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Sacubitril and Valsartan

Pronunciation

(sak UE bi tril & val SAR tan)

Index Terms

  • LCZ696
  • Sacubitril/Valsartan
  • Valsartan and Sacubitril

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Entresto: Sacubitril 24 mg and valsartan 26 mg, Sacubitril 49 mg and valsartan 51 mg, Sacubitril 97 mg and valsartan 103 mg

Brand Names: U.S.

  • Entresto

Pharmacologic Category

  • Angiotensin II Receptor Blocker
  • Neprilysin Inhibitor

Pharmacology

Sacubitril: Prodrug that inhibits neprilysin (neutral endopeptidase [NEP]) through the active metabolite LBQ657, leading to increased levels of peptides, including natriuretic peptides.

Valsartan: Produces direct antagonism of the angiotensin II (AT2) receptors. Displaces angiotensin II from the AT1 receptor; antagonizes AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Distribution

Vd: Sacubitril: 103 L; Valsartan: 75 L

Metabolism

Sacubitril: Converted to active metabolite LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent

Valsartan: Minimally metabolized (~20%; <10% as a hydroxyl metabolite)

Excretion

Sacubitril: Urine (52% to 68%, primarily as LBQ657); feces (37% to 48%, primarily as LBQ657)

Valsartan: Urine (~13%, parent drug and metabolites); feces (86%, parent drug and metabolites)

Time to Peak

Sacubitril: 0.5 hours; LBQ657: 2 hours; Valsartan: 1.5 hours

Half-Life Elimination

Sacubitril: 1.4 hours; LBQ657: 11.5 hours; Valsartan: 9.9 hours

Protein Binding

94% to 97%

Use: Labeled Indications

US labeling:

Heart failure: Reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction; usually administered in conjunction with other heart failure therapies, in place of an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin II receptor blocker (ARB)

Note: According to the ACC/AHA/HFSA heart failure guidelines, in patients with chronic symptomatic heart failure with reduced ejection fraction (HFrEF) NYHA Class II or III who tolerate an ACE inhibitor or ARB, replacement with sacubitril/valsartan is recommended (ACC/AHA/HFSA [Yancy 2016]). In addition, prior to enrollment in the PARADIGM-HF clinical trial, patients were already receiving a stable dose of an ACE inhibitor or ARB at daily doses equivalent to at least 10 mg of enalapril (McMurray 2014).

Canadian labeling:

Heart failure: Reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II or III) and reduced ejection fraction; should be administered in conjunction with other heart failure therapies, in place of an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin II receptor blocker (ARB).

Contraindications

Hypersensitivity to sacubitril, valsartan, or any component of the formulation; history of angioedema related to previous ACE inhibitor or ARB therapy; concomitant use or use within 36 hours of ACE inhibitors; concomitant use of aliskiren in patients with diabetes

According to the ACC/AHA/HFSA guidelines, the use of sacubitril/valsartan is contraindicated in patients with a history of angioedema, regardless of cause (ACC/AHA/HFSA [Yancy 2016]).

Canadian labeling: Additional contraindications (not in US labeling): Recent symptomatic hypotension prior to initiation of treatment with sacubitril/valsartan; history of hereditary or idiopathic angioedema; concomitant use of aliskiren in patients with moderate to severe renal impairment (eGFR <60 mL/minute/1.73 m2); pregnancy.

Dosing: Adult

US labeling: Note: Entresto contains sacubitril (24 mg, 49 mg, or 97 mg) and valsartan (26 mg, 51 mg, or 103 mg). Use caution when prescribing since dosing in clinical trials was based on the total amount of both components (ie, 24/26 mg, 49/51 mg and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively). To reduce the risk of errors, include the doses of both ingredients (eg, Entresto 24/26 mg) when prescribing Entresto. The valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations; valsartan 26 mg, 51 mg, and 103 mg in Entresto is equivalent to valsartan 40 mg, 80 mg, and 160 mg in other marketed tablet formulations, respectively.

Heart failure: Oral: Patients previously taking >10 mg/day of enalapril or >160 mg/day of valsartan or equivalent dose of another ACE inhibitor or ARB: Initial: Sacubitril 49 mg and valsartan 51 mg twice daily. Double the dose as tolerated after 2 to 4 weeks to the target maintenance dose of sacubitril 97 mg and valsartan 103 mg twice daily. Note: Concomitant use of an ACE inhibitor is contraindicated; allow a 36 hour washout period when switching from or to an ACE inhibitor.

Patients previously taking low doses of an ACE inhibitor (≤10 mg/day of enalapril or an equivalent dose of another ACE inhibitor) or ARB (≤160 mg/day of valsartan or an equivalent dose of another ARB): Initial: Sacubitril 24 mg and valsartan 26 mg twice daily. Double the dose as tolerated every 2 to 4 weeks to the target maintenance dose of sacubitril 97 mg and valsartan 103 mg twice daily.

Patients not currently taking an ACE inhibitor or an ARB: Initial: Sacubitril 24 mg and valsartan 26 mg twice daily. Double the dose as tolerated every 2 to 4 weeks to the target maintenance dose of sacubitril 97 mg and valsartan 103 mg twice daily.

Canadian labeling: Note: Use caution when prescribing since dosing in clinical trials was based on the total amount of both components (ie, 48.6/51.4 mg and 97.2/102.8 mg were referred to as 100 mg, and 200 mg respectively). To reduce the risk of errors, include the doses of both ingredients when prescribing Entresto. The valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations; valsartan 26 mg, 51 mg, and 103 mg in Entresto is equivalent to valsartan 40 mg, 80 mg, and 160 mg in other marketed tablet formulations, respectively.

Heart failure: Adults: Oral: Initial: Sacubitril 48.6 mg and valsartan 51.4 mg twice daily. Increase the dose as tolerated after 2 to 4 weeks to the target maintenance dose of sacubitril 97.2 mg and valsartan 102.8 mg twice daily. If tolerability becomes an issue, consider temporary down-titration or interruption of therapy. Note: Concomitant use of an ACE inhibitor is contraindicated; allow a 36 hour washout period when switching from or to an ACE inhibitor.

Patients with risk factors for hypotension or with low systolic blood pressure: Initial: Consider sacubitril 24.3 mg and valsartan 25.7 mg twice daily. Increase the dose as tolerated every 2 to 4 weeks to the target maintenance dose of sacubitril 97.2 mg and valsartan 102.8 mg twice daily.

Dosing: Geriatric

US labeling: Refer to adult dosing.

Canadian labeling:

<75 years: Refer to adult dosing.

≥75 years: Initial: Consider sacubitril 24.3 mg and valsartan 25.7 mg twice daily. Increase the dose as tolerated every 2 to 4 weeks to the target maintenance dose of sacubitril 97.3 mg and valsartan 102.8 mg twice daily.

Dosing: Renal Impairment

US labeling:

Estimated glomerular filtration rate (eGFR) ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: Initial: Sacubitril 24 mg and valsartan 26 mg twice daily

Canadian labeling:

Estimated glomerular filtration rate (eGFR) ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: Use is not recommended.

Dosing: Hepatic Impairment

US labeling:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Initial: Sacubitril 24 mg and valsartan 26 mg twice daily

Severe impairment (Child-Pugh class C): Use not recommended (has not been studied).

Canadian labeling:

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Initial: Sacubitril 24.3 mg and valsartan 25.7 mg twice daily.

Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

Administration

Oral: Administer with or without food.

Storage

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) . Protect from moisture.

Drug Interactions

ACE Inhibitors: May enhance the adverse/toxic effect of Sacubitril. Specifically, the risk of angioedema may be increased with this combination. Avoid combination

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Aliskiren: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Aliskiren may enhance the nephrotoxic effect of Angiotensin II Receptor Blockers. Management: Aliskiren use with ACEIs or ARBs in patients with diabetes is contraindicated. Combined use in other patients should be avoided, particularly when CrCl is less than 60 mL/min. If combined, monitor potassium, creatinine, and blood pressure closely. Consider therapy modification

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Antihepaciviral Combination Products: May increase the serum concentration of Valsartan. Management: Per antihepaciviral combination product US prescribing information, consider decreasing the valsartan dose and monitoring for evidence of hypotension and worsening renal function if these agents are used in combination. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canagliflozin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Canagliflozin may enhance the hypotensive effect of Angiotensin II Receptor Blockers. Monitor therapy

Ciprofloxacin (Systemic): Angiotensin II Receptor Blockers may enhance the arrhythmogenic effect of Ciprofloxacin (Systemic). Monitor therapy

CycloSPORINE (Systemic): Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of CycloSPORINE (Systemic). Monitor therapy

Dapoxetine: May enhance the orthostatic hypotensive effect of Angiotensin II Receptor Blockers. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Drospirenone: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Eltrombopag: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Gemfibrozil: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. See separate drug interaction monographs for agents listed as exceptions. Monitor therapy

Heparin: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Heparin (Low Molecular Weight): May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

HydroCHLOROthiazide: May enhance the hypotensive effect of Valsartan. Valsartan may increase the serum concentration of HydroCHLOROthiazide. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Consider therapy modification

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Teriflunomide: May increase the serum concentration of OATP1B1/SLCO1B1 Substrates. Monitor therapy

Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

Also see individual agents.

>10%:

Cardiovascular: Hypotension (18%)

Endocrine & metabolic: Increased serum potassium (4% to 16%), hyperkalemia (12%)

Renal: Increased serum creatinine (1% to 16%)

1% to 10%:

Cardiovascular: Orthostatic hypotension (2%)

Central nervous system: Dizziness (6%), falling (2%)

Hematologic & oncologic: Decreased hematocrit (≤5%), decreased hemoglobin (≤5%)

Hypersensitivity: Angioedema (black patients: 2%; others: <1%)

Renal: Renal failure (5%)

Respiratory: Cough (9%)

ALERT: U.S. Boxed Warning

Fetal toxicity:

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue sacubitril/valsartan as soon as possible.

Warnings/Precautions

Concerns related to adverse effects:

• Angioedema: Angioedema has been reported rarely with some angiotensin II receptor antagonists (ARBs) and may occur at any time during treatment (especially following first dose). It may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE-inhibitor therapy may be at an increased risk. Prolonged frequent monitoring may be required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Discontinue therapy immediately if angioedema occurs. Aggressive early management is critical. Intramuscular (IM) administration of epinephrine may be necessary. Do not readminister to patients who have had angioedema with ARBs.

• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, hypoaldosteronism, high potassium diet, concomitant use of aliskiren (contraindicated), potassium-sparing diuretics, potassium supplements, and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.

• Hypotension: During the initiation of therapy, hypotension may occur, particularly in patients with heart failure or post-MI patients. Symptomatic hypotension may occur upon initiation in patients who are salt- or volume-depleted (eg, those treated with high-dose diuretics); correct volume depletion prior to administration or initiate at a lower dose. This transient hypotensive response is not a contraindication to further treatment with sacubitril and valsartan.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns:

• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.

• Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy, because of valsartan-induced hypotension. Careful monitoring of BUN, serum creatinine, and potassium is necessary especially if preexisting renal disease exists.

• Hepatic impairment: Use with caution and reduce dosage in patients with moderate hepatic impairment; use is not recommended in patients with severe hepatic impairment.

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution in preexisting renal insufficiency; reduce initial dosage for severe impairment (eGFR <30 mL/minute/1.73 m2). The Canadian labeling recommends avoiding use in patients with eGFR <30 mL/minute/1.73 m2.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

• Surgical patients: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011).

Monitoring Parameters

Baseline and periodic serum potassium, renal function, BP.

2013 ACCF/AHA Heart Failure guideline recommendations: Within 1 to 2 weeks after initiation of an ARB, reassess blood pressure (including postural blood pressure changes), renal function, and serum potassium; follow closely after dose changes. Patients with systolic blood pressure <80 mm Hg, low serum sodium, diabetes mellitus, and impaired renal function should be closely monitored (Yancy, 2013). Note: Sacubitril/valsartan was not available for use at the time of the publication of these guidelines.

Pregnancy Considerations

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. Refer to the valsartan monograph for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of high potassium (abnormal heartbeat, confusion, dizziness, passing out, weak, shortness of breath, numbness or tingling feeling), dizziness, passing out, loss of strength and energy, or cough that will not go away (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating, and advising patients.

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