August 2020 I IE02/ENT20-006a
Abbreviated Prescribing Information
Please refer to Summary of Product Characteristics (SmPC) before prescribing.
Entresto® (sacubitril valsartan) 24 mg/26 mg film-coated tablets, 49 mg/51mg film-coated tablets and 97mg/103mg film-coated tablets
Presentation: Film-coated tablets of 24 mg/26 mg, 49 mg/51mg and 97 mg/103 mg of sacubitril and valsartan respectively (as sacubitril valsartan sodium salt complex). Indications: In adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction. Dosage and administration: The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient. In patients not currently taking an ACE inhibitor or an ARB, or taking low doses of these medicinal products, a starting dose of 24 mg/26 mg twice daily and slow dose titration (doubling every 3 – 4 weeks) are recommended. A starting dose of 24 mg/26 mg twice daily should be considered for patients with SBP ≥100 to 110 mmHg, moderate or severe renal impairment (use with caution in severe renal impairment) and moderate hepatic impairment. Do not co-administer with an ACE inhibitor or an ARB. Do not start treatment for at least 36 hours after discontinuing ACE inhibitor therapy. Entresto may be administered with or without food. The tablets must be swallowed with a glass of water. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Concomitant use with ACE inhibitors. Do not administer until 36 hours after discontinuing ACE inhibitor therapy. Known history of angioedema 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 trimesters of pregnancy.
Warnings/Precautions: Dual blockade of the renin angiotensin-aldosterone system (RAAS): Combination with an ACE inhibitor is contraindicated due to the increased risk of angioedema. Sacubitril/valsartan must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with sacubitril/valsartan is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of sacubitril/valsartan. Combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is not recommended. Sacubitril/valsartan should not be co-administered with another ARB containing product. Hypotension: Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were not studied. Cases of symptomatic hypotension have been reported in patients treated with sacubitril/valsartan during clinical studies, especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg). Blood pressure should be monitored routinely when initiating or during dose titration with sacubitril/valsartan. If hypotension occurs, temporary down-titration or discontinuation of sacubitril/valsartan is recommended. Impaired or worsening renal function: Limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m2). There is no experience in patients with end-stage renal disease and use of sacubitril/valsartan is not recommended. Use of sacubitril/valsartan may be associated with decreased renal function, and down-titration should be considered in these patients. Hyperkalaemia: Treatment should not be initiated if the serum potassium level is >5.4 mmol/l. Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists. If clinically significant hyperkalaemia occurs, consider adjustment of concomitant medicinal products or temporary down-titration or discontinuation of sacubitril/valsartan. If serum potassium level is >5.4 mmol/l discontinuation should be considered. Angioedema: Angioedema has been reported with sacubitril/valsartan. If angioedema occurs, discontinue sacubitril/valsartan immediately and provide appropriate therapy and monitoring until complete and sustained resolution of signs and symptoms has occurred. Sacubitril/valsartan must not be re-administered. Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if sacubitril/valsartan is used in these patients. Black patients have an increased susceptibility to develop angioedema. Patients with renal artery stenosis: Caution is required and monitoring of renal function is recommended. Patients with NYHA functional classification IV: Caution should be exercised due to limited clinical experience in this population. 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. Caution is therefore recommended in these patients. B-type natriuretic peptide (BNP): BNP is not a suitable biomarker of heart failure in patients treated with sacubitril/valsartan because it is a neprilysin substrate. Interactions: Contraindicated with ACE inhibitors, 36 hours washout is required. Use with aliskiren contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2). Should not be co-administered with another ARB. Use with caution when co-administering sacubitril/valsartan with statins or PDE5 inhibitors. No clinically relevant drug-drug interaction was observed when simvastatin and sacubitril/valsartan were co-administered. Monitoring serum potassium is recommended if sacubitril/valsartan is co-administered with potassium-sparing diuretics or substances containing potassium (such as heparin). Monitoring renal function is recommended when initiating or modifying treatment in patients on sacubitril/valsartan who are taking NSAIDs concomitantly. Interactions between sacubitril/valsartan and lithium have not been investigated. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Co-administration of sacubitril/valsartan and furosemide reduced Cmax and AUC of furosemide by 50% and 28%, respectively, with reduced urinary excretion of sodium. Co-administration of nitroglycerin and sacubitril/valsartan was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone, no dose adjustment is required. Co-administration of sacubitril/valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of sacubitril or valsartan. Appropriate care should be exercised. Co-administration of sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin by 23%. When initiating therapy with sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be evaluated. Fertility, pregnancy and lactation: The use of sacubitril/valsartan is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy. It is not known whether sacubitril/valsartan is excreted in human milk, but components were excreted in the milk of rats. Sacubitril/valsartan is not recommended during breast-feeding. A decision should be made whether to abstain from breast-feeding or to discontinue sacubitril/valsartan while breast-feeding, taking into account the importance of sacubitril/valsartan to the mother. No available data on the effect of sacubitril/valsartan on human fertility. Undesirable effects: Very common: Hyperkalaemia, hypotension, renal impairment. Common: Anaemia, hypokalaemia, hypoglycaemia, dizziness, headache, syncope, vertigo, orthostatic hypotension, cough, diarrhoea, nausea, gastritis, renal failure, acute renal failure, fatigue, asthenia. Uncommon: Hypersensitivity, postural dizziness, pruritus, rash, angioedema. Please refer to SmPC for a full list of adverse events for Entresto. Pack sizes: Entresto 24 mg/26 mg – 28 tablet pack; Entresto 49 mg/51 mg – 28 and 56 tablet pack; Entresto 97 mg/103 – 56 tablet pack. Legal Category: POM. Marketing Authorisation Holder: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road Dublin 4, Ireland. Marketing Authorisation Numbers: Entresto 24 mg/26 mg film coated tablets EU/1/15/1058/001; Entresto 49 mg/51 mg film coated tablets EU/1/15/1058/002-003; Entresto 97 mg/103 mg film coated tablets EU/1/15/1058/006. Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Merrion Road, Dublin 4. Tel: 01 2601255 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu. Prescribing Information last revised: June 2020
Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance on www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: firstname.lastname@example.org or by calling 01 2080 612.