sacubitril/valsartan: prescribing information – dosing, contraindications, interactions, side effects

Adult heart failure

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

Paediatric heart failure

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

Paediatric heart failure

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

Posology

General considerations
Entresto should not be co-administered with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (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.

Adult heart failure
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 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.

Paediatric heart failure
Table 1 shows the recommended dose for paediatric patients. The recommended dose should be taken orally twice daily. The dose should be increased every 2-4 weeks to the target dose, as tolerated by the patient.

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

Table 1
Recommended dose titration

Patient weight
To be given twice daily

Half the starting dose*
Starting dose
Intermediate dose
Target dose
Paediatric patients less than 40 kg
0.8 mg/kg#
1.6 mg/kg#
2.3 mg/kg#
3.1 mg/kg#
Paediatric patients at least
40 kg, less than 50 kg
0.8 mg/kg#
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
Paediatric patients at least
50 kg
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
97 mg/103 mg
* 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 moderate hepatic 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 and valsartan and are to be given using granules.

In patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, half of the starting dose is recommended. For paediatric patients weighing 40 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 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 inhibitor should 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 corresponds to 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 <5th percentile for the age of the patient. If patients experience tolerability issues (SBP <5th percentile for the age of the patient, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down-titration or discontinuation of Entresto is recommended (see section 4.4).

Special populations
Elderly
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 (eGFR 60-90 ml/min/1.73 m2) renal impairment.

Half of the starting dose 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 half of the starting dose is recommended. In paediatric patients weighing 40 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.

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 aspartate transaminase (AST)/alanine transaminase (ALT) values more than twice the upper limit of the normal range. Entresto should be used with caution in these patients and half of the starting dose is recommended (see sections 4.4 and 5.2). In paediatric patients weighing 40 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).

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

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. Splitting or crushing of the tablets is not recommended.

Posology

General considerations
Entresto should not be co-administered with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (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.

Paediatric heart failure
Table 1 shows the recommended dose for paediatric patients. The recommended dose should be taken orally twice daily. The dose should be increased every 2-4 weeks to the target dose, as tolerated by the patient.

The lowest recommended dose is 6 mg/6 mg. Doses can be rounded up or down to the closest combination of full 6 mg/6 mg and/or 15 mg/16 mg capsules. When rounding the dose up or down during the up-titration phase, consideration should be given to ensuring progressive increase to the target dose.

For patients weighing more than 40 kg, Entresto film-coated tablets can be used.

Table 1
Recommended dose titration

Patient weight
To be given twice daily
Half the starting dose*
Starting dose
Intermediate dose
Target dose
Paediatric patients less than
40 kg
0.8 mg/kg#
1.6 mg/kg#
2.3 mg/kg#
3.1 mg/kg#
Paediatric patients at least 40 kg, less than 50 kg
0.8 mg/kg#
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
Paediatric patients at least 50 kg
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
97 mg/103 mg
* 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 moderate hepatic 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 and valsartan and are to be given using granules.

In patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, half of the starting dose is recommended. For paediatric patients weighing 40 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 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 inhibitor should 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 corresponds to 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 systolic blood pressure (SBP) <5th percentile for the age of the patient. If patients experience tolerability issues (SBP <5th percentile for the age of the patient, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down-titration or discontinuation of Entresto is recommended (see section 4.4).

Special populations
Renal impairment
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 (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 half of the starting dose is recommended. In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily is recommended. After initiation, the dose should 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 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 aspartate transaminase (AST)/alanine transaminase (ALT) values more than twice the upper limit of the normal range. Entresto should be used with caution in these patients and half of the starting dose is recommended (see sections 4.4 and 5.2). In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily 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).

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

Method of administration

Oral use.

Entresto granules are administered by opening the capsule and sprinkling the contents onto a small amount of soft food (1 to 2 teaspoons). Food containing the granules must be consumed immediately.
Patients may receive either the 6 mg/6 mg (white cap) or 15 mg/16 mg (yellow cap) capsules or both to reach the required doses (see section 6.6). The capsule must not be swallowed. The empty shells must be discarded after use and not swallowed.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
• Concomitant use with ACE inhibitors (see sections 4.4 and 4.5). Entresto must not be administered until 36 hours after discontinuing ACE inhibitor therapy.
• Known history of angioedema related to previous ACE inhibitor or ARB therapy (see section 4.4).
• Hereditary or idiopathic angioedema (see section 4.4).
• Concomitant use with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see sections 4.4 and 4.5).
• Severe hepatic impairment, biliary cirrhosis and cholestasis (see section 4.2).
• Second and third trimesters of pregnancy (see section 4.6).

Summary of the safety profile

The most commonly reported adverse reactions in adults during treatment with sacubitril/valsartan were hypotension (17.6%), hyperkalaemia (11.6%) and renal impairment (10.1%) (see section 4.4).
Angioedema was reported in patients treated with sacubitril/valsartan (0.5%) (see description of selected adverse reactions).

Tabulated list of adverse reactions

Adverse reactions are ranked by System organ class and then by frequency with the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 2
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
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 mediastinal disorders
Cough
Common
Gastrointestinal disorders
Diarrhoea
Common
Nausea
Common
Gastritis
Common
Intestinal angioedema
Very rare
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.
**Including auditory and visual hallucinations

Description of selected adverse reactions

Angioedema
Angioedema has been reported in patients treated with sacubitril/valsartan. In PARADIGM-HF, angioedema was reported in 0.5% of patients treated with sacubitril/valsartan, compared with 0.2% of patients treated with enalapril. A higher incidence of angioedema was observed in Black patients treated with sacubitril/valsartan (2.4%) and enalapril (0.5%) (see section 4.4).

Hyperkalaemia and serum potassium
In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/l were reported in 11.6% and 19.7% of sacubitril/valsartan-treated patients and 14.0% and 21.1% of enalapril-treated patients, respectively.

Blood pressure
In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (<90 mmHg and decrease from baseline of >20 mmHg) were reported in 17.6% and 4.76% of sacubitril/valsartan- treated patients compared with 11.9% and 2.67% of enalapril-treated patients, respectively.

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

Paediatric population

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-label extension 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 in patients aged 1 month to <1 year was limited.

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

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.

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

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

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

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

Hypotension

Treatment should not be initiated unless SBP is ≥100 mmHg for adult patients or ≥5th percentile SBP for the age of the paediatric patient. Patients with SBP below these values were not studied (see

section 5.1). Cases of symptomatic hypotension have been reported in adult patients treated with sacubitril/valsartan during clinical studies (see section 4.8), especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg). When initiating therapy or during dose titration with sacubitril/valsartan, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of sacubitril/valsartan is recommended (see section 4.2). Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with sacubitril/valsartan, however, such corrective action must be carefully weighed against the risk of volume overload.

Renal impairment

Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild and moderate renal impairment are more at risk of developing hypotension (see section 4.2).
There is very limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m2) and these patients may be at greatest risk of hypotension (see section 4.2). There is no experience in patients with end-stage renal disease and use of sacubitril/valsartan is not recommended.

Worsening renal function

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

Hyperkalaemia

Treatment should not be initiated if the serum potassium level is >5.4 mmol/l in adult patients and >5.3 mmol/l in paediatric patients. Use of sacubitril/valsartan may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur (see section 4.8). Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists (see section 4.2). If patients experience clinically significant hyperkalaemia adjustment of concomitant medicinal products, or temporary down–titration or discontinuation is recommended. If serum potassium level is >5.4 mmol/l discontinuation should be considered.

Angioedema

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

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

Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if sacubitril/valsartan is used in these patients.
Sacubitril/valsartan is contraindicated in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy or with hereditary or idiopathic angioedema (see section 4.3).

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

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, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, sacubitril/valsartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Patients with renal artery stenosis

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

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

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

B-type natriuretic peptide (BNP)

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

Patients with hepatic impairment

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

Psychiatric disorders

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

Sodium

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

Interactions resulting in a contraindication

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

Aliskiren
The concomitant use of sacubitril/valsartan with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see section 4.3). The combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is not recommended (see section 4.4). Combination of sacubitril/valsartan with aliskiren is potentially associated with a higher frequency of adverse reactions such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) (see sections 4.3 and 4.4).

Interactions resulting in concomitant use not being recommended

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

Interactions requiring precautions

OATP1B1 and OATP1B3 substrates, e.g. statins
In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Entresto may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins.
Co-administration of sacubitril/valsartan increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Caution should be exercised when co-administering sacubitril/valsartan with statins. No clinically relevant interaction was observed when simvastatin and Entresto were co-administered.

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

Potassium
Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, salt substitutes containing potassium or other agents (such as heparin) may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if sacubitril/valsartan is co-administered with these agents (see section 4.4).

Non-steroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of sacubitril/valsartan and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying treatment in patients on sacubitril/valsartan who are taking NSAIDs concomitantly (see section 4.4).

Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists including sacubitril/valsartan. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased further.

Furosemide
Co-administration of sacubitril/valsartan and furosemide had no effect on the pharmacokinetics of sacubitril/valsartan but reduced Cmax and AUC of furosemide by 50% and 28%, respectively. While there was no relevant change in urine volume, the urinary excretion of sodium was reduced within

4 hours and 24 hours after co-administration. The average daily dose of furosemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with sacubitril/valsartan.

Nitrates, e.g. nitroglycerine
There was no interaction between sacubitril/valsartan and intravenously administered nitroglycerin with regard to blood pressure reduction. Co-administration of nitroglycerin and sacubitril/valsartan was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone. A similar effect on the heart rate may occur when sacubitril/valsartan is co- administered with sublingual, oral or transdermal nitrates. In general no dose adjustment is required.

OATP and MRP2 transporters
The active metabolite of sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of sacubitril/valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be exercised when initiating or ending concomitant treatment with such medicinal products.

Metformin
Co-administration of sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be evaluated.

No significant interaction

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

Pregnancy

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

Valsartan
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with ARBs, similar risks may exist for this class of medicinal product. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ARBs should be stopped immediately and, if appropriate, alternative therapy should be started. Exposure to ARBs therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

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

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

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

Breast-feeding

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

Fertility

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

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

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

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

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

Sacubitril/valsartan exhibits the mechanism of action of an angiotensin receptor neprilysin inhibitor by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite

of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits of sacubitril/valsartan in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by LBQ657 and the simultaneous inhibition of the effects of angiotensin II by valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), which could result in vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects.

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

Adult population

Absorption
Following oral administration, sacubitril/valsartan dissociates into valsartan and the prodrug sacubitril.
Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be more than 60% and 23%, respectively.

Following twice daily dosing of sacubitril/valsartan, steady-state levels of sacubitril, LBQ657 and valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril/valsartan can be administered with or without food.

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%).

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

Paediatric population

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

Adult population

Absorption
Following oral administration, sacubitril/valsartan dissociates into valsartan and the prodrug sacubitril.
Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be more than 60% and 23%, respectively.

Following twice daily dosing of sacubitril/valsartan, steady-state levels of sacubitril, LBQ657 and valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril/valsartan can be administered with or without food.

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

Adult heart failure

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

Paediatric heart failure

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

Paediatric heart failure

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

Posology

General considerations
Neparvis should not be co-administered with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (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.

Adult heart failure
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 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.

Paediatric heart failure
Table 1 shows the recommended dose for paediatric patients. The recommended dose should be taken orally twice daily. The dose should be increased every 2-4 weeks to the target dose, as tolerated by the patient.

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

Table 1
Recommended dose titration

Patient weight
To be given twice daily

Half the starting dose*
Starting dose
Intermediate dose
Target dose
Paediatric patients less than 40 kg
0.8 mg/kg#
1.6 mg/kg#
2.3 mg/kg#
3.1 mg/kg#
Paediatric patients at least
40 kg, less than 50 kg
0.8 mg/kg#
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
Paediatric patients at least
50 kg
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
97 mg/103 mg
* 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 moderate hepatic 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 and valsartan and are to be given using granules.

In patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, half of the starting dose is recommended. For paediatric patients weighing 40 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 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 inhibitor should 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 corresponds to 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 <5th percentile for the age of the patient. If patients experience tolerability issues (SBP <5th percentile for the age of the patient, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down–titration or discontinuation of Neparvis is recommended (see section 4.4).

Special populations
Elderly
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 (eGFR 60-90 ml/min/1.73 m2) renal impairment.

Half of the starting dose 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 half of the starting dose is recommended. In paediatric patients weighing 40 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.

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 aspartate transaminase (AST)/alanine transaminase (ALT) values more than twice the upper limit of the normal range. Neparvis should be used with caution in these patients and half of the starting dose is recommended (see sections 4.4 and 5.2). In paediatric patients weighing 40 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.

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 aged below 1 year have not been established.
Currently available data are described in section 5.1 but no recommendation on a posology can be made.

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. Splitting or crushing of the tablets is not recommended.

Posology

General considerations
Neparvis should not be co-administered with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (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.

Paediatric heart failure
Table 1 shows the recommended dose for paediatric patients. The recommended dose should be taken orally twice daily. The dose should be increased every 2-4 weeks to the target dose, as tolerated by the patient.

The lowest recommended dose is 6 mg/6 mg. Doses can be rounded up or down to the closest combination of full 6 mg/6 mg and/or 15 mg/16 mg capsules. When rounding the dose up or down during the up-titration phase, consideration should be given to ensuring progressive increase to the target dose.

For patients weighing more than 40 kg, Neparvis film-coated tablets can be used.

Table 1
Recommended dose titration

Patient weight
To be given twice daily
Half the starting dose*
Starting dose
Intermediate dose
Target dose
Paediatric patients less than
40 kg
0.8 mg/kg#
1.6 mg/kg#
2.3 mg/kg#
3.1 mg/kg#
Paediatric patients at least 40 kg, less than 50 kg
0.8 mg/kg#
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
Paediatric patients at least 50 kg
24 mg/26 mg
49 mg/51 mg
72 mg/78 mg
97 mg/103 mg
* 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 moderate hepatic 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 and valsartan and are to be given using granules.

In patients not currently taking an ACE inhibitor or an ARB or taking low doses of these medicinal products, half of the starting dose is recommended. For paediatric patients weighing 40 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 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 inhibitor should 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 corresponds to 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 systolic blood pressure (SBP) <5th percentile for the age of the patient. If patients experience tolerability issues (SBP <5th percentile for the age of the patient, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down–titration or discontinuation of Neparvis is recommended (see section 4.4).

Special populations
Renal impairment
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 (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 half of the starting dose is recommended. In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily is recommended. After initiation, the dose should 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 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 aspartate transaminase (AST)/alanine transaminase (ALT) values more than twice the upper limit of the normal range. Neparvis should be used with caution in these patients and half of the starting dose is recommended (see sections 4.4 and 5.2). In paediatric patients weighing 40 kg to less than 50 kg, a starting dose of 0.8 mg/kg twice daily is recommended. After initiation, the dose should be increased following the recommended dose titration every 2-4 weeks.

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 aged below 1 year have not been established.
Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Method of administration

Oral use.

Neparvis granules are administered by opening the capsule and sprinkling the contents onto a small amount of soft food (1 to 2 teaspoons). Food containing the granules must be consumed immediately.
Patients may receive either the 6 mg/6 mg (white cap) or 15 mg/16 mg (yellow cap) capsules or both to reach the required doses (see section 6.6). The capsule must not be swallowed. The empty shells must be discarded after use and not swallowed.

• 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 trimesters of pregnancy (see section 4.6).

Summary of the safety profile

The most commonly reported adverse reactions in adults during treatment with sacubitril/valsartan were hypotension (17.6%), hyperkalaemia (11.6%) and renal impairment (10.1%) (see section 4.4).
Angioedema was reported in patients treated with sacubitril/valsartan (0.5%) (see description of selected adverse reactions).

Tabulated list of adverse reactions

Adverse reactions are ranked by System organ class and then by frequency with the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 2
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
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 mediastinal disorders
Cough
Common
Gastrointestinal disorders
Diarrhoea
Common
Nausea
Common
Gastritis
Common
Intestinal angioedema
Very rare
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.
**Including auditory and visual hallucinations

Description of selected adverse reactions

Angioedema
Angioedema has been reported in patients treated with sacubitril/valsartan. In PARADIGM-HF, angioedema was reported in 0.5% of patients treated with sacubitril/valsartan, compared with 0.2% of patients treated with enalapril. A higher incidence of angioedema was observed in Black patients treated with sacubitril/valsartan (2.4%) and enalapril (0.5%) (see section 4.4).

Hyperkalaemia and serum potassium
In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/l were reported in 11.6% and 19.7% of sacubitril/valsartan-treated patients and 14.0% and 21.1% of enalapril-treated patients, respectively.

Blood pressure
In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (<90 mmHg and decrease from baseline of >20 mmHg) were reported in 17.6% and 4.76% of sacubitril/valsartan- treated patients compared with 11.9% and 2.67% of enalapril-treated patients, respectively.

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

Paediatric population

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-label extension 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 in patients aged 1 month to <1 year was limited.

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

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.

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

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

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

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

Hypotension

Treatment should not be initiated unless SBP is ≥100 mmHg for adult patients or ≥5th percentile SBP for the age of the paediatric patient. Patients with SBP below these values were not studied (see section 5.1). Cases of symptomatic hypotension have been reported in adult patients treated with sacubitril/valsartan during clinical studies (see section 4.8), especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg). When initiating therapy or during dose titration with sacubitril/valsartan, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of sacubitril/valsartan is recommended (see section 4.2). Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g. by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with sacubitril/valsartan, however, such corrective action must be carefully weighed against the risk of volume overload.

Renal impairment

Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild and moderate renal impairment are more at risk of developing hypotension (see section 4.2).
There is very limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m2) and these patients may be at greatest risk of hypotension (see section 4.2). There is no experience in patients with end-stage renal disease and use of sacubitril/valsartan is not recommended.

Worsening renal function

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

Hyperkalaemia

Treatment should not be initiated if the serum potassium level is >5.4 mmol/l in adult patients and >5.3 mmol/l in paediatric patients. Use of sacubitril/valsartan may be associated with an increased risk of hyperkalaemia, although hypokalaemia may also occur (see section 4.8). Monitoring of serum potassium is recommended, especially in patients who have risk factors such as renal impairment, diabetes mellitus or hypoaldosteronism or who are on a high potassium diet or on mineralocorticoid antagonists (see section 4.2). If patients experience clinically significant hyperkalaemia adjustment of concomitant medicinal products, or temporary down–titration or discontinuation is recommended. If serum potassium level is >5.4 mmol/l discontinuation should be considered.

Angioedema

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

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

Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if sacubitril/valsartan is used in these patients.
Sacubitril/valsartan is contraindicated in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy or with hereditary or idiopathic angioedema (see section 4.3).

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

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, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, sacubitril/valsartan should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Patients with renal artery stenosis

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

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

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

B-type natriuretic peptide (BNP)

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

Patients with hepatic impairment

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

Psychiatric disorders

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

Sodium

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

Interactions resulting in a contraindication

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

therapy must not be started until 36 hours after the last dose of sacubitril/valsartan (see sections 4.2 and 4.3).

Aliskiren
The concomitant use of sacubitril/valsartan with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see section 4.3). The combination of sacubitril/valsartan with direct renin inhibitors such as aliskiren is not recommended (see section 4.4). Combination of sacubitril/valsartan with aliskiren is potentially associated with a higher frequency of adverse reactions such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) (see sections 4.3 and 4.4).

Interactions resulting in concomitant use not being recommended

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

Interactions requiring precautions

OATP1B1 and OATP1B3 substrates, e.g. statins
In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Neparvis may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins.
Co-administration of sacubitril/valsartan increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Caution should be exercised when co-administering sacubitril/valsartan with statins. No clinically relevant interaction was observed when simvastatin and Neparvis were co-administered.

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

Potassium
Concomitant use of potassium-sparing diuretics (triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, salt substitutes containing potassium or other agents (such as heparin) may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if sacubitril/valsartan is co-administered with these agents (see section 4.4).

Non-steroidal anti-inflammatory agents (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of sacubitril/valsartan and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying treatment in patients on sacubitril/valsartan who are taking NSAIDs concomitantly (see section 4.4).

Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists including sacubitril/valsartan. Therefore, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased further.

Furosemide
Co-administration of sacubitril/valsartan and furosemide had no effect on the pharmacokinetics of sacubitril/valsartan but reduced Cmax and AUC of furosemide by 50% and 28%, respectively. While there was no relevant change in urine volume, the urinary excretion of sodium was reduced within 4 hours and 24 hours after co-administration. The average daily dose of furosemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with sacubitril/valsartan.

Nitrates, e.g. nitroglycerine
There was no interaction between sacubitril/valsartan and intravenously administered nitroglycerin with regard to blood pressure reduction. Co-administration of nitroglycerin and sacubitril/valsartan was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone. A similar effect on the heart rate may occur when sacubitril/valsartan is co- administered with sublingual, oral or transdermal nitrates. In general no dose adjustment is required.

OATP and MRP2 transporters
The active metabolite of sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of sacubitril/valsartan with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be exercised when initiating or ending concomitant treatment with such medicinal products.

Metformin
Co-administration of sacubitril/valsartan with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with sacubitril/valsartan in patients receiving metformin, the clinical status of the patient should be evaluated.

No significant interaction

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

Pregnancy

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

Valsartan
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with ARBs, similar risks may exist for this class of medicinal product. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ARBs should be stopped immediately and, if appropriate, alternative therapy should be started. Exposure to ARBs therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

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

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

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

Breast-feeding

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

Fertility

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

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

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

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

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

Sacubitril/valsartan exhibits the mechanism of action of an angiotensin receptor neprilysin inhibitor by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits of sacubitril/valsartan in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by LBQ657 and the simultaneous inhibition of the effects of angiotensin II by valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), which could result in vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects.

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

Adult population

Absorption
Following oral administration, sacubitril/valsartan dissociates into valsartan and the prodrug sacubitril.
Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be more than 60% and 23%, respectively.

Following twice daily dosing of sacubitril/valsartan, steady-state levels of sacubitril, LBQ657 and valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril/valsartan can be administered with or without food.

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%).

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

Paediatric population

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

Adult population

Absorption
Following oral administration, sacubitril/valsartan dissociates into valsartan and the prodrug sacubitril.
Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be more than 60% and 23%, respectively.

Following twice daily dosing of sacubitril/valsartan, steady-state levels of sacubitril, LBQ657 and valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril/valsartan can be administered with or without food.

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