Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

•       The combination of sacubitril/valsartan with an ACE inhibitor is contraindicated due to the increased risk of angioedema (see section 4.3). 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 (see sections 4.2, 4.3 and 4.5).

•       The combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is not recommended (see section 4.5). The combination of sacubitril/valsartan with aliskiren- containing medicinal products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see sections 4.3 and 4.5).

•       Entresto contains valsartan, and therefore should not be co-administered with another ARB containing medicinal product (see sections 4.2 and 4.5).

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 (see section 4.2). Patients with SBP <100 mmHg were not studied (see section 5.1). Cases of symptomatic hypotension have been reported in adult patients treated with sacubitril/valsartan during clinical studies (see section 4.8), especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg). When initiating therapy or during dose titration with sacubitril/valsartan, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of sacubitril/valsartan is recommended (see section 4.2). Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with sacubitril/valsartan , however, such corrective action must be carefully weighed against the risk of volume overload.

Renal impairment

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 (see section 4.2).
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 (see section 4.2). There is no experience in patients with end-stage renal disease and use of sacubitril/valsartan is not recommended.

ENT API JUL23 V3                                                                EU SmPC 05.2023 Worsening renal function

Use of sacubitril/valsartan 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) (see section 4.5). 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 sacubitril/valsartan may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur (see section 4.8). 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 (see section 4.2). If patients experience clinically significant hyperkalaemia adjustment of concomitant medicinal products, or temporary down–titration or discontinuation is recommended. If serum potassium level is >5.4 mmol/l discontinuation should be considered.

Angioedema

Angioedema has been reported in patients treated with sacubitril/valsartan. If angioedema occurs, sacubitril/valsartan should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. It must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms.

Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, e.g. adrenaline solution 1 mg/1 ml (0.3-0.5 ml), and/or measures necessary to ensure a patent airway, should be promptly 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.
sacubitril/valsartan is contraindicated in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy or with hereditary or idiopathic angioedema (see section 4.3).

Black patients have an increased susceptibility to develop angioedema (see section 4.8).

Patients with renal artery stenosis
Sacubitril/valsartan 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 New York Heart Association (NYHA) functional classification IV 
Caution should be exercised when initiating sacubitril/valsartan 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 sacubitril/valsartan because it is a neprilysin substrate (see section 5.1).


ENT API JUL23 V3                                                                  EU SmPC 05.2023 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. Caution is therefore recommended when using it in these patients (see section 4.2 and 5.2). Sacubitril/valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification) (see section 4.3).

Psychiatric disorders

Psychiatric events such as hallucinations, paranoia and sleep disorders, in context of psychotic events, have been associated with sacubitril/valsartan use. If a patient experiences such events, discontinuation of sacubitril/valsartan treatment should be considered.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 97 mg/103 mg dose, that is to say essentially ‘sodium free’.

Effects on Driving

4.7     Effects on ability to drive and use machines

Sacubitril/valsartan has a minor influence on the ability to drive and use machines. When driving
vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue
may occur.




ENT API JUL21 V2                                                             EU SmPC 05.2021