotensin receptor blockers.

It frequently co-administers medications for heart failure such as ACE inhibitors and angiotensin receptor blockers. In patients with a decreased ejection fraction and symptomatic heart failure who can take ACE inhibitors or ARBs, the ACC/AHA/HFSA advises therapy with sacubitril valsartan. Patients who were currently on ACE inhibitors or angiotensin receptor blockers were included in the Paradigm heart failure experiment. According to recent research, it may increase the ejection fraction in individuals with decompensated heart failure by up to 10%.

Sacubitril and Valsartan dose in adults

• When prescribing Entresto, which contains sacubitril and valsartan, it's important to be cautious about dosing.
• In clinical trials, dosing was based on the total amount of both components.
• For example, 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.
• To prevent errors, include the doses of both ingredients (e.g., Entresto 24/26 mg) when prescribing Entresto.
• Additionally, the valsartan in Entresto is more easily absorbed by the body compared to valsartan in other tablet forms.
• For instance, valsartan 26 mg, 51 mg, and 103 mg in Entresto is equivalent to valsartan 40 mg, 80 mg, and 160 mg in other tablet forms, respectively.

Sacubitril/Valsartan dose in the treatment of Heart failure:

In the treatment of heart failure with sacubitril/valsartan, the dosage depends on the patient's previous use of ACE inhibitors or ARBs:

• For patients previously on moderate to high doses of ACE inhibitors or ARBs, the initial dose is sacubitril 49 mg/valsartan 51 mg twice daily. The dose is doubled to the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily after 2 to 4 weeks if tolerated.
• For patients previously on low doses of ACE inhibitors or ARBs, the initial dose is sacubitril 24 mg/valsartan 26 mg twice daily. The dose is doubled every 2 to 4 weeks as tolerated until reaching the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily.
• For patients not currently taking ACE inhibitors or ARBs, the initial dose is sacubitril 24 mg/valsartan 26 mg twice daily. The dose is doubled every 2 to 4 weeks as tolerated until reaching the target maintenance dose of sacubitril 97 mg/valsartan 103 mg twice daily.

It's crucial to note that concomitant use of an ACE inhibitor is contraindicated, and a 36-hour washout period is required when switching from or to an ACE inhibitor.

Sacubitril/Valsartan dose in Children

Not recommended in children

Pregnancy category X

• The US boxed warning for sacubitril/valsartan highlights the risk of harm, including injury and death, to a developing fetus when drugs directly affecting the renin-angiotensin system are used during pregnancy.
• If pregnancy is detected, sacubitril/valsartan should be discontinued promptly.
• Additional information regarding this warning can be found in the valsartan monograph.

Use during lactation and breastfeeding

• Due to uncertainty about whether sacubitril or valsartan is present in breast milk, the manufacturer does not recommend breastfeeding while taking sacubitril/valsartan.
• This precaution is due to the potential for serious adverse reactions in the breastfeeding infant.

Sacubitril/Valsartan Dose in Renal disease:

• For individuals with an estimated glomerular filtration rate (eGFR) of 30 mL/minute/1.73 m² or higher, no dosage adjustment is required when prescribing sacubitril/valsartan.
• For those with an eGFR below 30 mL/minute/1.73 m², the initial dose is sacubitril 24 mg/valsartan 26 mg twice daily. It's worth noting that some experts do not recommend the use of sacubitril/valsartan in this population.

Sacubitril/Valsartan Dose in Liver disease:

• For individuals with mild impairment of liver function (Child-Pugh class A), no dosage adjustment is necessary when prescribing sacubitril/valsartan.
• In cases of moderate impairment (Child-Pugh class B), the initial dose is sacubitril 24 mg/valsartan 26 mg twice daily.
• For severe impairment (Child-Pugh class C), the use of sacubitril/valsartan is not recommended as it has not been studied in this population.

Common Side Effects of Valsartan and Sacubitril include:

• Cardiovascular:
  • Hypotension
• Renal:
  • Increased Serum Creatinine
• Endocrine & Metabolic:
  • Increased Serum Potassium
  • Hyperkalemia

Less Common Side Effects of Valsartan and sacubitril Include:

• Central Nervous System:
  • Dizziness
  • Falling
• Cardiovascular:
  • Orthostatic Hypotension
• Hematologic & Oncologic:
• • Decreased Hematocrit
  • Decreased Hemoglobin
• Renal:
  • Renal Failure
• Hypersensitivity:
  • Angioedema
• Respiratory:
  • Cough

Contraindication to Sacubitril Valsartan Include: 

• Sacubitril/valsartan is contraindicated in individuals with hypersensitivity to sacubitril, valsartan, or any component of the formulation, as well as those with a history of angioedema related to previous ACE inhibitor or ARB therapy.
• Concomitant use of sacubitril/valsartan with ACE inhibitors, use within 36 hours of ACE inhibitors, or use with aliskiren in patients with diabetes are also contraindicated.
• According to the ACC/AHA/HFSA guidelines, the medication is contraindicated in patients with a history of angioedema, regardless of cause.
• In Canada, additional contraindications include recent symptomatic hypotension before starting sacubitril/valsartan, concomitant use of aliskiren in patients with moderate to severe renal impairment (eGFR <60 mL/minute/1.73 m²), pregnancy, and breastfeeding.

Warnings and precautions

Angioedema

• Angioedema, though rare, has been reported with some angiotensin II receptor antagonists (ARBs) and can occur at any time during treatment, particularly following the first dose.
• It may affect the head and neck, potentially compromising the airway, or the intestine, presenting with abdominal pain.
• Close monitoring, especially if the tongue, glottis, or larynx are involved, is crucial as they can lead to airway obstruction and may be fatal, especially in patients with a history of airway surgery.
• If angioedema occurs, therapy should be discontinued immediately and not readministered.
• Early and aggressive management is essential, and intramuscular administration of epinephrine may be necessary.
• Patients with a history of angioedema may be at increased risk, and higher rates of angioedema may occur in black patients compared to non-black patients.
• Sacubitril/valsartan should not be given to patients with a history of hereditary angioedema or angioedema associated with an ACE inhibitor or ARB.

Hyperkalemia:

• Hyperkalemia, an elevated level of potassium in the blood, is a potential risk associated with sacubitril/valsartan.
• Factors contributing to this risk include renal dysfunction, diabetes mellitus, hypoaldosteronism, a high potassium diet, and the concurrent use of certain medications such as aliskiren (which is contraindicated), potassium-sparing diuretics, potassium supplements, and potassium-containing salts.
• It's advised to exercise caution, or avoid altogether, the use of sacubitril/valsartan with these agents, and closely monitor potassium levels in patients receiving this medication.

Hypotension

• Hypotension, or low blood pressure, is a possible side effect during the early stages of sacubitril/valsartan therapy, especially in patients with heart failure or those who have had a myocardial infarction (MI).
• Symptomatic hypotension may occur particularly in patients who are depleted in salt or volume, such as those treated with high-dose diuretics.
• To mitigate this risk, it's important to correct volume depletion before starting therapy or to initiate treatment at a lower dose.
• It's essential to note that this transient drop in blood pressure is not a reason to discontinue treatment with sacubitril and valsartan.

Renal function deterioration:

• Sacubitril/valsartan use may lead to deterioration in renal function and an increase in serum creatinine levels, especially in patients with conditions such as renal artery stenosis or heart failure, where renal blood flow is already compromised and glomerular filtration rate (GFR) depends on efferent arteriolar vasoconstriction by angiotensin II.
• This deterioration can manifest as oliguria, acute renal failure, and progressive azotemia.
• It's important to note that small increases in serum creatinine may occur initially after starting treatment.
• Discontinuation of sacubitril/valsartan should be considered only in patients experiencing progressive and/or significant deterioration in renal function.
• Regular monitoring of renal function is advisable during therapy with sacubitril/valsartan, especially in patients with pre-existing renal impairment or conditions predisposing to renal dysfunction.

Mitral and aortic stenosis:

• Sacubitril/valsartan should be used cautiously in patients with significant aortic or mitral stenosis.
• These conditions involve narrowing of the valves that regulate blood flow in the heart.
• The caution is warranted because sacubitril/valsartan can affect blood pressure and heart function, which may have implications in patients with compromised heart valve function.
• Close monitoring and careful assessment of the patient's condition are recommended when using sacubitril/valsartan in such individuals.

Heart failure:

• When initiating sacubitril/valsartan therapy in patients with heart failure, caution is advised due to the potential for hypotension, or low blood pressure.
• Depending on the patient's response, dose adjustments may be necessary, and concurrent diuretic therapy may need to be modified to manage hypotension effectively.
• It's essential to closely monitor blood urea nitrogen (BUN), serum creatinine, and potassium levels, especially in patients with preexisting renal disease.
• Regular monitoring helps to detect any changes in renal function or electrolyte levels early on, allowing for timely intervention if needed.

Renal artery stenosis

• In patients with unstented unilateral or bilateral renal artery stenosis, sacubitril/valsartan should be used with caution.
• However, in cases of unstented bilateral renal artery stenosis, the use of sacubitril/valsartan is generally avoided due to the increased risk of renal function deterioration.

Hepatic impairment

• In patients with moderate hepatic impairment, sacubitril/valsartan should be used with caution, and dosage reduction may be necessary.
• However, its use is not recommended in patients with severe hepatic impairment.
• Hepatic impairment can affect the metabolism and clearance of medications, potentially leading to increased drug levels and a higher risk of adverse effects.
• Therefore, careful monitoring and dose adjustments are important to ensure the safe and effective use of sacubitril/valsartan in patients with hepatic impairment.

Renal impairment

• In patients with preexisting renal insufficiency, sacubitril/valsartan should be used with caution.
• For those with severe renal impairment, indicated by an estimated glomerular filtration rate (eGFR) less than 30 mL/minute/1.73 m², the initial dosage should be reduced.
• Renal impairment can affect the clearance and metabolism of medications, potentially leading to increased drug levels and a higher risk of adverse effects.
• Therefore, cautious dosing and close monitoring are important to ensure the safe and effective use of sacubitril/valsartan in patients with renal impairment.

Monitor:

• Baseline Assessment:
  • Measure serum potassium levels, renal function, and blood pressure (BP) before starting sacubitril/valsartan.
• Periodic Monitoring:
  • Regularly check serum potassium, renal function, and BP during treatment.
• 2013 ACCF/AHA Heart Failure Guideline Recommendations:
  • Within 1 to 2 weeks after starting an ARB (angiotensin II receptor blocker), reassess BP (including postural changes), renal function, and serum potassium.
  • Monitor closely after any dose adjustments.
  • Special attention should be given to patients with:
    • Systolic blood pressure <80 mm Hg
    • Low serum sodium
    • Diabetes mellitus
    • Impaired renal function

Please note that these guidelines were formulated before the availability of sacubitril/valsartan, so they do not specifically address this medication.

How to administer Sacubitril/Valsartan?

• Oral Administration:
  • Sacubitril/valsartan can be taken with or without food.

Mechanism of action of Sacubitril/Valsartan:

Sacubitril:

• Sacubitril is a prodrug that works by inhibiting neprilysin, also known as neutral endopeptidase.
• Its active metabolite, LBQ657, inhibits neprilysin, which leads to increased levels of peptides, including natriuretic peptides.
• This increase in peptides induces vasodilation (widening of blood vessels) and natriuresis (excretion of sodium in the urine), ultimately reducing the workload on the heart.

Valsartan:

• Valsartan acts by directly antagonizing the angiotensin II type 1 (AT1) receptors.
• It displaces angiotensin II from the AT1 receptor, thereby inhibiting AT1-induced vasoconstriction (narrowing of blood vessels), aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic (enlargement of heart muscle) responses.

This combination of mechanisms helps to lower blood pressure, reduce fluid overload, and improve symptoms in patients with heart failure.

Distribution:

• Sacubitril: Volume of distribution (V) is 103 L.
• Valsartan: Volume of distribution (V) is 75 L.
• Both drugs are highly protein-bound, with 94% to 97% of sacubitril/valsartan bound to plasma proteins.

Metabolism:

• Sacubitril is metabolized to its active metabolite LBQ657 by esterases.
• LBQ657 is not further metabolized to a significant extent.
• Valsartan undergoes minimal metabolism, with only around 20% being metabolized, primarily to a hydroxyl metabolite.

Bioavailability:

• Sacubitril has a bioavailability of over 60%.

Half-life:

• Sacubitril has a half-life of 1.4 hours.
• LBQ657, the active metabolite of sacubitril, has a half-life of 11.5 hours.
• Valsartan has a half-life of 9.9 hours.

Time to Peak:

• Sacubitril reaches peak plasma concentration in 0.5 hours.
• LBQ657 reaches peak plasma concentration in 2 hours.
• Valsartan reaches peak plasma concentration in 1.5 hours.

Excretion:

• Sacubitril is primarily excreted in the urine (52% to 68%), mainly as LBQ657, and in the feces (37% to 48%), also primarily as LBQ657.
• Valsartan is excreted in the urine (~13%), both as the parent drug and metabolites, and in the feces (86%), primarily as the parent drug and metabolites.

Sacubitril/Valsartan International Brands:

• Entresto
• Azmada
• Sacutrend
• Uperio
• Vacubitron

Sacubitril/Valsartan brands in Pakistan:

Cubil - Genix Sacvin - Pharamevo Savesto - Getz Uperio - Novartis Valsar-S - Helix Valsatril - Sami