Neparvis · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-098155 · has-adverse-reaction-information · PDF-Seite 30

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 Anaemia Common disorders Immune system disorders Hypersensitivity Uncommon Metabolism and nutrition Hyperkalaemia* Very common disorders Hypokalaemia Common Hypoglycaemia Common Hyponatraemia Uncommon Psychiatric disorders Hallucinations** Rare Sleep disorders Rare Paranoia Very rare Nervous system disorders Dizziness Common Headache Common Syncope Common Dizziness postural Uncommon Myoclonus Not known Ear and labyrinth disorders Vertigo Common Vascular disorders Hypotension* Very common Orthostatic hypotension Common Respiratory, thoracic and Cough Common

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HOS-098149 · has-adverse-reaction-information · PDF-Seite 10

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. 10 Table 2 List of adverse reactions System organ class Preferred term Frequency category Blood and lymphatic system Anaemia Common disorders Immune system disorders Hypersensitivity Uncommon Metabolism and nutrition Hyperkalaemia* Very common disorders 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

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HOS-098145 · has-contraindication-information · PDF-Seite 5

• 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).

HOS-098151 · has-contraindication-information · PDF-Seite 24

• 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). 24

HOS-098144 · has-indication-information · PDF-Seite 2

Adult heart failure Neparvis is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction (see section 5.1). 2 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).

HOS-098150 · has-indication-information · PDF-Seite 22

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).

HOS-098153 · has-interaction-information · PDF-Seite 27

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

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HOS-098147 · has-interaction-information · PDF-Seite 7

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 7 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. spironolacton

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HOS-098154 · has-pregnancy-information · PDF-Seite 29

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 demo

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HOS-098148 · has-pregnancy-information · PDF-Seite 9

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). 9 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

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HOS-098146 · has-warning-information · PDF-Seite 5

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). 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 a

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HOS-098152 · has-warning-information · PDF-Seite 25

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 developi

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