Paediatric heart failure Entresto is indicated in children and adolescents aged one year or older for treatment of symptomatic chronic heart failure with left ventricular systolic dysfunction (see section 5.1).

Posology General considerations Entresto should not be co-administered with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (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 (see sections 4.3, 4.4 and 4.5). The valsartan contained within Entresto is more bioavailable than the valsartan in other marketed tablet formulations (see section 5.2). If a dose is missed, the patient should take the next dose at the scheduled time. Paediatric heart failure Table 1 shows the recommended dose for paediatric patients. The recommended dose should be taken orally twice daily. The dose should be increased every 2-4 weeks to the target dose, as tolerated by the patient. The lowest recommended dose is 6 mg/6 mg. Doses can be rounded up or down to the closest combination of full 6 mg/6 mg and/or 15 mg/16 mg capsules. When rounding the dose up or down during the up-titration phase, consideration should be given to ensuring progressive increase to the target dose. For patients weighing more than 40 kg, Entresto film-coated tablets can be used. Table 1 Recommended dose titration To be given twice daily Patient weight Half the starting dose* Starting dose Intermediate dose Target dose Paediatric patients less than 40 kg 0.8 mg/kg# 1.6 mg/kg# 2.3 mg/kg# 3.1 mg/kg# Paediatric patients at least 40 kg, less than 50 kg 0.8 mg/kg# 24 mg/26 mg 49 mg/51 mg 72 mg/78 mg Paediatric patients at least 50 kg 24 mg/26 mg 49 mg/51 mg 72 mg/78 mg 97 mg/103 mg * Half the starting dose is recommended in patients who have not been taking an ACE inhibitor or an ARB or have been taking low doses of these medicinal products, patients who have renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) and patients who have moderate hepatic impairment (see special populations). #0.8 mg/kg, 1.6 mg/kg, 2.3 mg/kg and 3.1 mg/kg refer to the combined amount of sacubitril and valsartan and are to be given using granules. In patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, half of the starting dose is recommended. For paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended. After initiation, the dose should be increased to the standard starting dose following the recommended dose titration in Table 1 and adjusted every 3-4 weeks. For example, a paediatric patient weighing 25 kg who has not previously taken an ACE inhibitor should start with half the standard starting dose, which corresponds to 20 mg (25 kg × 0.8 mg/kg) twice daily, given as granules. After rounding to the closest number of full capsules, this corresponds to 2 capsules of 6 mg/6 mg sacubitril/valsartan twice daily. Treatment should not be initiated in patients with serum potassium level >5.3 mmol/l or with systolic blood pressure (SBP) <5th percentile for the age of the patient. If patients experience tolerability issues (SBP <5th percentile for the age of the patient, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down-titration or discontinuation of Entresto is recommended (see section 4.4). Special populations Renal impairment No dose adjustment is required in patients with mild (eGFR 60-90 ml/min/1.73 m2) renal impairment. Half of the starting dose 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) (see section 5.1), Entresto should be used with caution and half of the starting dose is recommended. In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily is recommended. After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks. There is no experience in patients with end-stage renal disease and use of Entresto is not recommended. Hepatic impairment No dose adjustment is required when administering Entresto 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 aspartate transaminase (AST)/alanine transaminase (ALT) values more than twice the upper limit of the normal range. Entresto should be used with caution in these patients and half of the starting dose is recommended (see sections 4.4 and 5.2). In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily is recommended. After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks. Entresto is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification) (see section 4.3). Paediatric population The safety and efficacy of Entresto in children aged below 1 year have not been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Method of administration Oral use. Entresto granules are administered by opening the capsule and sprinkling the contents onto a small amount of soft food (1 to 2 teaspoons). Food containing the granules must be consumed immediately. Patients may receive either the 6 mg/6 mg (white cap) or 15 mg/16 mg (yellow cap) capsules or both to reach the required doses (see section 6.6). The capsule must not be swallowed. The empty shells must be discarded after use and not swallowed.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. • Concomitant use with ACE inhibitors (see sections 4.4 and 4.5). Entresto must not be administered until 36 hours after discontinuing ACE inhibitor therapy. • Known history of angioedema related to previous ACE inhibitor or ARB therapy (see section 4.4). • Hereditary or idiopathic angioedema (see section 4.4). • 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) (see sections 4.4 and 4.5). • Severe hepatic impairment, biliary cirrhosis and cholestasis (see section 4.2). • Second and third trimesters of pregnancy (see section 4.6). 4.8 Undesirable effects Summary of the safety profile The most commonly reported adverse reactions in adults during treatment with sacubitril/valsartan were hypotension (17.6%), hyperkalaemia (11.6%) and renal impairment (10.1%) (see section 4.4). Angioedema was reported in patients treated with sacubitril/valsartan (0.5%) (see description of selected adverse reactions). Tabulated list of adverse reactions Adverse reactions are ranked by System organ class and then by frequency with the most frequent first, using the following convention: very common (=1/10); common (=1/100 to <1/10); uncommon (=1/1 000 to <1/100); rare (=1/10 000 to <1/1 000); very rare (<1/10 000). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. Table 2 List of adverse reactions System organ class Preferred term Frequency category Blood and lymphatic system disorders Anaemia Common Immune system disorders Hypersensitivity Uncommon Hyperkalaemia* Very common Hypokalaemia Common Hypoglycaemia Common Metabolism and nutrition disorders Hyponatraemia Uncommon Hallucinations** Rare Sleep disorders Rare Psychiatric disorders Paranoia Very rare Dizziness Common Headache Common Syncope Common Nervous system disorders Dizziness postural Uncommon Ear and labyrinth disorders Vertigo Common Hypotension* Very common Vascular disorders Orthostatic hypotension Common Respiratory, thoracic and mediastinal disorders Cough Common Diarrhoea Common Nausea Common Gastritis Common Gastrointestinal disorders Intestinal angioedema Very rare Pruritus Uncommon Rash Uncommon Skin and subcutaneous tissue disorders Angioedema* Uncommon Renal impairment* Very common Renal and urinary disorders Renal failure (renal failure, acute renal failure) Common Fatigue Common General disorders and administration site conditions Asthenia Common *See description of selected adverse reactions. **Including auditory and visual hallucinations Description of selected adverse reactions Angioedema Angioedema has been reported in patients treated with sacubitril/valsartan. In PARADIGM-HF, angioedema was reported in 0.5% of patients treated with sacubitril/valsartan, compared with 0.2% of patients treated with enalapril. A higher incidence of angioedema was observed in Black patients treated with sacubitril/valsartan (2.4%) and enalapril (0.5%) (see section 4.4). Hyperkalaemia and serum potassium In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/l were reported in 11.6% and 19.7% of sacubitril/valsartan-treated patients and 14.0% and 21.1% of enalapril-treated patients, respectively. Blood pressure In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (<90 mmHg and decrease from baseline of >20 mmHg) were reported in 17.6% and 4.76% of sacubitril/valsartan-treated patients compared with 11.9% and 2.67% of enalapril-treated patients, respectively. Renal impairment In PARADIGM-HF, renal impairment was reported in 10.1% of sacubitril/valsartan-treated patients and 11.5% of enalapril-treated patients. Paediatric population In the PANORAMA-HF study, the safety of sacubitril/valsartan was assessed in a randomised, active-controlled, 52-week study of 375 paediatric heart failure (HF) patients aged 1 month to <18 years compared to enalapril. The safety profile observed in paediatric patients aged 1 month to <18 years who received treatment with sacubitril/valsartan was similar to that observed in adult patients. Safety data in patients aged 1 month to <1 year was limited. Limited safety data are available in paediatric patients with moderate hepatic impairment or moderate to severe renal impairment. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. 4.5

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