ENTRESTO 97mg / 103mg tablets medication leaflet

Each film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartansodium salt complex).

Each film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartansodium salt complex).

Each film-coated tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartansodium salt complex).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

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.

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.

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.

Adult heart failure

Entresto is indicated in adult patients for treatment of symptomatic chronic heart failure with reducedejection fraction (see section 5.1).

Paediatric heart failure

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

General considerations

Entresto should not be co-administered with an angiotensin-converting enzyme (ACE) inhibitor or anangiotensin II receptor blocker (ARB). Due to the potential risk of angioedema when usedconcomitantly with an ACE inhibitor, it must not be started for at least 36 hours after discontinuing

ACE inhibitor therapy (see sections pct. 4.3, pct. 4.4 and 4.5).

The valsartan contained within Entresto is more bioavailable than the valsartan in other marketedtablet formulations (see section 5.2).

If a dose is missed, the patient should take the next dose at the scheduled time.

Adult heart failure

The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, except in thesituations described below. The dose should be doubled at 2-4 weeks to the target dose of one tablet of97 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, symptomatichypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products,temporary down-titration or discontinuation of Entresto is recommended (see section 4.4).

In PARADIGM-HF study, Entresto was administered in conjunction with other heart failure therapies,in place of an ACE inhibitor or other ARB (see section 5.1). There is limited experience in patients notcurrently 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 every3-4 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 forpatients with SBP ≥100 to 110 mmHg.

Paediatric heart failure

Table 1 shows the recommended dose for paediatric patients. The recommended dose should be takenorally twice daily. The dose should be increased every 2-4 weeks to the target dose, as tolerated by thepatient.

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

Table 1 Recommended dose titration

Patient weight To be given twice daily

Half the

Starting dose Intermediate dose Target dosestarting dose*

Paediatric patients less 0.8 mg/kg#1.6 mg/kg# 2.3 mg/kg# 3.1 mg/kg#than 40 kg

Paediatric patients at least 0.8 mg/kg#24 mg/26 mg 49 mg/51 mg 72 mg/78 mg40 kg, less than 50 kg

Paediatric patients at least 24 mg/26 mg49 mg/51 mg 72 mg/78 mg 97 mg/103 mg50 kg

* Half the starting dose is recommended in patients who have not been taking an ACE inhibitor or an

ARB or have been taking low doses of these medicinal products, patients who have renal impairment(estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) and patients who have moderatehepatic impairment (see special populations).#0.8 mg/kg, 1.6 mg/kg, 2.3 mg/kg and 3.1 mg/kg refer to the combined amount of sacubitril andvalsartan and are to be given using granules.

In patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinalproducts, half of the starting dose is recommended. For paediatric patients weighing 40 kg to less than50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended. After initiation,the dose should be increased to the standard starting dose following the recommended dose titration in

Table 1 and adjusted every 3-4 weeks.

For example, a paediatric patient weighing 25 kg who has not previously taken an ACE inhibitorshould start with half the standard starting dose, which corresponds to 20 mg (25 kg × 0.8 mg/kg)twice daily, given as granules. After rounding to the closest number of full capsules, this correspondsto 2 capsules of 6 mg/6 mg sacubitril/valsartan twice daily.

Treatment should not be initiated in patients with serum potassium level >5.3 mmol/l or with SBP <5thpercentile for the age of the patient. If patients experience tolerability issues (SBP <5th percentile forthe age of the patient, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment ofconcomitant medicinal products, temporary down-titration or discontinuation of Entresto isrecommended (see section 4.4).

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

No dose adjustment is required in patients with mild (eGFR 60-90 ml/min/1.73 m2) renal impairment.

Half of the starting dose should be considered in patients with moderate renal impairment (eGFR30-60 ml/min/1.73 m2). As there is very limited clinical experience in patients with severe renalimpairment (eGFR <30 ml/min/1.73 m2) (see section 5.1), Entresto should be used with caution andhalf of the starting dose is recommended. In paediatric patients weighing 40 kg to less than 50 kg, astarting dose of 0.8 mg/kg twice daily (given as granules) is recommended. After initiation, the doseshould be increased following the recommended dose titration every 2-4 weeks.

There is no experience in patients with end-stage renal disease and use of Entresto is notrecommended.

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 Bclassification) or with aspartate transaminase (AST)/alanine transaminase (ALT) values more thantwice the upper limit of the normal range. Entresto should be used with caution in these patients andhalf of the starting dose is recommended (see sections 4.4 and 5.2). In paediatric patients weighing40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily (given as granules) is recommended.

After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks.

Entresto is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis(Child-Pugh C classification) (see section 4.3).

The safety and efficacy of Entresto in children aged below 1 year have not been established. Currentlyavailable data are described in section 5.1 but no recommendation on a posology can be made.

Oral use.

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

* 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 beadministered until 36 hours after discontinuing ACE inhibitor therapy.

* Known history of angioedema related to previous ACE inhibitor or ARB therapy (seesection 4.4).

* Hereditary or idiopathic angioedema (see section 4.4).

* Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitusor 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).

* The combination of sacubitril/valsartan with an ACE inhibitor is contraindicated due to theincreased risk of angioedema (see section 4.3). Sacubitril/valsartan must not be initiated until36 hours after taking the last dose of ACE inhibitor therapy. If treatment withsacubitril/valsartan is stopped, ACE inhibitor therapy must not be initiated until 36 hours afterthe last dose of sacubitril/valsartan (see sections 4.2, pct. 4.3 and 4.5).

* The combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is notrecommended (see section 4.5). The combination of sacubitril/valsartan with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or in patientswith 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 ARBcontaining medicinal product (see sections 4.2 and 4.5).

Treatment should not be initiated unless SBP is ≥100 mmHg for adult patients or ≥5th percentile SBPfor the age of the paediatric patient. Patients with SBP below these values were not studied (seesection 5.1). Cases of symptomatic hypotension have been reported in adult patients treated withsacubitril/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 orduring dose titration with sacubitril/valsartan, blood pressure should be monitored routinely. Ifhypotension occurs, temporary down-titration or discontinuation of sacubitril/valsartan isrecommended (see section 4.2). Dose adjustment of diuretics, concomitant antihypertensives andtreatment of other causes of hypotension (e.g. hypovolaemia) should be considered. Symptomatichypotension 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 correctedbefore starting treatment with sacubitril/valsartan, however, such corrective action must be carefullyweighed against the risk of volume overload.

Evaluation of patients with heart failure should always include assessment of renal function. Patientswith 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). Thereis no experience in patients with end-stage renal disease and use of sacubitril/valsartan is notrecommended.

Use of sacubitril/valsartan may be associated with decreased renal function. The risk may be furtherincreased by dehydration or concomitant use of non-steroidal anti-inflammatory agents (NSAIDs) (seesection 4.5). Down-titration should be considered in patients who develop a clinically significantdecrease in renal function.

Treatment should not be initiated if the serum potassium level is >5.4 mmol/l in adult patients and>5.3 mmol/l in paediatric patients. Use of sacubitril/valsartan may be associated with an increased riskof hyperkalaemia, although hypokalaemia may also occur (see section 4.8). Monitoring of serumpotassium 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 mineralocorticoidantagonists (see section 4.2). If patients experience clinically significant hyperkalaemia adjustment ofconcomitant medicinal products, or temporary down-titration or discontinuation is recommended. Ifserum potassium level is >5.4 mmol/l discontinuation should be considered.

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

Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of thetongue, glottis or larynx likely to cause airway obstruction, appropriate therapy, e.g. adrenalinesolution 1 mg/1 ml (0.3-0.5 ml), and/or measures necessary to ensure a patent airway, should bepromptly administered.

Patients with a prior history of angioedema were not studied. As they may be at higher risk forangioedema, caution is recommended if sacubitril/valsartan is used in these patients.

Sacubitril/valsartan is contraindicated in patients with a known history of angioedema related toprevious 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).

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists,including valsartan (see section 4.8). These patients presented with abdominal pain, nausea, vomitingand diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. Ifintestinal angioedema is diagnosed, sacubitril/valsartan should be discontinued and appropriatemonitoring should be initiated until complete resolution of symptoms has occurred.

Sacubitril/valsartan may increase blood urea and serum creatinine levels in patients with bilateral orunilateral renal artery stenosis. Caution is required in patients with renal artery stenosis andmonitoring of renal function is recommended.

Patients with New York Heart Association (NYHA) functional classification IV

Caution should be exercised when initiating sacubitril/valsartan in patients with NYHA functionalclassification IV due to limited clinical experience in this population.

BNP is not a suitable biomarker of heart failure in patients treated with sacubitril/valsartan because itis a neprilysin substrate (see section 5.1).

There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh Bclassification) or with AST/ALT values more than twice the upper limit of the normal range. In thesepatients, exposure may be increased and safety is not established. Caution is therefore recommendedwhen using it in these patients (see section 4.2 and 5.2). Sacubitril/valsartan is contraindicated inpatients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification)(see section 4.3).

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

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

The concomitant use of sacubitril/valsartan with ACE inhibitors is contraindicated, as the concomitantinhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. Sacubitril/valsartanmust not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitortherapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.2and 4.3).

The concomitant use of sacubitril/valsartan with aliskiren-containing medicinal products iscontraindicated 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 renininhibitors such as aliskiren is not recommended (see section 4.4). Combination of sacubitril/valsartanwith aliskiren is potentially associated with a higher frequency of adverse reactions such ashypotension, hyperkalaemia and decreased renal function (including acute renal failure) (seesections 4.3 and 4.4).

Sacubitril/valsartan contains valsartan, and therefore should not be co-administered with another ARBcontaining medicinal product (see section 4.4).

In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Entresto maytherefore 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 to2-fold and AUC by up to 1.3-fold. Caution should be exercised when co-administeringsacubitril/valsartan with statins. No clinically relevant interaction was observed when simvastatin and

Entresto were co-administered.

Addition of a single dose of sildenafil to sacubitril/valsartan at steady state in patients withhypertension was associated with a significantly greater blood pressure reduction compared toadministration of sacubitril/valsartan alone. Therefore, caution should be exercised when sildenafil oranother PDE5 inhibitor is initiated in patients treated with sacubitril/valsartan.

Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoidantagonists (e.g. spironolactone, eplerenone), potassium supplements, salt substitutes containingpotassium or other agents (such as heparin) may lead to increases in serum potassium, and to increasesin serum creatinine. Monitoring of serum potassium is recommended if sacubitril/valsartan isco-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 withcompromised renal function, concomitant use of sacubitril/valsartan and NSAIDs may lead to anincreased risk of worsening of renal function. Therefore, monitoring of renal function is recommendedwhen initiating or modifying treatment in patients on sacubitril/valsartan who are taking NSAIDsconcomitantly (see section 4.4).

Reversible increases in serum lithium concentrations and toxicity have been reported duringconcomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonistsincluding sacubitril/valsartan. Therefore, this combination is not recommended. If the combinationproves necessary, careful monitoring of serum lithium levels is recommended. If a diuretic is alsoused, the risk of lithium toxicity may be increased further.

Co-administration of sacubitril/valsartan and furosemide had no effect on the pharmacokinetics ofsacubitril/valsartan but reduced Cmax and AUC of furosemide by 50% and 28%, respectively. Whilethere was no relevant change in urine volume, the urinary excretion of sodium was reduced within4 hours and 24 hours after co-administration. The average daily dose of furosemide was unchangedfrom baseline until the end of the PARADIGM-HF study in patients treated with sacubitril/valsartan.

There was no interaction between sacubitril/valsartan and intravenously administered nitroglycerinwith regard to blood pressure reduction. Co-administration of nitroglycerin and sacubitril/valsartanwas associated with a treatment difference of 5 bpm in heart rate compared to the administration ofnitroglycerine 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.

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

OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration ofsacubitril/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 concomitanttreatment with such medicinal products.

Co-administration of sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin by23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy withsacubitril/valsartan in patients receiving metformin, the clinical status of the patient should beevaluated.

No clinically meaningful interaction was observed when sacubitril/valsartan was co-administered withdigoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination oflevonorgestrel/ethinyl estradiol.

The use of sacubitril/valsartan is not recommended during the first trimester of pregnancy and iscontraindicated during the second and third trimesters of pregnancy (see section 4.3).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however, a small increase in riskcannot be excluded. Whilst there is no controlled epidemiological data on the risk with ARBs, similarrisks may exist for this class of medicinal product. Unless continued ARB therapy is consideredessential, patients planning pregnancy should be changed to alternative antihypertensive treatmentswhich 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 bestarted. Exposure to ARBs therapy during the second and third trimesters is known to induce humanfoetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonataltoxicity (renal failure, hypotension, hyperkalaemia).

Should exposure to ARBs have occurred from the second trimester of pregnancy, ultrasound check ofrenal function and skull is recommended. Infants whose mothers have taken ARBs should be closelyobserved for hypotension (see section 4.3).

There are no data from the use of sacubitril in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Sacubitril/valsartan

There are no data from the use of sacubitril/valsartan in pregnant women. Animal studies withsacubitril/valsartan have shown reproductive toxicity (see section 5.3).

Limited data show that sacubitril and its active metabolite LBQ657 are excreted in human milk in verylow amounts with an estimated relative infant dose of 0.01% for sacubitril and 0.46% for the activemetabolite LBQ657 when administered to breast-feeding women at a dose of 24 mg/26 mgsacubitril/valsartan, twice daily. In the same data, valsartan was under the limit of detection. There isinsufficient information on the effects of sacubitril/valsartan in newborns/infants. Because of thepotential risk for adverse reactions in breast-fed newborns/infants, Entresto is not recommended inwomen who are breast-feeding.

There are no available data on the effect of sacubitril/valsartan on human fertility. No impairment offertility was demonstrated in studies with it in male and female rats (see section 5.3).

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

The most commonly reported adverse reactions in adults during treatment with sacubitril/valsartanwere 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 ofselected adverse reactions).

Adverse reactions are ranked by System organ class and then by frequency with the most frequentfirst, 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); not known (frequencycannot be estimated from the available data). Within each frequency grouping, adverse reactions areranked in order of decreasing seriousness.

Table 2 List of adverse reactions

System organ class Preferred term Frequency category

Blood and lymphatic system

Anaemia Commondisorders

Immune system disorders Hypersensitivity Uncommon

Metabolism and nutrition Hyperkalaemia* Very commondisorders Hypokalaemia Common

Hypoglycaemia Common

Hyponatraemia Uncommon

Psychiatric disorders Hallucinations** Rare

Sleep disorders Rare

Paranoia Very rare

Nervous system disorders Dizziness Common

Headache Common

Syncope Common

Dizziness postural Uncommon

Myoclonus Not known

Ear and labyrinth disorders Vertigo Common

Vascular disorders Hypotension* Very common

Orthostatic hypotension Common

Respiratory, thoracic and

Cough Commonmediastinal disorders

Gastrointestinal disorders Diarrhoea Common

Nausea Common

Gastritis Common

Intestinal angioedema Very rare

Skin and subcutaneous tissue Pruritus Uncommondisorders Rash Uncommon

Angioedema* Uncommon

Renal and urinary disorders Renal impairment* Very common

Renal failure (renal failure,

Commonacute renal failure)

General disorders and Fatigue Commonadministration site conditions Asthenia Common

*See description of selected adverse reactions.

**Including auditory and visual hallucinations

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% ofpatients treated with enalapril. A higher incidence of angioedema was observed in Black patientstreated with sacubitril/valsartan (2.4%) and enalapril (0.5%) (see section 4.4).

In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/l were reported in11.6% and 19.7% of sacubitril/valsartan-treated patients and 14.0% and 21.1% of enalapril-treatedpatients, respectively.

In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (<90 mmHg anddecrease 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.

In PARADIGM-HF, renal impairment was reported in 10.1% of sacubitril/valsartan-treated patientsand 11.5% of enalapril-treated patients.

In the PANORAMA-HF study, the safety of sacubitril/valsartan was assessed in a randomised,active-controlled, 52-week study of 375 paediatric heart failure (HF) patients aged 1 month to<18 years compared to enalapril. The 215 patients who rolled over into the long-term open-labelextension study (PANORAMA-HF OLE) were treated for a median of 2.5 years, for up to 4.5 years.

The safety profile observed in both studies was similar to that observed in adult patients. Safety data inpatients aged 1 month to <1 year was limited.

Limited safety data are available in paediatric patients with moderate hepatic impairment or moderateto severe renal impairment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; angiotensin II receptorblockers (ARBs), other combinations, ATC code: C09DX04

Sacubitril/valsartan exhibits the mechanism of action of an angiotensin receptor neprilysin inhibitor bysimultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metaboliteof the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. Thecomplementary cardiovascular benefits of sacubitril/valsartan in heart failure patients are attributed tothe 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 theireffects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increasedconcentrations of the second messenger cyclic guanosine monophosphate (cGMP), which could resultin vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow,inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophicand anti-fibrotic effects.

Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blockingthe AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. This preventssustained activation of the renin-angiotensin-aldosterone system that would result in vasoconstriction,renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequentmaladaptive cardiovascular remodelling.

The pharmacodynamic effects of sacubitril/valsartan were evaluated after single and multiple doseadministrations in healthy subjects and in patients with heart failure, and are consistent withsimultaneous neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study inpatients with reduced ejection fraction (HFrEF), administration of sacubitril/valsartan resulted in aninitial increase in natriuresis, increased urine cGMP, and decreased plasma levels of mid-regionalpro-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/valsartansignificantly 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 evidencedby 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 cGMPcompared with enalapril. In the PANORAMA-HF study, a reduction in NT-proBNP was observed atweeks 4 and 12 for sacubitril/valsartan (40.2% and 49.8%) and enalapril (18.0% and 44.9%) comparedto baseline. The NT-proBNP levels continued to decrease over the duration of the study with areduction of 65.1% for sacubitril/valsartan and 61.6% for enalapril at week 52 compared to baseline.

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 istherefore a more suitable biomarker.

In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril/valsartan 194 mgsacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiacrepolarisation.

Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain andcerebrospinal fluid (CSF). Administration of sacubitril/valsartan 194 mg sacubitril/206 mg valsartanonce daily for two weeks to healthy subjects was associated with an increase in CSF Aβ1-38 comparedto placebo; there were no changes in concentrations of CSF Aβ1-40 and 1-42. The clinical relevanceof this finding is not known (see section 5.3).

The 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg strengths are in some publications referred to as50, 100 or 200 mg.

PARADIGM-HF, the pivotal phase 3 study, was a multinational, randomised, double-blind study of8 442 patients comparing sacubitril/valsartan to enalapril, both given to adult patients with chronicheart 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 primaryendpoint 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 severehepatic 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 asequential single-blind run-in period during which they received treatment with enalapril 10 mg twicedaily, followed by single-blind treatment with sacubitril/valsartan 100 mg twice daily, increasing to200 mg twice daily (see section 4.8 for discontinuations during this period). They were thenrandomised to the double-blind period of the study, during which they received eithersacubitril/valsartan 200 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. Atrandomisation, 70% of patients were NYHA class II, 24% were class III and 0.7% were class IV. Themean 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 atthe end of the study (mean daily dose of 375 mg). In the enalapril group, 75% of patients remained onthe 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 failurehospitalisations to 21.8% compared to 26.5% for enalapril treated patients. The absolute riskreductions were 4.7% for the composite of the CV death or HF hospitalisation, 3.1% for CV deathalone, and 2.8% for first HF hospitalisation alone. The relative risk reduction was 20% versusenalapril (see Table 3). This effect was observed early and was sustained throughout the duration ofthe study (see Figure 1). Both components contributed to the risk reduction. Sudden death accountedfor 45% of cardiovascular deaths and was reduced by 20% in sacubitril/valsartan-treated patientscompared to enalapril-treated patients (hazard ratio [HR] 0.80, p=0.0082). Pump failure accounted for26% of cardiovascular deaths and was reduced by 21% in sacubitril/valsartan-treated patientscompared 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 withenalapril (see Table 3).

Table 3 Treatment effect for the primary composite endpoint, its components and all-causemortality over a median follow-up of 27 months

Sacubitril/ Enalapril Hazard ratio Relative p-value ***valsartan N=4 212♯ (95% CI) risk

N=4 187♯ n (%) reductionn (%)

Primary composite 914 (21.83) 1 117 (26.52) 0.80 (0.73, 0.87) 20% 0.0000002endpoint of CV deathand heart failurehospitalisations*

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

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 previoushospitalisation.

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

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

Time to first occurrence of CV death or

Time to occurrence of CV death in PARADIGM-HFheart failure hospitalisations in PARADIGM-HF40 40

P<0.0001

HR (95%CI):30 Enalapril (N=4212) 30 Enalapril (N=4212)0.799 (0.715, 0.893)

Entresto (N=4187) Entresto (N=4187)20 20

P<0.0001

HR (95%CI):10 100.798 (0.731, 0.871)0 00 180 360 540 720 900 1080 1260 0 180 360 540 720 900 1080 1260

Time since randomisation (days) Time since randomisation (days)

No. at risk No. at risk

Entresto 4187 3922 3663 3018 2257 1544 896 249 Entresto 4187 4056 3891 3282 2478 1716 1005 280

Enalapril 4212 3883 3579 2922 2123 1488 853 236 Enalapril 4212 4051 3860 3231 2410 1726 994 279

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 ACEinhibitor or ARB therapy or on varying doses of ACE inhibitors or ARBs prior to study entry. Patientsreceived a starting dose of sacubitril/valsartan of 50 mg twice daily and were up-titrated to 100 mgtwice 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 mgwhen up-titrated over 6 weeks (84.8%) versus 3 weeks (73.6%). Overall, 76% of patients achieved andmaintained the target dose of sacubitril/valsartan 200 mg twice daily without any dose interruption ordown-titration over 12 weeks.

KM estimate of cumulativefailure rate (%)

KM estimate of cumulativefailure rate (%)

PANORAMA-HF

PANORAMA-HF, a phase 3 study, was a multinational, randomised, double-blind study comparingsacubitril/valsartan and enalapril in 375 paediatric patients aged 1 month to <18 years with heartfailure due to systemic left ventricular systolic dysfunction (LVEF ≤45% or fractional shortening≤22.5%). The primary objective was to determine whether sacubitril/valsartan was superior toenalapril in paediatric HF patients over a 52-week treatment duration based on a global rank endpoint.

The global rank primary endpoint was derived by ranking patients (worst-to-best outcome) based onclinical events such as death, initiation of mechanical life support, listing for urgent heart transplant,worsening HF, measures of functional capacity (NYHA/ROSS scores), and patient-reported HFsymptoms (Patient Global Impression Scale [PGIS]). Patients with systemic right ventricles or singleventricles and patients with restrictive or hypertrophic cardiomyopathy were excluded from the study.

The target maintenance dose of sacubitril/valsartan was 2.3 mg/kg twice daily in paediatric patientsaged 1 month to <1 year and 3.1 mg/kg twice daily in patients aged 1 to <18 years with a maximumdose of 200 mg twice daily. The target maintenance dose of enalapril was 0.15 mg/kg twice daily inpaediatric patients aged 1 month to <1 year and 0.2 mg/kg twice daily in patients aged 1 to <18 yearswith a maximum dose of 10 mg twice daily.

In the study, 9 patients were aged 1 month to <1 year, 61 patients were aged 1 year to <2 years,85 patients were aged 2 to <6 years and 220 patients were aged 6 to <18 years. At baseline, 15.7% ofpatients were NYHA/ROSS class I, 69.3% were class II, 14.4% were class III and 0.5% were class IV.

The mean LVEF was 32%. The most common underlying causes of heart failure were cardiomyopathyrelated (63.5%). Prior to study participation, patients were treated most commonly with ACEinhibitors/ARBs (93%), beta-blockers (70%), aldosterone antagonists (70%), and diuretics (84%).

The Mann-Whitney Odds of the global rank primary endpoint was 0.907 (95% CI 0.72, 1.14),numerically in favour of sacubitril/valsartan (see Table 4). Sacubitril/valsartan and enalapril showedcomparable clinically relevant improvements in the secondary endpoints of NYHA/ROSS class and

PGIS score change compared to baseline. At week 52, the NYHA/ROSS functional class changesfrom baseline were: improved in 37.7% and 34.0%; unchanged in 50.6% and 56.6%; worsened in11.7% and 9.4% of patients for sacubitril/valsartan and enalapril respectively. Similarly, the PGISscore changes from baseline were: improved in 35.5% and 34.8%; unchanged in 48.0% and 47.5%;worsened in 16.5% and 17.7% of patients for sacubitril/valsartan and enalapril respectively.

NT-proBNP was substantially reduced from baseline in both treatment groups. The magnitude of

NT-proBNP reduction with Entresto was similar to that observed in adult heart failure patients in

PARADIGM-HF. Because sacubitril/valsartan improved outcomes and reduced NT-proBNP in

PARADIGM-HF, the reductions in NT-proBNP coupled with the symptomatic and functionalimprovements from baseline seen in PANORAMA-HF were considered a reasonable basis to inferclinical benefits in paediatric heart failure patients. There were too few patients aged below 1 year toevaluate the efficacy of sacubitril/valsartan in this age group.

Table 4 Treatment effect for the primary global rank endpoint in PANORAMA-HF

Sacubitril/valsartan Enalapril

N=187 N=188 Treatment effect

Probability of favourable Probability of favourable Odds**

Global rankoutcome (%)* outcome (%)* (95% CI)primary endpoint52.4 47.6 0.907 (0.72, 1.14)

*The probability of favourable outcome or Mann-Whitney probability (MWP) for the given treatmentwas estimated based on percentage of wins in pairwise comparisons of global rank score betweensacubitril/valsartan-treated patients versus enalapril-treated patients (each higher score counts as onewin and each equal score counts as half a win).

**Mann-Whitney Odds was calculated as the estimated MWP for enalapril divided by the estimated

MWP for sacubitril/valsartan, with odds <1 in favour of sacubitril/valsartan and >1 in favour ofenalapril.

The valsartan contained within sacubitril/valsartan is more bioavailable than the valsartan in othermarketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril/valsartan isequivalent to 40 mg, 80 mg and 160 mg of valsartan in other marketed tablet formulations,respectively.

Adult population

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

Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasmaconcentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability ofsacubitril 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 andvalsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulatesignificantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinicallysignificant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril/valsartancan be administered with or without food.

Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94-97%). Based on thecomparison 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 to103 litres, respectively.

Sacubitril is readily converted to LBQ657 by carboxylesterases 1b and 1c; LBQ657 is not furthermetabolised to a significant extent. Valsartan is minimally metabolised, as only about 20% of the doseis recovered as metabolites. A hydroxyl metabolite of valsartan has been identified in plasma at lowconcentrations (<10%).

Since CYP450-enzyme-mediated metabolism of sacubitril and valsartan is minimal, co-administrationwith 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 sincethere is limited metabolism of sacubitril/valsartan via CYP450 enzymes. Sacubitril/valsartan does notinduce or inhibit CYP450 enzymes.

Following oral administration, 52-68% of sacubitril (primarily as LBQ657) and ~13% of valsartan andits metabolites are excreted in urine; 37-48% of sacubitril (primarily as LBQ657) and 86% of valsartanand its metabolites are excreted in faeces.

Sacubitril, LBQ657 and valsartan are eliminated from plasma with a mean elimination half-life (T½) ofapproximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.

The pharmacokinetics of sacubitril, LBQ657 and valsartan were approximately linear over asacubitril/valsartan dose range of 24 mg sacubitril/26 mg valsartan to 97 mg sacubitril/103 mgvalsartan.

LBQ657 and valsartan exposure are increased in subjects over 65 years of age by 42% and 30%,respectively, compared to younger subjects.

A correlation was observed between renal function and systemic exposure to LBQ657 in patients withmild 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 renalimpairment (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 renalimpairment compared to patients with mild renal impairment. No studies have been performed inpatients undergoing dialysis. However, LBQ657 and valsartan are highly bound to plasma protein andtherefore unlikely to be effectively removed by dialysis.

In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5- and3.4- 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 moderatehepatic 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 and2.20-fold, respectively, compared to matching healthy subjects. Sacubitril/valsartan has not beenstudied in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (see sections 4.3 and4.4).

The pharmacokinetics of sacubitril/valsartan (sacubitril, LBQ657 and valsartan) are similar betweenmale and female subjects.

The pharmacokinetics of sacubitril/valsartan were evaluated in paediatric heart failure patients aged1 month to <1 year and 1 year to <18 years and indicated that the pharmacokinetic profile ofsacubitril/valsartan in paediatric and adult patients is similar.

Non-clinical data (including studies with sacubitril and valsartan components and/orsacubitril/valsartan) reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and fertility.

Sacubitril/valsartan treatment during organogenesis resulted in increased embryofoetal lethality in ratsat doses ≥49 mg sacubitril/51 mg valsartan/kg/day (≤0.72-fold the maximum recommended humandose [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 isteratogenic 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 mgvalsartan/kg/day. Cardiovascular abnormalities (mainly cardiomegaly) were observed in rabbitfoetuses at a maternally non-toxic dose (1.46 mg sacubitril/1.54 mg valsartan/kg/day). A slightincrease in two foetal skeletal variations (misshapen sternebra, sternebra bipartite ossification) wasobserved in rabbits at a sacubitril/valsartan dose of 4.9 mg sacubitril/5.1 mg valsartan/kg/day. Theadverse embryofoetal effects of sacubitril/valsartan are attributed to the angiotensin receptorantagonist activity (see section 4.6).

Sacubitril treatment during organogenesis resulted in embryo-foetal lethality and embryo-foetaltoxicity (decreased foetal body weights and skeletal malformations) in rabbits at doses associated withmaternal toxicity (500 mg/kg/day; 5.7-fold the MRHD on the basis of LBQ657 AUC). A slightgeneralised delay in ossification was observed at doses of >50 mg/kg/day. This finding is notconsidered adverse. No evidence of embryo-foetal toxicity or teratogenicity was observed in ratstreated with sacubitril. The embryo-foetal no-observed adverse effect level (NOAEL) for sacubitrilwas 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 to750 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 duringorganogenesis, gestation and lactation may affect pup development and survival.

Sacubitril/valsartan

The effects of sacubitril/valsartan on amyloid-β concentrations in CSF and brain tissue were assessedin young (2-4 years old) cynomolgus monkeys treated with sacubitril/valsartan (24 mgsacubitril/26 mg valsartan/kg/day) for two weeks. In this study CSF Aβ clearance in cynomolgusmonkeys was reduced, increasing CSF Aβ1-40, 1-42 and 1-38 levels; there was no correspondingincrease in Aβ levels in the brain. Increases in CSF Aβ1-40 and 1-42 were not observed in a two-weekhealthy volunteer study in humans (see section 5.1). Additionally, in a toxicology study in cynomolgusmonkeys 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.

In juvenile rats treated with sacubitril (postnatal days 7 to 70), there was a reduction in age-relatedbone mass development and bone elongation at approximately 2-fold the AUC exposure to the activemetabolite of sacubitril, LBQ657, based on sacubitril/valsartan paediatric clinical dose of 3.1 mg/kgtwice daily. The mechanism for these findings in juvenile rats, and consequently the relevance to thehuman paediatric population, is unknown. A study in adult rats showed only a minimal transientinhibitory 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 normalconditions. However, a mild transient interference of sacubitril with the early phase of fracture healingin adults cannot be excluded. Clinical data in paediatric patients (PANORAMA-HF study) did notshow evidence that sacubitril/valsartan has an impact on body weight, height, head circumference andfracture rate. Bone density was not measured in the study. Long-term data in paediatric patients(PANORAMA-HF OLE) showed no evidence of adverse effects of sacubitril/valsartan on (bone)growth or fracture rates.

In juvenile rats treated with valsartan (postnatal days 7 to 70), doses as low as 1 mg/kg/day producedpersistent irreversible kidney changes consisting of tubular nephropathy (sometimes accompanied bytubular epithelial necrosis) and pelvic dilatation. These kidney changes represent an expectedexaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin IItype 1 blockers; such effects are observed if rats are treated during the first 13 days of life. This periodcoincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks afterconception in humans. Functional renal maturation is an ongoing process within the first year of life inhumans. Consequently, a clinical relevance in paediatric patients less than 1 year of age cannot beexcluded, while preclinical data do not indicate a safety concern for paediatric patients older than1 year.

Microcrystalline cellulose

Low-substituted hydroxypropylcellulose

Crospovidone, type A

Magnesium stearate

Talc

Silica colloidal anhydrous

Hypromellose, substitution type 2910 (3 mPa·s)

Titanium dioxide (E171)

Macrogol (4000)

Talc

Iron oxide red (E172)

Iron oxide black (E172)

Hypromellose, substitution type 2910 (3 mPa·s)

Titanium dioxide (E171)

Macrogol (4000)

Talc

Iron oxide red (E172)

Iron oxide yellow (E172)

Hypromellose, substitution type 2910 (3 mPa·s)

Titanium dioxide (E171)

Macrogol (4000)

Talc

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable.

3 years

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

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

PVC/PVDC blisters.

Pack sizes: 14, 20, 28, 56 or 196 film-coated tablets and multipacks containing 196 (7 packs of28) film-coated tablets.

Pack sizes: 14, 20, 28, 56, 168 or 196 film-coated tablets and multipacks containing 168 (3 packs of56) or 196 (7 packs of 28) film-coated tablets.

Pack sizes: 14, 20, 28, 56, 168 or 196 film-coated tablets and multipacks containing 168 (3 packs of56) or 196 (7 packs of 28) film-coated tablets.

Not all pack sizes may be marketed.

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

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/15/1058/001

EU/1/15/1058/008-010

EU/1/15/1058/017-018

EU/1/15/1058/002-004

EU/1/15/1058/011-013

EU/1/15/1058/019-020

EU/1/15/1058/005-007

EU/1/15/1058/014-016

EU/1/15/1058/021-022

Date of first authorisation: 19 November 2015

Date of latest renewal: 25 June 2020

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

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