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  • Entresto
    / Novartis


    Active Ingredient *
    Sacubitril 24, 49, 97 mg
    Valsartan (as sodium salt complex) 26, 51, 103 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    28 X 50 mg

    partial basket chart 32618 5596

    Film Coated Tablets

    56 X 100 mg

    partial basket chart 32620 5598

    Film Coated Tablets

    56 X 200 mg

    partial basket chart 32621 5599

    Dosage

    The recommended starting dose of the formulation is one tablet of 100 mg twice daily, except in the situations described below. The dose should be doubled after 2-4 weeks to the target maintenance dose of one tablet of 200 mg twice daily, as tolerated by the patient. If patients experience tolerability issues (systolic blood pressure [SBP] ≤95 mmHg, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down–titration or discontinuation is recommended. In PARADIGM-HF study, this formulation was administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other angiotensin II receptor blocker (ARB). There is limited experience in patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, therefore a starting dose of 50 mg twice daily and slow dose titration (doubling every 3-4 weeks) are recommended in these patients. Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg. A starting dose of 50 mg twice daily should be considered for patients with SBP≥100 to 110 mmHg. This formulation should not be co-administered with an ACE inhibitor or an ARB. Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, it must not be started for at least 36 hours after discontinuing ACE inhibitor therapy. The valsartan contained within this formulation is more bioavailable than the valsartan in other marketed tablet formulations. If a dose is missed, the patient should take the next dose at the scheduled time.
    Special populations
    Elderly population: The dose should be in line with the renal function of the elderly patient. In patients ≥ 75 years old, a starting dose of 50 mg twice daily should be considered.
    Renal impairment: No dose adjustment is required in patients with mild (Estimated Glomerular Filtration Rate [eGFR] 60-90 ml/min/1.73 m²) renal impairment. A starting dose of 50 mg twice daily should be considered in patients with moderate renal impairment (eGFR 30-60 ml/min/1.73 m²). As  there is very limited clinical experience in patients with severe renal impairment (eGFR <30 ml/min/1.73 m²). This formulation should be used with caution and a starting dose of 50 mg twice daily is recommended. There is no experience in patients with end-stage renal disease and use of the drug is not recommended.
    Hepatic impairment: No dose adjustment is required when administering this formulation to patients with mild hepatic impairment (Child-Pugh A classification). There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. This formulation should be used with caution in these patients and the recommended starting dose is 50 mg twice daily. This formulation is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification).
    Paediatric population: The safety and efficacy of this formulation in children and adolescents aged below 18 years have not been established. No data are available.
    Method of administration: Oral use. This formulation may be administered with or without food. The tablets must be swallowed with a glass of water.


    Indications

    Treatment of heart failure (NYHA class II-IV) in patients with systolic dysfunction. This formulation has been shown to reduce the rate of cardiovascular death and heart failure hospitalisation compared to angiotensin-converting enzyme (ACE) inhibitor therapy.


    Contra-Indications

    Hypersensitivity to the active substances or to any of the excipients.
    Concomitant use with ACE inhibitors, must not be administered until 36 hours after discontinuing ACE inhibitor therapy.
    Known history of angiedema related to previous ACE inhibitor or ARB therapy.
    Hereditary or idiopathic angioedema.
    Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m²).
    Severe hepatic impairment, biliary cirrhosis and cholestasis.
    Second and third trimester of pregnancy.
    Patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg.


    Special Precautions

    Dual blockade of the renin-angiotensin-aldosterone system (RAAS): The combination of this formulation with an ACE inhibitor is contraindicated due to the increased risk of angioedema. This formulation must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with this formulation is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of this formulation. The combination of this formulation with direct renin inhibitors such as aliskiren is not recommended. The combination of this formulation with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m²). This formulation contains valsartan, and therefore should not be co-administered with another ARB containing product.
    Hypotension: Treatment should not be initiated unless SBP is ≥100 mmHg. A starting dose of 50 mg twice daily should be considered for patients with SBP ≥100 mmHg to 110 mmHg. Patients with SBP <100 mmHg were not studied.
    Impaired renal function: Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild and moderate renal impairment are more at risk of developing hypotension. There is very limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m²) and these patients may be at greatest risk of hypotension. There is no experience in patients with end-stage renal disease and use of this formulation is not recommended.
    Worsening renal function: Use of this formulation may be associated with decreased renal function. The risk may be further increased by dehydration or concomitant use of non-steroidal anti-inflammatory agents (NSAIDs). Down-titration should be considered in patients who develop a clinically significant decrease in renal function.
    Hyperkalaemia: Treatment should not be initiated if the serum potassium level is >5.4 mmol/l. Use of this formulation may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur.
    Angioedema: Angioedema has been reported in patients treated with this formulation. If angioedema occurs, this formulation should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred.
    Patients with renal artery stenosis: Entresto may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended.
    Patients with NYHA functional classification IV: Caution should be exercised when initiating Entresto in patients with NYHA functional classification IV due to limited clinical experience in this population.
    B-type natriuretic peptide (BNP): BNP is not a suitable biomarker of heart failure in patients treated with Entresto because it is a neprilysin substrate.
    Patients with hepatic impairment: There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. In these patients, exposure may be increased and safety is not established.
    See prescribing information for full details.


    Side Effects

    Very common: Hyperkalaemia, Hypotension, Renal impairment.
    Common: Anemia, Hypokalaemia, Hypoglycaemia, Dizziness, Headache, Syncope, Vertigo, Orthostatic hypotension, Cough, Diarrhoea, Nausea, Gastritis, Renal failure (renal failure, acute renal failure), Fatigue, Asthenia.
    See prescribing information for full details.


    Drug interactions

    Interactions resulting in a contraindication
    ACE inhibitors: The concomitant use of this formulation with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. this formulation  must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of this formulation.
    Aliskiren: The concomitant use of this formulation with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m²). The combination of this formulation with direct renin inhibitors such as aliskiren is not recommended. Combination of this drug  with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure).
    Interactions resulting in concomitant use not being recommended: This formulation contains valsartan, and therefore should not be co-administered with another ARB containing product.
    Interactions requiring precautions
    OAT1B1 and OATP1B3 substrates, e.g. statins: In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. This formulation may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of with  this formulation increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Therefore, caution should be exercised when co-administering of this formulation  with statins.
    PDE5 inhibitors including sildenafil: Addition of a single dose of sildenafil to this formulation at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of this formulation alone. Therefore, caution should be exercised when sildenafil or another PDE5 inhibitor is initiated in patients treated with this formulation.
    Potassium: Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, salt substitutes containing potassium or other agents (such as heparin) may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if this formulation is co-administered with these agents.
    Non-steroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors: In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of this formulation and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying treatment in patients on this formulation who are taking NSAIDs concomitantly.
    See prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: The use of this drug is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.
    Lactation: It is not known whether this formulation is excreted in human milk. Because of the potential risk for adverse reactions in breast-fed newborns/infants, it is not recommended during breast-feeding.
    See prescribing information for full details.                        


    Overdose

    Limited data are available with regard to overdose in humans. A single dose of Entresto 1200 mg and multiple doses of 900 mg (14 days) were studied in healthy volunteers and were well tolerated. Hypotension is the most likely symptom of overdose due to the blood pressure lowering effects of Entresto. Symptomatic treatment should be provided. The medicinal product is unlikely to be removed by haemodialysis due to high protein binding.


    Important notes

    Storage: Store below 30°C. Protect from moisture.     


    Manufacturer
    Novartis Pharma Stein AG Switzerland
    Licence holder
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