Neparvis

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 
 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Neparvis 24 mg/26 mg film-coated tablets 

Neparvis 49 mg/51 mg film-coated tablets 

Neparvis 97 mg/103 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Neparvis 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). 

 

Neparvis 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). 

 

Neparvis 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) 

 

Neparvis 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. 
 

Neparvis 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. 

 

Neparvis 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. 

 

 



 

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4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

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

ejection fraction (see section 5.1). 

 

4.2 Posology and method of administration 

 

Posology 

 

The recommended starting dose of Neparvis 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 Neparvis is recommended (see section 4.4). 

 

In PARADIGM-HF study, Neparvis 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. 

 

Neparvis 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 Neparvis 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) Neparvis 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 Neparvis is 

not recommended. 

 

Hepatic impairment 

No dose adjustment is required when administering Neparvis 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 



 

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the normal range. Neparvis 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). Neparvis 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 Neparvis in children and adolescents aged below 18 years have not been 

established. No data are available. 

 

Method of administration 

 

Oral use. 

Neparvis 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). Neparvis 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 trimester 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 Neparvis with an ACE inhibitor is contraindicated due to the increased risk 
of angioedema (see section 4.3). Neparvis must not be initiated until 36 hours after taking the 

last dose of ACE inhibitor therapy. If treatment with Neparvis is stopped, ACE inhibitor therapy 

must not be initiated until 36 hours after the last dose of Neparvis (see sections 4.2, 4.3 and 4.5). 

 

 The combination of Neparvis with direct renin inhibitors such as aliskiren is not recommended 
(see section 4.5). The combination of Neparvis with aliskiren-containing 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). 

 

 Neparvis contains valsartan, and therefore should not be co-administered with another ARB 
containing 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 Neparvis 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 Neparvis, blood pressure should be monitored routinely. If hypotension occurs, 

temporary down-titration or discontinuation of Neparvis 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 



 

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vomiting. Sodium and/or volume depletion should be corrected before starting treatment with 

Neparvis, however, such corrective action must be carefully weighed against the risk of volume 

overload. 

 

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 Neparvis is not recommended. 

 

Worsening renal function 

 

Use of Neparvis 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 Neparvis 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 Neparvis. If angioedema occurs, Neparvis 

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 Neparvis is used in these patients. Neparvis 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 

 

Neparvis 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. 

 



 

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Patients with NYHA functional classification IV 

 

Caution should be exercised when initiating Neparvis 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 Neparvis 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). Neparvis 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 Neparvis with ACE inhibitors is contraindicated, as the concomitant inhibition 

of neprilysin (NEP) and ACE may increase the risk of angioedema. Neparvis 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 Neparvis (see sections 4.2 and 4.3). 

 

Aliskiren 

The concomitant use of Neparvis with aliskiren-containing 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 Neparvis with direct renin inhibitors such as aliskiren is not recommended (see 

section 4.4). Combination of Neparvis 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 

 

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

containing 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. Neparvis may 

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

Co-administration of Neparvis 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 Neparvis with statins. 

No clinically relevant drug-drug interaction was observed when simvastatin and Neparvis were co-

administered. 

 

PDE5 inhibitors including sildenafil 

Addition of a single dose of sildenafil to Neparvis at steady state in patients with hypertension was 

associated with a significantly greater blood pressure reduction compared to administration of 

Neparvis alone. Therefore, caution should be exercised when sildenafil or another PDE5 inhibitor is 

initiated in patients treated with Neparvis. 



 

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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 Neparvis 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 Neparvis 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 Neparvis 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 Neparvis 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 Neparvis and furosemide had no effect on the pharmacokinetics of Neparvis 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 Neparvis. 

 
Nitrates, e.g. nitroglycerine 

There was no drug-drug interaction between Neparvis and intravenously administered nitroglycerin 

with regard to blood pressure reduction. Co-administration of nitroglycerin and Neparvis 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 Neparvis 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 Neparvis 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 Neparvis with metformin reduced both Cmax and AUC of metformin by 23%. The 

clinical relevance of these findings is unknown. Therefore, when initiating therapy with Neparvis in 

patients receiving metformin, the clinical status of the patient should be evaluated. 

 

No significant interaction 

 

No clinically meaningful drug-drug interaction was observed when Neparvis was co-administered 

with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of 

levonorgestrel/ethinyl estradiol. 

 



 

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CYP 450 interactions 

In vitro metabolism studies indicate that potential for CYP 450-based drug interactions is low since 

there is limited metabolism of Neparvis via CYP450 enzymes. Neparvis does not induce or inhibit 

CYP450 enzymes. 
 
4.6 Fertility, pregnancy and lactation 
 

Pregnancy 

 

The use of Neparvis 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). 

 

Neparvis 

There are no data from the use of Neparvis in pregnant women. Animal studies with Neparvis have 

shown reproductive toxicity (see section 5.3). 

 

Breast-feeding 

 

It is not known whether Neparvis is excreted in human milk. The components of Neparvis, 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 Neparvis while 

breast-feeding, taking into account the importance of Neparvis to the mother. 

 

Fertility 

 

There are no available data on the effect of Neparvis 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 
 

Neparvis 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. 

 



 

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4.8 Undesirable effects 

 

Summary of the safety profile 

 

The most commonly reported adverse reactions during treatment with Neparvis were hypotension, 

hyperkalaemia and renal impairment (see section 4.4). Angioedema was reported in patients treated 

with Neparvis (see description of selected adverse reactions). 

 

The safety of Neparvis in patients with chronic heart failure was evaluated in the pivotal phase 3 study 

PARADIGM-HF, which compared patients treated twice daily with Neparvis 97 mg/103 mg 

(n=4,203) or enalapril 10 mg (n=4,229). Patients randomised to the Neparvis group received treatment 

for a median duration of exposure of 24 months; 3,271 patients were treated for more than one year. 

 

In the PARADIGM-HF study, subjects were previously treated with ACE inhibitors and/or ARBs and 

also had to successfully complete sequential enalapril and Neparvis run-in periods (median drug 

exposure of 15 and 29 days, respectively) prior to the randomised double-blind period. During the 

enalapril run-in period, 1,102 patients (10.5%) permanently discontinued from the study, 5.6% 

because of an adverse reaction, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and 

hypotension (1.4%). During the Neparvis run-in period, 10.4% of patients permanently discontinued, 

5.9% because of an adverse reaction, most commonly renal dysfunction (1.8%), hypotension (1.7%) 

and hyperkalemia (1.3%). Due to discontinuations during the run-in period, the adverse reaction rates 

as presented in table below may be lower than the adverse reaction rates expected in clinical practice. 

 

Discontinuation of therapy due to an adverse reaction in the double-blind period of the 

PARADIGM-HF study occurred in 450 Neparvis-treated patients (10.7%) and 516 enalapril-treated 

patients (12.2%). 

 



 

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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 Neparvis. In PARADIGM-HF, angioedema 

was reported in 0.5% of patients treated with Neparvis, compared with 0.2% of patients treated with 

enalapril. A higher incidence of angioedema was observed in Black patients treated with Neparvis 

(2.4%) and enalapril (0.5%) (see section 4.4). 
 

Hyperkalaemia and serum potassium 

In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/l were reported in 

11.6% and 19.7% of Neparvis-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 Neparvis-treated patients 

compared with 11.9% and 2.67% of enalapril-treated patients, respectively. 

 



 

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Renal impairment 

In PARADIGM-HF, renal impairment was reported in 10.1% of Neparvis-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 Neparvis 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 

Neparvis. Symptomatic treatment should be provided. 

 

The medicinal product is unlikely to be removed by haemodialysis due to high protein binding. 

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

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

other combinations, ATC code: C09DX04 

 

Mechanism of action 

 

Neparvis 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 Neparvis 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. 

 

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 Neparvis 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 Neparvis resulted in an initial 

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

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


 

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

compared to valsartan. In a 21-day study in HFrEF patients, Neparvis 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, Neparvis 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 Neparvis 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 Neparvis 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 Neparvis 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 was a multinational, randomised, double-blind study of 8,442 patients comparing 

Neparvis 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. 

 

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 Neparvis 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 Neparvis 200 mg or enalapril 

10 mg twice daily [Neparvis (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 Neparvis 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). 

 

Neparvis 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 



 

13 

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 Neparvis-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 Neparvis-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. 

 

Neparvis improved survival with a significant reduction in all-cause mortality of 2.8% (Neparvis, 

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 

 

 Neparvis 

N=4187♯ 

n (%) 

Enalapril 

N=4212♯ 

n (%) 

Hazard ratio 

(95% CI) 

Relative 

risk 

reduction 

p-value *** 

Primary composite 

endpoint of CV death 

and heart failure 

hospitalisations* 

914 (21.83) 1117 (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 

 

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)

Neparvis(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

Neparvis

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)

Neparvis (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
il
u

re
 r

a
te

 (
%

)

4187 4056 3891 3282 2478 1716 1005 280

4212

Neparvis

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 Neparvis of 50 mg twice daily and were up-titrated to 100 mg twice daily, 



 

14 

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 Neparvis 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 Neparvis 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 

Neparvis 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 Neparvis is more bioavailable than the valsartan in other marketed 

tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in Neparvis is equivalent to 40 mg, 80 mg 

and 160 mg of valsartan in other marketed tablet formulations, respectively. 

 

Absorption 

 

Following oral administration, Neparvis 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 Neparvis, 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. Neparvis can be administered with or without 

food. 

 

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. 

 

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 



 

15 

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 an 

Neparvis 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. 

 

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. Neparvis 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 Neparvis (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 Neparvis) 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 

 

Neparvis 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 an Neparvis 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 an Neparvis dose of 

4.9 mg sacubitril/5.1 mg valsartan/kg/day. The adverse embryofoetal effects of Neparvis are 

attributed to the angiotensin receptor antagonist activity (see section 4.6). 
 



 

16 

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 Neparvis during 

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

 

Other preclinical findings 

 

Neparvis 

The effects of Neparvis on amyloid-β concentrations in CSF and brain tissue were assessed in young 

(2-4 years old) cynomolgus monkeys treated with Neparvis (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 Neparvis 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. 

 

 



 

17 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Tablet core 

 

Microcrystalline cellulose 

Low-substituted hydroxypropylcellulose 

Crospovidone, type A 

Magnesium stearate 

Talc 

Colloidal anhydrous silica 

 

Film coat 

 

Neparvis 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) 

 

Neparvis 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) 

 

Neparvis 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. 

 



 

18 

6.5 Nature and contents of container 

 

PVC/PVDC/Aluminium blisters. One blister contains either 10 or 14 film-coated tablets. 

 

Neparvis 24 mg/26 mg film-coated tablets 

 

Pack sizes: 14, 20, 28 or 56 film-coated tablets and multipacks containing 196 (7x28) film-coated 

tablets. 

 

Neparvis 49 mg/51 mg film-coated tablets 

 

Pack sizes: 14, 20, 28 or 56 film-coated tablets and multipacks containing 168 (3x56) or 

196 (7x28) film-coated tablets. 

 

Neparvis 97 mg/103 mg film-coated tablets 

 

Pack sizes: 14, 20, 28 or 56 film-coated tablets and multipacks containing 168 (3x56) or 

196 (7x28) 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. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Neparvis 24 mg/26 mg film-coated tablets 

 

EU/1/16/1103/001 

EU/1/16/1103/008-010 

EU/1/16/1103/017 

 

Neparvis 49 mg/51 mg film-coated tablets 

 

EU/1/16/1103/002-004 

EU/1/16/1103/011-013 

 

Neparvis 97 mg/103 mg film-coated tablets 

 

EU/1/16/1103/005-007 

EU/1/16/1103/014-016 

 

 



 

19 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

26 May 2016 

 

 

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/


 

20 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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 

 



 

21 

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 
 

The requirements for submission of periodic safety update reports 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 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. 

 



 

22 

 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. 

For all N-nitrosamines the MAH must ensure a control strategy is in place in drug 

substance batches used for their drug products. 

At the time of 

Commission 

Decision. 

For N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) the MAH 

must introduce the following specifications for the drug substance: 

 

1) Limits for NDMA and NDEA outlined below should be implemented for a 

transitional period of 2 years: 

 

Drug 

substance* 

Max. 

daily 

dose (mg) 

NDEA 

Limit in 

ng/day 

NDEA 

Limit in 

ppm in 

API 

NDMA 

Limit in 

ng/day 

NDMA 

Limit in 

ppm in 

API 

Valsartan 320 26.5 0.082 96.0 0.300 

Losartan 150 26.5 0.177 96.0 0.640 

Olmesartan 40 26.5 0.663 96.0 2.400 

Irbesartan 300 26.5 0.088 96.0 0.320 

Candesartan 32 26.5 0.820 96.0 3.000 

* These limits are not applicable for batches where more than one of the above 

N-nitrosamines has been identified simultaneously; such batches should be rejected. 

 

2) After the transitional period of 2 years, a limit for NDMA and NDEA of 

maximum 0.03 ppm should be implemented. 

At the time of 

Commission 

Decision 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Within 

2 years after 

Commission 

Decision. 

 



 

23 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

24 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



 

25 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 

 

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 

 

 



 

26 

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/1/16/1103/001 28 film-coated tablets 

EU/1/16/1103/008 14 film-coated tablets 

EU/1/16/1103/009 20 film-coated tablets 

EU/1/16/1103/010 56 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 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 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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. 

 

 



 

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/1/16/1103/017 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 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: 



 

29 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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. 

 

 



 

30 

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/1/16/1103/017 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 24 mg/26 mg 

 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 



 

31 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 



 

32 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 

14 film-coated tablets 

20 film-coated tablets 

28 film-coated tablets 

56 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 

 

 



 

33 

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/1/16/1103/002 28 film-coated tablets 

EU/1/16/1103/003 56 film-coated tablets 

EU/1/16/1103/011 14 film-coated tablets 

EU/1/16/1103/012 20 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 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: 



 

34 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 

 



 

35 

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/1/16/1103/004 168 film-coated tablets 
EU/1/16/1103/013 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 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: 



 

36 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 

 



 

37 

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/1/16/1103/004 168 film-coated tablets 
EU/1/16/1103/013 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 49 mg/51 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

 



 

38 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 



 

39 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF UNIT PACK 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 

 

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 

 

 



 

40 

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/1/16/1103/005 28 film-coated tablets 

EU/1/16/1103/006 56 film-coated tablets 

EU/1/16/1103/014 14 film-coated tablets 

EU/1/16/1103/015 20 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 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: 



 

41 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Neparvis 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 

 

 



 

42 

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/1/16/1103/007 168 film-coated tablets 
EU/1/16/1103/016 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 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 

 

Neparvis 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 

 

 



 

44 

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/1/16/1103/007 168 film-coated tablets 
EU/1/16/1103/016 196 film-coated tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Neparvis 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 

 

Neparvis 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 
 

Neparvis 24 mg/26 mg film-coated tablets 

Neparvis 49 mg/51 mg film-coated tablets 

Neparvis 97 mg/103 mg film-coated tablets 

sacubitril/valsartan 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects. 
 

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 Neparvis is and what it is used for 

2. What you need to know before you take Neparvis 

3. How to take Neparvis 

4. Possible side effects 

5. How to store Neparvis 

6. Contents of the pack and other information 

 

 

1. What Neparvis is and what it is used for 

 

Neparvis is a medicine known as an angiotensin receptor neprilysin inhibitor. It dissociates into two 

active substances, sacubitril and valsartan. 

 

Neparvis 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 Neparvis 

 

Do not take Neparvis: 

 if you are allergic to sacubitril, valsartan or any of the other ingredients of this medicine (listed 
in section 6). If you think you may be allergic to any component of this medicine, talk to your 

doctor before taking Neparvis. 

 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 Neparvis (see “Other medicines and Neparvis”). 

 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 Neparvis”). 



 

48 

 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 breastfeeding”). 

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

 

Warnings and precautions 

Talk to your doctor, pharmacist or nurse before taking Neparvis 

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

 if you have ever had angioedema (see “Do not take Neparvis” 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 Neparvis 

treatment. 

 

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

Neparvis. 
 

Children and adolescents 

This medicine is not for use in children (aged below 18 years). This is because it has not been studied 

in this age group. 

 

Other medicines and Neparvis 
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 Neparvis 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 

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

your last dose of Neparvis 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 Neparvis”). 

 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. 

 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 Neparvis. 



 

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 Neparvis. 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. 

 

Breastfeeding 

Neparvis is not recommended for mothers who are breastfeeding. Tell your doctor if you are 

breastfeeding or about to start breastfeeding. 

 

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 Neparvis 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 Neparvis 

 

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 Neparvis 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 Neparvis dose, or stop your Neparvis treatment completely. 

 

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

 

If you take more Neparvis than you should 

If you have accidentally taken too many Neparvis 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 Neparvis 

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 Neparvis 

Stopping your treatment with Neparvis 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 Neparvis 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. 

 

 

5. How to store Neparvis 

 

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 any Neparvis pack that is damaged or shows signs of tampering. 

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

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


 

51 

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

 

 

6. Contents of the pack and other information 

 

What Neparvis 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 Neparvis looks like and contents of the pack 

Neparvis 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. 

Neparvis 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 

Neparvis 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 PVC/PVDC/Aluminium blister packs of 14, 20, 28 tablets or 56 tablets and 

in multipacks of 196 tablets (7 packs of 28 tablets). The 49 mg/51 mg and 97 mg/103 mg tablets are 

also supplied in multipacks of 168 tablets (3 packs of 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 26 37 82 111 

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 

Laboratorios Farmacéuticos ROVI, S.A. 

Tel: +34 91 375 62 30 

 

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 

Servier Portugal - Especialidades Farmacêuticas, 

Lda. 

Tel: +351 21 312 2000 

 

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