1. NAME OF THE MEDICINAL PRODUCT
Entresto 24 mg/26 mg film-coated tablets
Entresto 49 mg/51 mg film-coated tablets
Entresto 97 mg/103 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Entresto 24 mg/26 mg film-coated tablets
Each film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartan sodium salt complex).
Entresto 49 mg/51 mg film-coated tablets
Each film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartan sodium salt complex).
Entresto 97 mg/103 mg film-coated tablets
Each film-coated tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartan sodium salt complex).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet)
Entresto 24 mg/26 mg film-coated tablets
Violet white ovaloid biconvex film-coated tablet with bevelled edges, unscored, debossed with “NVR” on one side and “LZ” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm.
Entresto 49 mg/51 mg film-coated tablets
Pale yellow ovaloid biconvex film-coated tablet with bevelled edges, unscored, debossed with “NVR” on one side and “L1” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm.
Entresto 97 mg/103 mg film-coated tablets
Light pink ovaloid biconvex film-coated tablet with bevelled edges, unscored, debossed with “NVR” on one side and “L11” on the other side. Approximate tablet dimensions 15.1 mm x 6.0 mm.
4. CLINICAL PARTICULARS
Entresto 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 Entresto is one tablet of 49 mg/51 mg twice daily, except in the situations described below. The dose should be doubled at 2-4 weeks to the target dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient (see section 5.1).
If patients experience tolerability issues (systolic blood pressure [SBP] ≤95 mmHg, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down–titration or discontinuation of Entresto is recommended (see section 4.4).
In PARADIGM-HF study, Entresto was administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other angiotensin II receptor blocker (ARB) (see section 5.1). There is limited experience in patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, therefore a starting dose of 24 mg/26 mg twice daily and slow dose titration (doubling every 3-4 weeks) are recommended in these patients (see “Titration” in section 5.1).
Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg (see section 4.4). A starting dose of 24 mg/26 mg twice daily should be considered for patients with SBP ≥100 to 110 mmHg.
Entresto should not be co-administered with an ACE inhibitor or an ARB. Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, it must not be started for at least 36 hours after discontinuing ACE inhibitor therapy (see sections 4.3, 4.4 and 4.5).
The valsartan contained within Entresto is more bioavailable than the valsartan in other marketed tablet formulations (see section 5.2).
If a dose is missed, the patient should take the next dose at the scheduled time.
Special populations
Elderly population
The dose should be in line with the renal function of the elderly patient.
Renal impairment
No dose adjustment is required in patients with mild (Estimated Glomerular Filtration Rate [eGFR] 60-90 ml/min/1.73 m2) renal impairment. A starting dose of 24 mg/26 mg twice daily should be considered in patients with moderate renal impairment (eGFR 30-60 ml/min/1.73 m2). As there is very limited clinical experience in patients with severe renal impairment (eGFR <30 ml/min/1.73 m2) (see section 5.1) Entresto should be used with caution and a starting dose of 24 mg/26 mg twice daily is recommended. There is no experience in patients with end-stage renal disease and use of Entresto is not recommended.
Hepatic impairment
No dose adjustment is required when administering Entresto to patients with mild hepatic impairment (Child-Pugh A classification). There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. Entresto should be used with caution in these patients and the recommended starting dose is 24 mg/26 mg twice daily (see sections 4.4 and 5.2). Entresto is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification) (see section 4.3).
Paediatric population
The safety and efficacy of Entresto in children and adolescents aged below 18 years have not been established. No data are available.
Method of administration
Oral use.
Entresto may be administered with or without food (see section 5.2). The tablets must be swallowed with a glass of water.
4.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
• Concomitant use with ACE inhibitors (see sections 4.4 and 4.5). Entresto must not be administered until 36 hours after discontinuing ACE inhibitor therapy.
• Known history of angioedema related to previous ACE inhibitor or ARB therapy (see section 4.4).
• Hereditary or idiopathic angioedema (see section 4.4).
• Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see sections 4.4 and 4.5).
• Severe hepatic impairment, biliary cirrhosis and cholestasis (see section 4.2).
• Second and third 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 Entresto with an ACE inhibitor is contraindicated due to the increased risk of angioedema (see section 4.3). Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Entresto (see sections 4.2, 4.3 and 4.5).
• The combination of Entresto with direct renin inhibitors such as aliskiren is not recommended (see section 4.5). The combination of Entresto 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).
• Entresto 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 Entresto 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 Entresto, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of Entresto is recommended (see section 4.2). Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with Entresto, however, such corrective action must be carefully weighed against the risk of volume overload.
Impaired renal function
eva luation 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 Entresto is not recommended.
Worsening renal function
Use of Entresto 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 Entresto 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 Entresto. If angioedema occurs, Entresto 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 Entresto is used in these patients. Entresto 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
Entresto may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended.
Patients with NYHA functional classification IV
Caution should be exercised when initiating Entresto 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 Entresto 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). Entresto 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 Entresto with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE may increase the risk of angioedema. Entresto 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 Entresto (see sections 4.2 and 4.3).
Aliskiren
Theconcomitant use of Entresto 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 Entresto with direct renin inhibitors such as aliskiren is not recommended (see section 4.4). Combination of Entresto 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
Entresto 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. Entresto may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of Entresto increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Therefore, caution should be exercised when co-administering Entresto with statins.
PDE5 inhibitors including sildenafil
Addition of a single dose of sildenafil to Entresto at steady state in patients with hypertension was associated with a significantly greater blood pressure reduction compared to administration of Entresto alone. Therefore, caution should be exercised when sildenafil or another PDE5 inhibitor is initiated in patients treated with Entresto.
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 Entresto 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 Entresto 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 Entresto 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 Entresto 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 Entresto and furosemide had no effect on the pharmacokinetics of Entresto 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 Entresto.
Nitrates, e.g. nitroglycerine
There was no drug-drug interaction between Entresto and intravenously administered nitroglycerin with regard to blood pressure reduction. Co-administration of nitroglycerin and Entresto 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 Entresto 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 Entresto 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 Entresto with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with Entresto in patients receiving metformin, the clinical status of the patient should be eva luated.
No significant interaction
No clinically meaningful drug-drug interaction was observed when Entresto was co-administered with digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of levonorgestrel/ethinyl estradiol.
CYP 450 interactions
In vitro metabolism studies indicate that potential for CYP 450-based drug interactions is low since there is limited metabolism of Entresto via CYP450 enzymes. Entresto does not induce or inhibit CYP450 enzymes.
4.6 Fertility, pregnancy and lactation
Pregnancy
The use of Entresto 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).
Entresto
There are no data from the use of Entresto in pregnant women. Animal studies with Entresto have shown reproductive toxicity (see section 5.3).
Breast-feeding
It is not known whether Entresto is excreted in human milk. The components of Entresto, sacubitril and valsartan, were excreted in the milk of lactating rats (see section 5.3). Because of the potential risk for adverse reactions in breast-fed newborns/infants, it is not recommended during breast-feeding. A decision should be made whether to abstain from breast-feeding or to discontinue Entresto while breast-feeding, taking into account the importance of Entresto to the mother.
Fertility
There are no available data on the effect of Entresto 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
Entresto 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.
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions during treatment with Entresto were hypotension, hyperkalaemia and renal impairment (see section 4.4). Angioedema was reported in patients treated with Entresto (see description of selected adverse reactions).
The safety of Entresto in patients with chronic heart failure was eva luated in the pivotal phase 3 study PARADIGM-HF, which compared patients treated twice daily with Entresto 97 mg/103 mg (n=4,203) or enalapril 10 mg (n=4,229). Patients randomised to the Entresto 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 Entresto 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 Entresto 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 Entresto-treated patients (10.7%) and 516 enalapril-treated patients (12.2%).
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

*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

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 Entresto of 50 mg twice daily and were up-titrated to 100 mg twice daily, then to the target dose of 200 mg twice daily, with either a 3-week or a 6-week regimen.
More patients who were naïve to previous ACE inhibitor or ARB therapy or on low-dose therapy (equivalent to <10 mg enalapril/day) were able to achieve and maintain Entresto 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 Entresto 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 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 Entresto is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in Entresto is equivalent to 40 mg, 80 mg and 160 mg of valsartan in other marketed tablet formulations, respectively.
Absorption
Following oral administration, Entresto 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 Entresto, 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. Entresto 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 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 Entresto 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. Entresto 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 Entresto (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 Entresto) 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
Entresto 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 Entresto 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 Entresto dose of 4.9 mg sacubitril/5.1 mg valsartan/kg/day. The adverse embryofoetal effects of Entresto are attributed to the angiotensin receptor antagonist activity (see section 4.6).
Sacubitril treatment during organogenesis resulted in embryo-foetal lethality and embryo-foetal toxicity (decreased foetal body weights and skeletal malformations) in rabbits at doses associated with maternal toxicity (500 mg/kg/day; 5.7-fold the MRHD on the basis of LBQ657 AUC). A slight generalised delay in ossification was observed at doses of >50 mg/kg/day. This finding is not considered adverse. No evidence of embryo-foetal toxicity or teratogenicity was observed in rats treated with sacubitril. The embryo-foetal no-observed adverse effect level (NOAEL) for sacubitril was at least 750 mg/kg/day in rats and 200 mg/kg/day in rabbits (2.2-fold the MRHD on the basis of LBQ657 AUC).
Pre- and postnatal development studies in rats conducted with sacubitril at high doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with Entresto during organogenesis, gestation and lactation may affect pup development and survival.
Other preclinical findings
Entresto
The effects of Entresto on amyloid-β concentrations in CSF and brain tissue were assessed in young (2-4 years old) cynomolgus monkeys treated with Entresto (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 Entresto at 146 mg sacubitril/154 mg valsartan/kg/day for 39 weeks, there was no evidence for the presence of amyloid plaques in the brain. Amyloid content was not, however, measured quantitatively in this study.
Sacubitril
In juvenile rats treated with sacubitril (postnatal days 7 to 70), there was a reduction in age-related bone mass development and bone elongation. A study in adult rats showed only a minimal transient inhibitory effect on bone mineral density but not on any other parameters relevant for bone growth, suggesting no relevant effect of sacubitril on bone in adult patient populations under normal conditions. However, a mild transient interference of sacubitril with the early phase of fracture healing in adults cannot be excluded.
Valsartan
In juvenile rats treated with valsartan (postnatal days 7 to 70), doses as low as 1 mg/kg/day produced persistent irreversible kidney changes consisting of tubular nephropathy (sometimes accompanied by tubular epithelial necrosis) and pelvic dilatation. These kidney changes represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers; such effects are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipient(s)
Tablet core
Microcrystalline cellulose
Low-substituted hydroxypropylcellulose
Crospovidone, type A
Magnesium stearate
Talc
Colloidal anhydrous silica
Film coat
Entresto 24 mg/26 mg film-coated tablets
Hypromellose, substitution type 2910 (3 mPa·s)
Titanium dioxide (E171)
Macrogol 4000
Talc
Iron oxide red (E172)
Iron oxide black (E172)
Entresto 49 mg/51 mg film-coated tablets
Hypromellose, substitution type 2910 (3 mPa·s)
Titanium dioxide (E171)
Macrogol 4000
Talc
Iron oxide red (E172)
Iron oxide yellow (E172)
Entresto 97 mg/103 mg film-coated tablets
Hypromellose, substitution type 2910 (3 mPa·s)
Titanium dioxide (E171)
Macrogol 4000
Talc
Iron oxide red (E172)
Iron oxide black (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PVDC/Aluminium blisters. One blister contains either 10 or 14 film-coated tablets.
Entresto 24 mg/26 mg film-coated tablets
Pack sizes: 14, 20, 28 or 56 film-coated tablets.
Entresto 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.
Entresto 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 and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
United Kingdom
8. MARKETING AUTHORISATION NUMBER(S)
Entresto 24 mg/26 mg film-coated tablets
EU/1/15/1058/001
EU/1/15/1058/008-010
Entresto 49 mg/51 mg film-coated tablets
EU/1/15/1058/002-004
EU/1/15/1058/011-013
Entresto 97 mg/103 mg film-coated tablets
EU/1/15/1058/005-007
EU/1/15/1058/014-016
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
19 November 2015
10. DATE OF REVISION OF THE TEXT
05 February 2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.