ENTRESTO Film-coated tablet Ref.[10513] Active ingredients: Sacubitril Valsartan Valsartan and Sacubitril

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.

Adult heart failure

The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, except in the situations described below. The dose should be doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient (see section 5.1).

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 of Entresto is recommended (see section 4.4).

In PARADIGM-HF study, Entresto was administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB (see section 5.1). 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 24 mg/26 mg twice daily and slow dose titration (doubling every 3-4 weeks) are recommended in these patients (see “Titration” in section 5.1).

Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg (see section 4.4). A starting dose of 24 mg/26 mg twice daily should be considered for patients with SBP ≥100 to 110 mmHg.

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.

Entresto film-coated tablets are not suitable for children weighing less than 40 kg. Entresto granules are available for these patients.

Table 1. Recommended dose titration:

^* 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 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

Elderly

The dose should be in line with the renal function of the elderly patient.

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 (given as granules) 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 (given as granules) 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 may be administered with or without food (see section 5.2). The tablets must be swallowed with a glass of water. Splitting or crushing of the tablets is not recommended.

Limited data are available with regard to overdose in humans. A single dose of 583 mg sacubitril/617 mg valsartan and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) were studied in healthy adult volunteers and were well tolerated.

Hypotension is the most likely symptom of overdose due to the blood pressure lowering effects of sacubitril/valsartan. Symptomatic treatment should be provided.

The medicinal product is unlikely to be removed by haemodialysis due to high protein binding (see section 5.2).

3 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture.

PVC/PVDC/Aluminium blisters.

Entresto 24 mg/26 mg film-coated tablets:

Pack sizes: 14, 20, 28, 56 or 196 film-coated tablets and multipacks containing 196 (7 packs of 28) film-coated tablets.

Entresto 49 mg/51 mg film-coated tablets:

Pack sizes: 14, 20, 28, 56, 168 or 196 film-coated tablets and multipacks containing 168 (3 packs of 56) or 196 (7 packs of 28) film-coated tablets.

Entresto 97 mg/103 mg film-coated tablets:

Pack sizes: 14, 20, 28, 56, 168 or 196 film-coated tablets and multipacks containing 168 (3 packs of 56) or 196 (7 packs of 28) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.