Entresto

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 

Entresto 24 mg/26 mg film-coated tablets 

Entresto 49 mg/51 mg film-coated tablets 

Entresto 97 mg/103 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Entresto 24 mg/26 mg film-coated tablets 

 

Each film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

Entresto 49 mg/51 mg film-coated tablets 

 

Each film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

Entresto 97 mg/103 mg film-coated tablets 

 

Each film-coated tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Film-coated tablet (tablet) 

 

Entresto 24 mg/26 mg film-coated tablets 

 

Violet white ovaloid biconvex film-coated tablet with bevelled edges, unscored, debossed with “NVR” 

on one side and “LZ” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm. 

 

Entresto 49 mg/51 mg film-coated tablets 

 

Pale yellow ovaloid biconvex film-coated tablet with bevelled edges, unscored, debossed with “NVR” 

on one side and “L1” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm. 

 

Entresto 97 mg/103 mg film-coated tablets 

 

Light pink ovaloid biconvex film-coated tablet with bevelled edges, unscored, debossed with “NVR” 

on one side and “L11” on the other side. Approximate tablet dimensions 15.1 mm x 6.0 mm. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Entresto is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced 

ejection fraction (see section 5.1). 

 



3 

4.2 Posology and method of administration 

 

Posology 

 

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 angiotensin II receptor blocker (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. 

 

Entresto 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 (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. 

 

Special populations 

 

Elderly population 

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 (Estimated Glomerular Filtration Rate [eGFR] 

60-90 ml/min/1.73 m2) renal impairment. A starting dose of 24 mg/26 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) (see 

section 5.1) Entresto should be used with caution and a starting dose of 24 mg/26 mg twice daily is 

recommended. 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 AST/ALT values more than twice the upper limit of 

the normal range. Entresto should be used with caution in these patients and the recommended starting 

dose is 24 mg/26 mg twice daily (see sections 4.4 and 5.2). 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 and adolescents aged below 18 years have not been 

established. No data are available. 



4 

 

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. 

 

4.3 Contraindications 

 

 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). 
 

4.4 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. Patients with SBP <100 mmHg were not 

studied (see section 5.1). Cases of symptomatic hypotension have been reported in 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. 

 



5 

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 (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. 

 

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. 

 



6 

Patients with 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). 

 

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). 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Interactions resulting in a contraindication 

 

ACE inhibitors 

The concomitant use of sacubitril/valsartan with ACE inhibitors is contraindicated, as the concomitant 

inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. Sacubitril/valsartan 

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 sacubitril/valsartan (see sections 4.2 

and 4.3). 

 

Aliskiren 

The concomitant use 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 section 4.3). The combination of sacubitril/valsartan with direct renin 

inhibitors such as aliskiren is not recommended (see section 4.4). Combination of sacubitril/valsartan 

with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension, 

hyperkalaemia and decreased renal function (including acute renal failure) (see sections 4.3 and 4.4). 

 

Interactions resulting in concomitant use not being recommended 

 

Sacubitril/valsartan contains valsartan, and therefore should not be co-administered with another ARB 

containing medicinal product (see section 4.4). 

 

Interactions requiring precautions 

 

OATP1B1 and OATP1B3 substrates, e.g. statins 

In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Entresto may 

therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. 

Co-administration of sacubitril/valsartan increased the Cmax of atorvastatin and its metabolites by up to 

2-fold and AUC by up to 1.3-fold. Caution should be exercised when co-administering 

sacubitril/valsartan with statins. No clinically relevant interaction was observed when simvastatin and 

Entresto were co-administered. 

 



7 

PDE5 inhibitors including sildenafil 

Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients with 

hypertension was associated with a significantly greater blood pressure reduction compared to 

administration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil or 

another PDE5 inhibitor is initiated in patients treated with sacubitril/valsartan. 

 

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 sacubitril/valsartan is 

co-administered with these agents (see section 4.4). 

 

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 sacubitril/valsartan 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 sacubitril/valsartan who are taking NSAIDs 

concomitantly (see section 4.4). 

 

Lithium 

Reversible increases in serum lithium concentrations and toxicity have been reported during 

concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists. 

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. If a diuretic is also used, the risk of lithium toxicity may be increased 

further. 

 
Furosemide 

Co-administration of sacubitril/valsartan and furosemide had no effect on the pharmacokinetics of 

sacubitril/valsartan but reduced Cmax and AUC of furosemide by 50% and 28%, respectively. While 

there was no relevant change in urine volume, the urinary excretion of sodium was reduced within 

4 hours and 24 hours after co-administration. The average daily dose of furosemide was unchanged 

from baseline until the end of the PARADIGM-HF study in patients treated with sacubitril/valsartan. 

 

Nitrates, e.g. nitroglycerine 

There was no drug-drug interaction between sacubitril/valsartan and intravenously administered 

nitroglycerin with regard to blood pressure reduction. 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. A similar effect on the heart rate may occur when 

sacubitril/valsartan is co-administered with sublingual, oral or transdermal nitrates. In general no dose 

adjustment is required. 

 

OATP and MRP2 transporters 

The active metabolite of sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3, OAT1 and 

OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, 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 

LBQ657 or valsartan. Appropriate care should be exercised when initiating or ending concomitant 

treatment with such medicinal products. 

 

Metformin 

Co-administration of sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin by 

23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with 

sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be 

evaluated. 



8 

 

No significant interaction 

 

No clinically meaningful drug-drug interaction was observed when sacubitril/valsartan was 

co-administered with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a 

combination of levonorgestrel/ethinyl estradiol. 

 

4.6 Fertility, pregnancy and lactation 
 

Pregnancy 

 

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 (see section 4.3). 

 

Valsartan 

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors 

during the first trimester of pregnancy has not been conclusive; however, a small increase in risk 

cannot be excluded. Whilst there is no controlled epidemiological data on the risk with ARBs, similar 

risks may exist for this class of medicinal product. Unless continued ARB therapy is considered 

essential, patients planning pregnancy should be changed to alternative antihypertensive treatments 

which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, 

treatment with ARBs should be stopped immediately and, if appropriate, alternative therapy should be 

started. Exposure to ARBs therapy during the second and third trimesters is known to induce human 

foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 

toxicity (renal failure, hypotension, hyperkalaemia). 

 

Should exposure to ARBs have occurred from the second trimester of pregnancy, ultrasound check of 

renal function and skull is recommended. Infants whose mothers have taken ARBs should be closely 

observed for hypotension (see section 4.3). 

 

Sacubitril 

There are no data from the use of sacubitril in pregnant women. Studies in animals have shown 

reproductive toxicity (see section 5.3). 

 

Sacubitril/valsartan 

There are no data from the use of sacubitril/valsartan in pregnant women. Animal studies with 

sacubitril/valsartan have shown reproductive toxicity (see section 5.3). 

 

Breast-feeding 

 

It is not known whether sacubitril/valsartan is excreted in human milk. The components of Entresto, 

sacubitril and valsartan, were excreted in the milk of lactating rats (see section 5.3). Because of the 

potential risk for adverse reactions in breast-fed newborns/infants, it is not recommended during 

breast-feeding. A decision should be made whether to abstain from breast-feeding or to discontinue 

Entresto while breast-feeding, taking into account the importance of sacubitril/valsartan to the mother. 

 

Fertility 

 

There are no available data on the effect of sacubitril/valsartan on human fertility. No impairment of 

fertility was demonstrated in studies with it in male and female rats (see section 5.3). 

 

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. 

 



9 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

The most commonly reported adverse reactions 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 1 List of adverse reactions 

 

System organ class Preferred term Frequency category 

Blood and lymphatic system 

disorders 
Anaemia Common 

Immune system disorders Hypersensitivity Uncommon 

Metabolism and nutrition 

disorders 

Hyperkalaemia* Very common 

Hypokalaemia Common 

Hypoglycaemia Common 

Nervous system disorders Dizziness Common 

Headache Common 

Syncope Common 

Dizziness postural Uncommon 

Ear and labyrinth disorders Vertigo Common 

Vascular disorders Hypotension* Very common 

Orthostatic hypotension Common 

Respiratory, thoracic and 

mediastinal disorders 
Cough Common 

Gastrointestinal disorders Diarrhoea Common 

Nausea Common 

Gastritis Common 

Skin and subcutaneous tissue 

disorders 

Pruritus Uncommon 

Rash Uncommon 

Angioedema* Uncommon 

Renal and urinary disorders Renal impairment* Very common 

Renal failure (renal failure, 

acute renal failure) 
Common 

General disorders and 

administration site conditions 

Fatigue Common 

Asthenia Common 

*See description of selected adverse reactions. 

 

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). 

 



10 

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. 

 
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 national reporting system 

listed in Appendix V. 
 

4.9 Overdose 

 

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 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). 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; angiotensin II receptor 

blockers (ARBs), other combinations, ATC code: C09DX04 

 

Mechanism of action 

 

Sacubitril/valsartan exhibits the mechanism of action of an angiotensin receptor neprilysin inhibitor by 

simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite 

of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The 

complementary cardiovascular benefits of sacubitril/valsartan in heart failure patients are attributed to 

the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by 

LBQ657 and the simultaneous inhibition of the effects of angiotensin II by valsartan. NPs exert their 

effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased 

concentrations of the second messenger cyclic guanosine monophosphate (cGMP), which could result 

in vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, 

inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic 

and anti-fibrotic effects. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


11 

Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking 

the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. This prevents 

sustained activation of the renin-angiotensin-aldosterone system that would result in vasoconstriction, 

renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent 

maladaptive cardiovascular remodelling. 

 

Pharmacodynamic effects 

 

The pharmacodynamic effects of sacubitril/valsartan were evaluated after single and multiple dose 

administrations in healthy subjects and in patients with heart failure, and are consistent with 

simultaneous neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study in 

patients with reduced ejection fraction (HFrEF), administration of sacubitril/valsartan resulted in an 

initial increase in natriuresis, increased urine cGMP, and decreased plasma levels of mid-regional pro-

atrial natriuretic peptide (MR-proANP) and N-terminal prohormone brain natriuretic peptide 

(NT-proBNP) compared to valsartan. In a 21-day study in HFrEF patients, sacubitril/valsartan 

significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, 

aldosterone and endothelin-1 compared to baseline. The AT1-receptor was also blocked as evidenced 

by increased plasma renin activity and plasma renin concentrations. In the PARADIGM-HF study, 

sacubitril/valsartan decreased plasma NT-proBNP and increased plasma BNP and urine cGMP 

compared with enalapril. BNP is not a suitable biomarker of heart failure in patients treated with 

sacubitril/valsartan because BNP is a neprilysin substrate (see section 4.4). NT-proBNP is not a 

neprilysin substrate and is therefore a more suitable biomarker. 
 

In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril/valsartan 194 mg 

sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac 

repolarisation. 

 

Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and 

cerebrospinal fluid (CSF). Administration of sacubitril/valsartan 194 mg sacubitril/206 mg valsartan 

once daily for two weeks to healthy subjects was associated with an increase in CSF Aβ1-38 compared 

to placebo; there were no changes in concentrations of CSF Aβ1-40 and 1-42. The clinical relevance 

of this finding is not known (see section 5.3). 

 

Clinical efficacy and safety 

 

The 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg strengths are in some publications referred to as 

50, 100 or 200 mg. 

 

PARADIGM-HF 

PARADIGM-HF, the pivotal phase 3 study, was a multinational, randomised, double-blind study of 

8,442 patients comparing sacubitril/valsartan to enalapril, both given to adult patients with chronic 

heart failure, NYHA class II-IV and reduced ejection fraction (left ventricular ejection fraction 

[LVEF] ≤40%, amended later to ≤35%) in addition to other heart failure therapy. The primary 

endpoint was the composite of cardiovascular (CV) death or hospitalisation for heart failure (HF). 

Patients with SBP <100 mmHg, severe renal impairment (eGFR <30 ml/min/1.73 m2) and severe 

hepatic impairment were excluded at screening and therefore not prospectively studied. 

 

Prior to study participation, patients were well treated with standard of care therapy which included 

ACE inhibitors/ARBs (>99%), beta blockers (94%), mineralocorticoid antagonists (58%) and diuretics 

(82%). The median follow-up duration was 27 months and patients were treated for up to 4.3 years. 

 



12 

Patients were required to discontinue their existing ACE inhibitor or ARB therapy and enter a 

sequential single-blind run-in period during which they received treatment with enalapril 10 mg twice 

daily, followed by single-blind treatment with sacubitril/valsartan 100 mg twice daily, increasing to 

200 mg twice daily (see section 4.8 for discontinuations during this period). They were then 

randomised to the double-blind period of the study, during which they received either 

sacubitril/valsartan200 mg or enalapril 10 mg twice daily [sacubitril/valsartan (n=4,209); enalapril 

(n=4,233)]. 

 

The mean age of the population studied was 64 years of age and 19% were 75 years of age or older. At 

randomisation, 70% of patients were NYHA class II, 24% were class III and 0.7% were class IV. The 

mean LVEF was 29% and there were 963 (11.4%) patients with a baseline LVEF >35% and ≤40%. 

 
In the sacubitril/valsartan group, 76% of patients remained on the target dose of 200 mg twice daily at 

the end of the study (mean daily dose of 375 mg). In the enalapril group, 75% of patients remained on 

the target dose of 10 mg twice daily at the end of the study (mean daily dose of 18.9 mg). 

 

Sacubitril/valsartan was superior to enalapril, reducing the risk of cardiovascular death or heart failure 

hospitalisations to 21.8% compared to 26.5% for enalapril treated patients. The absolute risk 

reductions were 4.7% for the composite of the CV death or HF hospitalisation, 3.1% for CV death 

alone, and 2.8% for first HF hospitalisation alone. The relative risk reduction was 20% versus 

enalapril (see Table 2). This effect was observed early and was sustained throughout the duration of 

the study (see Figure 1). Both components contributed to the risk reduction. Sudden death accounted 

for 45% of cardiovascular deaths and was reduced by 20% in sacubitril/valsartan-treated patients 

compared to enalapril-treated patients (HR 0.80, p=0.0082). Pump failure accounted for 26% of 

cardiovascular deaths and was reduced by 21% in sacubitril/valsartan-treated patients compared to 

enalapril-treated patients (HR 0.79, p=0.0338). 

 

This risk reduction was consistently observed across subgroups including: gender, age, race, 

geography, NYHA class (II/III), ejection fraction, renal function, history of diabetes or hypertension, 

prior heart failure therapy, and atrial fibrillation. 

 

Sacubitril/valsartan improved survival with a significant reduction in all-cause mortality of 2.8% 

(sacubitril/valsartan, 17%, enalapril, 19.8%). The relative risk reduction was 16% compared with 

enalapril (see Table 2). 

 

Table 2 Treatment effect for the primary composite endpoint, its components and all-cause 

mortality over a median follow-up of 27 months 

 

 Sacubitril/ 

valsartan 

N=4,187♯ 

n (%) 

Enalapril 

N=4,212♯ 

n (%) 

Hazard ratio 

(95% CI) 

Relative 

risk 

reduction 

p-value *** 

Primary composite 

endpoint of CV death 

and heart failure 

hospitalisations* 

914 (21.83) 1,117 (26.52) 0.80 (0.73, 0.87) 20% 0.0000002 

Individual components of the primary composite endpoint 

CV death** 558 (13.33) 693 (16.45) 0.80 (0.71, 0.89) 20% 0.00004 

First heart failure 

hospitalisation 

537 (12.83) 658 (15.62) 0.79 (0.71, 0.89) 21% 0.00004 

Secondary endpoint 

All-cause mortality 711 (16.98) 835 (19.82) 0.84 (0.76, 0.93) 16% 0.0005 

*The primary endpoint was defined as the time to first event of CV death or hospitalisation for HF. 

**CV death includes all patients who died up to the cut-off date irrespective of previous 

hospitalisation. 

***One-sided p-value 
♯ Full analysis set 



13 

 

Figure 1 Kaplan-Meier curves for the primary composite endpoint and the CV death 

component 

 
Time to first occurrence of CV death or
heart failure hospitalisations in PARADIGM-HF

0
0

40

30 Enalapril (N=4212)

Entresto (N=4187)

P<0.0001
HR (95%CI):

0.798 (0.731, 0.871)

20

10

180 360 540 720

Time since randomisation (days)

900 1080 1260

K
M

 e
s
ti
m

a
te

 o
f 
c
u

m
u

la
ti
ve

fa
il
u

re
 r
a

te
 (

%
)

4187 3922 3663 3018 2257 1544 896 249

4212

Entresto

No. at risk

3883 3579 2922 2123 1488 853 236Enalapril

Time to occurrence of CV death in PARADIGM-HF

0

0

40

30 Enalapril (N=4212)

Entresto (N=4187)

P<0.0001

HR (95%CI):

0.799 (0.715, 0.893)

20

10

180 360 540 720

Time since randomisation (days)

900 1080 1260

K
M

 e
s
ti
m

a
te

 o
f 

c
u

m
u

la
ti
ve

fa
ilu

re
 r

a
te

 (
%

)

4187 4056 3891 3282 2478 1716 1005 280

4212

Entresto

4051 3860 3231 2410 1726 994 279Enalapril

No. at risk

 
 

TITRATION 

TITRATION was a 12-week safety and tolerability study in 538 patients with chronic heart failure 

(NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤35%) naïve to ACE 

inhibitor or ARB therapy or on varying doses of ACE inhibitors or ARBs prior to study entry. Patients 

received a starting dose of sacubitril/valsartan of 50 mg twice daily and were up-titrated to 100 mg 

twice daily, then to the target dose of 200 mg twice daily, with either a 3-week or a 6-week regimen. 

 

More patients who were naïve to previous ACE inhibitor or ARB therapy or on low-dose therapy 

(equivalent to <10 mg enalapril/day) were able to achieve and maintain sacubitril/valsartan 200 mg 

when up-titrated over 6 weeks (84.8%) versus 3 weeks (73.6%). Overall, 76% of patients achieved and 

maintained the target dose of sacubitril/valsartan 200 mg twice daily without any dose interruption or 

down-titration over 12 weeks. 

 

Paediatric population 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

sacubitril/valsartan in one or more subsets of the paediatric population in the treatment of heart failure 

(see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

The valsartan contained within sacubitril/valsartan is more bioavailable than the valsartan in other 

marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril/valsartan is 

equivalent to 40 mg, 80 mg and 160 mg of valsartan in other marketed tablet formulations, 

respectively. 

 

Absorption 

 

Following oral administration, sacubitril/valsartan dissociates into valsartan and the prodrug sacubitril. 

Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma 

concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of 

sacubitril and valsartan is estimated to be more than 60% and 23%, respectively. 

 

Following twice daily dosing of sacubitril/valsartan, steady-state levels of sacubitril, LBQ657 and 

valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate 

significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically 

significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril/valsartan 

can be administered with or without food. 

 



14 

Distribution 

 

Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94-97%). Based on the 

comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent 

(0.28%). The average apparent volume of distribution of valsartan and sacubitril were 75 litres to 

103 litres, respectively. 

 

Biotransformation 

 

Sacubitril is readily converted to LBQ657 by carboxylesterases 1b and 1c; LBQ657 is not further 

metabolised to a significant extent. Valsartan is minimally metabolised, as only about 20% of the dose 

is recovered as metabolites. A hydroxyl metabolite of valsartan has been identified in plasma at low 

concentrations (<10%). 

 

Since CYP450-enzyme-mediated metabolism of sacubitril and valsartan is minimal, co-administration 

with medicinal products that impact CYP450 enzymes is not expected to impact the pharmacokinetics. 

 

In vitro metabolism studies indicate that potential for CYP450-based drug interactions is low since 

there is limited metabolism of sacubitril/valsartan via CYP450 enzymes. Sacubitril/valsartan does not 

induce or inhibit CYP450 enzymes. 

 

Elimination 

 

Following oral administration, 52-68% of sacubitril (primarily as LBQ657) and ~13% of valsartan and 

its metabolites are excreted in urine; 37-48% of sacubitril (primarily as LBQ657) and 86% of valsartan 

and its metabolites are excreted in faeces. 

 

Sacubitril, LBQ657 and valsartan are eliminated from plasma with a mean elimination half-life (T½) of 

approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively. 

 

Linearity/non-linearity 

 

The pharmacokinetics of sacubitril, LBQ657 and valsartan were approximately linear over a 

sacubitril/valsartan dose range of 24 mg sacubitril/26 mg valsartan to 97 mg sacubitril/103 mg 

valsartan. 

 

Special populations 

 

Elderly patients 

LBQ657 and valsartan exposure are increased in subjects over 65 years of age by 42% and 30%, 

respectively, compared to younger subjects. 

 

Impaired renal function 

A correlation was observed between renal function and systemic exposure to LBQ657 in patients with 

mild to severe renal impairment. The exposure of LBQ657 in patients with moderate 

(30 ml/min/1.73 m2 ≤ eGFR <60 ml/min/1.73 m2) and severe renal impairment (15 ml/min/1.73 m2 ≤ 

eGFR <30 ml/min/1.73 m2) was 1.4-fold and 2.2-fold higher compared to patients with mild renal 

impairment (60 ml/min/1.73 m2 ≤ eGFR <90 ml/min/1.73 m2), the largest group of patients enrolled in 

PARADIGM-HF). The exposure of valsartan was similar in patients with moderate and severe renal 

impairment compared to patients with mild renal impairment. No studies have been performed in 

patients undergoing dialysis. However, LBQ657 and valsartan are highly bound to plasma protein and 

therefore unlikely to be effectively removed by dialysis. 

 



15 

Impaired hepatic function 

In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5- and 

3.4- fold, LBQ657 increased by 1.5- and 1.9-fold, and valsartan increased by 1.2-fold and 2.1-fold, 

respectively, compared to matching healthy subjects. However, in patients with mild to moderate 

hepatic impairment, the exposures of free concentrations of LBQ657 increased by 1.47- and 3.08-fold, 

respectively, and the exposures of free concentrations of valsartan increased by 1.09-fold and 

2.20-fold, respectively, compared to matching healthy subjects. Sacubitril/valsartan has not been 

studied in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (see sections 4.3 and 

4.4). 
 

Effect of gender 

The pharmacokinetics of sacubitril/valsartan (sacubitril, LBQ657 and valsartan) are similar between 

male and female subjects. 

 

5.3 Preclinical safety data 

 

Non-clinical data (including studies with sacubitril and valsartan components and/or 

sacubitril/valsartan) reveal no special hazard for humans based on conventional studies of safety 

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility. 

 

Fertility, reproduction and development 

 

Sacubitril/valsartan treatment during organogenesis resulted in increased embryofoetal lethality in rats 

at doses ≥49 mg sacubitril/51 mg valsartan/kg/day (≤0.72-fold the maximum recommended human 

dose [MRHD] on the basis of AUC) and rabbits at doses ≥4.9 mg sacubitril/5.1 mg valsartan/kg/day 

(2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively). It is 

teratogenic based on a low incidence of foetal hydrocephaly, associated with maternally toxic doses, 

which was observed in rabbits at a sacubitril/valsartan dose of ≥4.9  mg sacubitril/5.1 mg 

valsartan/kg/day. Cardiovascular abnormalities (mainly cardiomegaly) were observed in rabbit 

foetuses at a maternally non-toxic dose (1.46 mg sacubitril/1.54 mg valsartan/kg/day). A slight 

increase in two foetal skeletal variations (misshapen sternebra, sternebra bipartite ossification) was 

observed in rabbits at a sacubitril/valsartan dose of 4.9 mg sacubitril/5.1 mg valsartan/kg/day. The 

adverse embryofoetal effects of sacubitril/valsartan are attributed to the angiotensin receptor 

antagonist activity (see section 4.6). 

 

Sacubitril treatment during organogenesis resulted in embryo-foetal lethality and embryo-foetal 

toxicity (decreased foetal body weights and skeletal malformations) in rabbits at doses associated with 

maternal toxicity (500 mg/kg/day; 5.7-fold the MRHD on the basis of LBQ657 AUC). A slight 

generalised delay in ossification was observed at doses of >50 mg/kg/day. This finding is not 

considered adverse. No evidence of embryo-foetal toxicity or teratogenicity was observed in rats 

treated with sacubitril. The embryo-foetal no-observed adverse effect level (NOAEL) for sacubitril 

was at least 750 mg/kg/day in rats and 200 mg/kg/day in rabbits (2.2-fold the MRHD on the basis of 

LBQ657 AUC). 

 

Pre- and postnatal development studies in rats conducted with sacubitril at high doses up to 

750 mg/kg/day (2.2-fold the MRHD on the basis of AUC) and valsartan at doses up to 600 mg/kg/day 

(0.86-fold the MRHD on the basis of AUC) indicate that treatment with sacubitril/valsartan during 

organogenesis, gestation and lactation may affect pup development and survival. 

 



16 

Other preclinical findings 

 

Sacubitril/valsartan 

The effects of sacubitril/valsartan on amyloid-β concentrations in CSF and brain tissue were assessed 

in young (2-4 years old) cynomolgus monkeys treated with sacubitril/valsartan (24 mg 

sacubitril/26 mg valsartan/kg/day) for two weeks. In this study CSF Aβ clearance in cynomolgus 

monkeys was reduced, increasing CSF Aβ1-40, 1-42 and 1-38 levels; there was no corresponding 

increase in Aβ levels in the brain. Increases in CSF Aβ1-40 and 1-42 were not observed in a two-week 

healthy volunteer study in humans (see section 5.1). Additionally, in a toxicology study in cynomolgus 

monkeys treated with sacubitril/valsartan at 146 mg sacubitril/154 mg valsartan/kg/day for 39 weeks, 

there was no evidence for the presence of amyloid plaques in the brain. Amyloid content was not, 

however, measured quantitatively in this study. 

 

Sacubitril 

In juvenile rats treated with sacubitril (postnatal days 7 to 70), there was a reduction in age-related 

bone mass development and bone elongation. A study in adult rats showed only a minimal transient 

inhibitory effect on bone mineral density but not on any other parameters relevant for bone growth, 

suggesting no relevant effect of sacubitril on bone in adult patient populations under normal 

conditions. However, a mild transient interference of sacubitril with the early phase of fracture healing 

in adults cannot be excluded. 

 

Valsartan 

In juvenile rats treated with valsartan (postnatal days 7 to 70), doses as low as 1 mg/kg/day produced 

persistent irreversible kidney changes consisting of tubular nephropathy (sometimes accompanied by 

tubular epithelial necrosis) and pelvic dilatation. These kidney changes represent an expected 

exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II 

type 1 blockers; such effects are observed if rats are treated during the first 13 days of life. This period 

coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after 

conception in humans. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Tablet core 

 

Microcrystalline cellulose 

Low-substituted hydroxypropylcellulose 

Crospovidone, type A 

Magnesium stearate 

Talc 

Silica colloidal anhydrous 

 

Film coat 

 

Entresto 24 mg/26 mg film-coated tablets 

Hypromellose, substitution type 2910 (3 mPa·s) 

Titanium dioxide (E171) 

Macrogol (4000) 

Talc 

Iron oxide red (E172) 

Iron oxide black (E172) 

 



17 

Entresto 49 mg/51 mg film-coated tablets 

Hypromellose, substitution type 2910 (3 mPa·s) 

Titanium dioxide (E171) 

Macrogol (4000) 

Talc 

Iron oxide red (E172) 

Iron oxide yellow (E172) 

 

Entresto 97 mg/103 mg film-coated tablets 

Hypromellose, substitution type 2910 (3 mPa·s) 

Titanium dioxide (E171) 

Macrogol (4000) 

Talc 

Iron oxide red (E172) 

Iron oxide black (E172) 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years 

 

6.4 Special precautions for storage 

 

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

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

 

6.5 Nature and contents of container 

 

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. 

 

6.6 Special precautions for disposal 
 

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

requirements. 

 

 



18 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Entresto 24 mg/26 mg film-coated tablets 

 

EU/1/15/1058/001 

EU/1/15/1058/008-010 

EU/1/15/1058/017-018 

 

Entresto 49 mg/51 mg film-coated tablets 

 

EU/1/15/1058/002-004 

EU/1/15/1058/011-013 

EU/1/15/1058/019-020 

Entresto 97 mg/103 mg film-coated tablets 

 

EU/1/15/1058/005-007 

EU/1/15/1058/014-016 

EU/1/15/1058/021-022 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 19 November 2015 

Date of latest renewal: 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

  

http://www.ema.europa.eu/


19 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



20 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 

authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result 

of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 Obligation to conduct post-authorisation measures 
 

The MAH shall complete, within the stated timeframe, the below measures: 

 

Conditions to the MA Due date 

The MAH must ensure that the manufacturing processes of the drug substances 

used for their drug products are reviewed for the potential risk of formation of 

N-nitrosamines and changed as necessary to minimise nitrosamine contamination 

as much as possible. 

Within 

2 years after 

Commission 

Decision. 

N-nitrosodimethylamine (NDMA) 

 

After the transitional period of 2 years, a limit for NDMA of maximum 0.03 ppm 

should be implemented. 

Within 

2 years after 

Commission 

Decision. 

 

  



21 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



22 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

  



23 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 24 mg/26 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 24 mg/26 mg tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

14 film-coated tablets 

20 film-coated tablets 

28 film-coated tablets 

56 film-coated tablets 

196 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



24 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/1058/001 28 film-coated tablets 

EU/1/15/1058/008 14 film-coated tablets 

EU/1/15/1058/009 20 film-coated tablets 

EU/1/15/1058/010 56 film-coated tablets 

EU/1/15/1058/018 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 24 mg/26 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN  



25 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 24 mg/26 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 24 mg/26 mg tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

Multipack: 196 (7 packs of 28) film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 



26 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 
Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/15/1058/017 196 film-coated tablets (7 packs of 28) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 24 mg/26 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



27 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 24 mg/26 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 24 mg/26 mg tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

28 film-coated tablets. Component of a multipack. Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 



28 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 
Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/15/1058/017 196 film-coated tablets (7 packs of 28) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 24 mg/26 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

 

  



29 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 24 mg/26 mg tablets 

sacubitril/valsartan 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



30 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 49 mg/51 mgfilm-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 49 mg/51 mg tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

14 film-coated tablets 

20 film-coated tablets 

28 film-coated tablets 

56 film-coated tablets 

168 film-coated tablets 

196 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



31 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/1058/002 28 film-coated tablets 

EU/1/15/1058/003 56 film-coated tablets 

EU/1/15/1058/011 14 film-coated tablets 

EU/1/15/1058/012 20 film-coated tablets 

EU/1/15/1058/019 168 film-coated tablets 

EU/1/15/1058/020 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 49 mg/51 mg 
 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 



32 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



33 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 49 mg/51 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 49 mg/51 mg tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

Multipack: 168 (3 packs of 56) film-coated tablets 

Multipack: 196 (7 packs of 28) film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



34 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 
Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/15/1058/004 168 film-coated tablets (3 packs of 56) 

EU/1/15/1058/013 196 film-coated tablets (7 packs of 28) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 49 mg/51 mg 
 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



35 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 49 mg/51 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 49 mg/51 mg tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

28 film-coated tablets. Component of a multipack. Not to be sold separately. 

56 film-coated tablets. Component of a multipack. Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



36 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 
Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/15/1058/004 168 film-coated tablets (3 packs of 56) 

EU/1/15/1058/013 196 film-coated tablets (7 packs of 28) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 49 mg/51 mg 
 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

  



37 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 49 mg/51 mg tablets 

sacubitril/valsartan 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



38 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 97 mg/103 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 97 mg/103 mg tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

14 film-coated tablets 

20 film-coated tablets 

28 film-coated tablets 

56 film-coated tablets 

168 film-coated tablets 

196 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



39 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/15/1058/005 28 film-coated tablets 

EU/1/15/1058/006 56 film-coated tablets 

EU/1/15/1058/014 14 film-coated tablets 

EU/1/15/1058/015 20 film-coated tablets 

EU/1/15/1058/021 168 film-coated tablets 

EU/1/15/1058/022 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 97 mg/103 mg 
 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 



40 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



41 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 97 mg/103 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 97 mg/103 mg tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

Multipack: 168 (3 packs of 56) film-coated tablets 

Multipack: 196 (7 packs of 28) film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



42 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 
Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/15/1058/007 168 film-coated tablets (3 packs of 56) 

EU/1/15/1058/016 196 film-coated tablets (7 packs of 28) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 97 mg/103 mg 
 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC 

SN 

NN 

  



43 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 97 mg/103 mg film-coated tablets 

sacubitril/valsartan 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each 97 mg/103 mg tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartan 

sodium salt complex). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

28 film-coated tablets. Component of a multipack. Not to be sold separately. 

56 film-coated tablets. Component of a multipack. Not to be sold separately. 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



44 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 
Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/15/1058/007 168 film-coated tablets (3 packs of 56) 

EU/1/15/1058/016 196 film-coated tablets (7 packs of 28) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Entresto 97 mg/103 mg 
 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

  



45 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Entresto 97 mg/103 mg tablets 

sacubitril/valsartan 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



46 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



47 

Package leaflet: Information for the patient 
 

Entresto 24 mg/26 mg film-coated tablets 

Entresto 49 mg/51 mg film-coated tablets 

Entresto 97 mg/103 mg film-coated tablets 

sacubitril/valsartan 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 

What is in this leaflet 

 

1. What Entresto is and what it is used for 

2. What you need to know before you take Entresto 

3. How to take Entresto 

4. Possible side effects 

5. How to store Entresto 

6. Contents of the pack and other information 

 

 

1. What Entresto is and what it is used for 

 

Entresto is a medicine containing an angiotensin receptor neprilysin inhibitor. It delivers two active 

substances, sacubitril and valsartan. 

 

Entresto is used to treat a type of long-term heart failure in adults. 

 

This type of heart failure occurs when the heart is weak and cannot pump enough blood to the lungs 

and the rest of the body. The most common symptoms of heart failure are breathlessness, fatigue, 

tiredness and ankle swelling. 

 

 

2. What you need to know before you take Entresto 

 

Do not take Entresto 

 if you are allergic to sacubitril, valsartan or any of the other ingredients of this medicine (listed 
in section 6). 

 if you are taking another type of medicine called an angiotensin converting enzyme (ACE) 
inhibitor (for example enalapril, lisinopril or ramipril). ACE inhibitors are used to treat high 

blood pressure or heart failure. If you have been taking an ACE inhibitor, wait for 36 hours after 

taking the last dose before you start to take Entresto (see “Other medicines and Entresto”). 

 if you or a member of your family have ever had a reaction called angioedema (swelling of the 
face, lips, tongue and/or throat, difficulties in breathing) when taking an ACE inhibitor or an 

angiotensin receptor blocker (ARB) (such as valsartan, telmisartan or irbesartan). 

 if you have diabetes or impaired kidney function and you are being treated with a blood pressure 
lowering medicine containing aliskiren (see “Other medicines and Entresto”). 

 if you have severe liver disease. 

 if you are more than 3 months pregnant (it is also better to avoid this medicine in early 
pregnancy, see “Pregnancy and breast-feeding”). 

If any of the above applies to you, do not take Entresto and talk to your doctor. 

 



48 

Warnings and precautions 

Talk to your doctor, pharmacist or nurse before taking Entresto: 

 if you are being treated with an angiotensin receptor blocker (ARB) or aliskiren (see “Do not 
take Entresto”). 

 if you have ever had angioedema (see “Do not take Entresto” and section 4 “Possible side 
effects”). 

 if you have low blood pressure or are taking any other medicines that reduce your blood 
pressure (for example, a diuretic) or are suffering from vomiting or diarrhoea, especially if you 

are aged 65 years or more, or if you have kidney disease and low blood pressure. 

 if you have severe kidney disease. 

 if you are suffering from dehydration. 

 if your kidney artery has narrowed. 

 if you have liver disease. 
 

Your doctor may check the amount of potassium in your blood at regular intervals during Entresto 

treatment. 

 

If any of the above applies to you, tell your doctor, pharmacist or nurse before you take 

Entresto. 
 

Children and adolescents 

Do not give this medicine to children (aged below 18 years) because it has not been studied in this age 

group. 

 

Other medicines and Entresto 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. It may be necessary to change the dose, to take other precautions, or even to stop taking 

one of the medicines. This is particularly important for the following medicines: 

 ACE inhibitors. Do not take Entresto with ACE inhibitors. If you have been taking an ACE 
inhibitor, wait 36 hours after taking the last dose of the ACE inhibitor before starting to take 

Entresto (see “Do not take Entresto”). If you stop taking Entresto, wait 36 hours after taking 

your last dose of Entresto before starting an ACE inhibitor. 

 other medicines used to treat heart failure or lower blood pressure, such as angiotensin receptor 
blockers or aliskiren (see “Do not take Entresto”). 

 some medicines known as statins that are used to lower high cholesterol levels (for example 
atorvastatin). 

 sildenafil, a medicine used to treat erectile dysfunction or lung hypertension. 

 medicines that increase the amount of potassium in the blood. These include potassium 
supplements, salt substitutes containing potassium, potassium-sparing medicines and heparin. 

 painkillers of the type called non-steroidal anti-inflammatory medicines (NSAIDs) or selective 
cyclooxygenase-2 (Cox-2) inhibitors. If you are taking one of these, your doctor may want to 

check your kidney function when starting or adjusting treatment (see “Warnings and 

precautions”). 

 lithium, a medicine used to treat some types of psychiatric illness. 

 furosemide, a medicine belonging to the type known as diuretics, which are used to increase the 
amount of urine you produce. 

 nitroglycerine, a medicine used to treat angina pectoris. 

 some types of antibiotics (rifamycin group), ciclosporin (used to prevent rejection of 
transplanted organs) or antivirals such as ritonavir (used to treat HIV/AIDS). 

 metformin, a medicine used to treat diabetes. 
If any of the above applies to you, tell your doctor or pharmacist before you take Entresto. 
 



49 

Pregnancy and breastfeeding 

 

Pregnancy 

You must tell your doctor if you think that you are (or might become) pregnant. Your doctor will 

normally advise you to stop taking this medicine before you become pregnant or as soon as you know 

you are pregnant, and will advise you to take another medicine instead of Entresto. 

 

This medicine is not recommended in early pregnancy, and must not be taken when more than 

3 months pregnant, as it may cause serious harm to your baby if it is used after the third month of 

pregnancy. 

 

Breast-feeding 

Entresto is not recommended for mothers who are breast-feeding. Tell your doctor if you are 

breast-feeding or about to start breast-feeding. 

 

Driving and using machines 
Before you drive a vehicle, use tools or operate machines, or carry out other activities that require 

concentration, make sure you know how Entresto affects you. If you feel dizzy or very tired while 

taking this medicine, do not drive a vehicle, cycle or use any tools or machines. 

 

 

3. How to take Entresto 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

You will usually start by taking 24 mg/26 mg or 49 mg/51 mg twice a day (one tablet in the morning 

and one tablet in the evening). Your doctor will decide your exact starting dose based on which 

medicines you have been taking previously. Your doctor will then adjust the dose depending on how 

you respond to the treatment until the best dose for you is found. 

 

The usual recommended target dose is 97 mg/103 mg twice a day (one tablet in the morning and one 

tablet in the evening). 

 

Patients taking Entresto can develop low blood pressure (dizziness, light-headedness), a high level of 

potassium in the blood (which would be detected when your doctor performed a blood test) or 

decreased kidney function. If this happens, your doctor may reduce the dose of any other medicine you 

are taking, temporarily reduce your Entresto dose, or stop your Entresto treatment completely. 

 

Swallow the tablets with a glass of water. You can take Entresto with or without food. 

 

If you take more Entresto than you should 

If you have accidentally taken too many Entresto tablets, or if someone else has taken your tablets, 

contact your doctor immediately. If you experience severe dizziness and/or fainting, tell your doctor as 

quickly as possible and lie down. 

 

If you forget to take Entresto 

It is advisable to take your medicine at the same time each day. However, if you forget to take a dose, 

you should simply take the next one at the scheduled time. Do not take a double dose to make up for a 

forgotten tablet. 

 

If you stop taking Entresto 

Stopping your treatment with Entresto may cause your condition to get worse. Do not stop taking your 

medicine unless your doctor tells you to. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 

 



50 

 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Some side effects may be serious. 

 Stop taking Entresto and seek immediate medical attention if you notice any swelling of the 
face, lips, tongue and/or throat, which may cause difficulties in breathing or swallowing. These 

may be signs of angioedema (an uncommon side effect which may affect up to 1 in 100 people). 

 

Other possible side effects: 

If any of the side effects listed below becomes severe, tell your doctor or pharmacist. 

 

Very common (may affect more than 1 in 10 people) 

 low blood pressure (dizziness, light-headedness) 

 high level of potassium in the blood (shown in a blood test) 

 decreased renal function (renal impairment) 
 

Common (may affect up to 1 in 10 people) 

 cough 

 dizziness 

 diarrhoea 

 low level of red blood cells (shown in a blood test) 

 tiredness 

 (acute) renal failure (severe kidney disorder) 

 low level of potassium in the blood (shown in a blood test) 

 headache 

 fainting 

 weakness 

 feeling sick (nausea) 

 low blood pressure (dizziness, light-headedness) when switching from sitting or lying to 
standing position 

 gastritis (stomach pain, nausea) 

 spinning sensation 

 low level of sugar in the blood (shown in a blood test) 
 

Uncommon (may affect up to 1 in 100 people) 

 allergic reaction with rash and itching 

 dizziness when switching from sitting to standing position 

 
Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

 

  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


51 

5. How to store Entresto 

 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 

expiry date refers to the last day of that month. 

This medicine does not require any special temperature storage conditions. 

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

Do not use this medicine if you notice that the pack is damaged or shows signs of tampering. 

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines 

you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Entresto contains 

 The active substances are sacubitril and valsartan. 
o Each 24 mg/26 mg film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan 

(as sacubitril valsartan sodium salt complex). 

o Each 49 mg/51 mg film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan 
(as sacubitril valsartan sodium salt complex). 

o Each 97 mg/103 mg film-coated tablet contains 97.2 mg sacubitril and 102.8 mg valsartan 
(as sacubitril valsartan sodium salt complex). 

 The other ingredients in the tablet core are microcrystalline cellulose, low-substituted 
hydroxypropylcellulose, crospovidone, magnesium stearate, talc and silica colloidal anhydrous. 

 The 24 mg/26 mg and the 97 mg/103 mg tablet coatings contain hypromellose, titanium dioxide 
(E171), Macrogol (4000), talc, iron oxide red (E172) and iron oxide black (E172). 

 The 49 mg/51 mg tablet coating contains hypromellose, titanium dioxide (E171), Macrogol 
(4000), talc, iron oxide red (E172) and iron oxide yellow (E172). 

 

What Entresto looks like and contents of the pack 

Entresto 24 mg/26 mg film-coated tablets are violet-white oval tablets with “NVR” on one side and 

“LZ” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm. 

Entresto 49 mg/51 mg film-coated tablets are pale yellow oval tablets with “NVR” on one side and 

“L1” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm 

Entresto 97 mg/103 mg film-coated tablets are light pink oval tablets with “NVR” on one side and 

“L11” on the other side. Approximate tablet dimensions 15.1 mm x 6.0 mm. 
 

The tablets are supplied in packs containing 14, 20, 28, 56, 168 or 196 tablets and in multipacks 

comprising 7 cartons, each containing 28 tablets. The 49 mg/51 mg and 97 mg/103 mg tablets are also 

supplied in multipacks comprising 3 cartons, each containing 56 tablets. 

 

Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 
Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 

Germany 

 



52 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 88 04 52 111 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



53 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

 

This leaflet was last revised in 
 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET