sacubitril/valsartan: package leaflet

Entresto is a heart medicine containing an angiotensin receptor neprilysin inhibitor. It delivers two active substances, sacubitril and valsartan.

Entresto is used to treat a type of long-term heart failure in adults, children and adolescents (one year and older).

This type of heart failure occurs when the heart is weak and cannot pump enough blood to the lungs and the rest of the body. The most common symptoms of heart failure are breathlessness, fatigue, tiredness and ankle swelling.

Do not take Entresto
- if you are allergic to sacubitril, valsartan or any of the other ingredients of this medicine (listed in section 6).
- if you are taking another type of medicine called an angiotensin converting enzyme (ACE) inhibitor (for example enalapril, lisinopril or ramipril), which is used to treat high blood pressure or heart failure. If you have been taking an ACE inhibitor, wait for 36 hours after taking the last dose before you start to take Entresto (see “Other medicines and Entresto”).
- if you have ever had a reaction called angioedema (rapid swelling under the skin in areas such as the face, throat, arms and legs which can be life threatening if throat swelling blocks the airway) when taking an ACE inhibitor or an angiotensin receptor blocker (ARB) (such as valsartan, telmisartan or irbesartan).
- if you have a history of angioedema which is hereditary or for which the cause is unknown (idiopathic).
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren (see “Other medicines and Entresto”).

- if you have severe liver disease.
- if you are more than 3 months pregnant (see “Pregnancy and breast-feeding”).
If any of the above applies to you, do not take Entresto and talk to your doctor.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before or when taking Entresto:
- if you are being treated with an angiotensin receptor blocker (ARB) or aliskiren (see “Do not take Entresto”).
- if you have ever had angioedema (see “Do not take Entresto” and section 4 “Possible side effects”).
- if you experience abdominal pain, nausea, vomiting or diarrhoea after taking Entresto. Your doctor will decide on further treatment. Do not stop taking Entresto on your own.
- if you have low blood pressure or are taking any other medicines that reduce your blood pressure (for example, a medicine that increases urine production (diuretic)) or are suffering from vomiting or diarrhoea, especially if you are aged 65 years or more, or if you have kidney disease and low blood pressure.
- if you have kidney disease.
- if you are suffering from dehydration.
- if your kidney artery has narrowed.
- if you have liver disease.
- if you experience hallucinations, paranoia or changes in sleeping pattern while taking Entresto.
- if you have hyperkalaemia (high levels of potassium in the blood).
- if you suffer from heart failure classified as NYHA class IV (unable to carry on any physical activity without discomfort and may have symptoms even when resting).

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

Your doctor may check the amount of potassium and sodium in your blood at regular intervals during Entresto treatment. In addition, your doctor may check your blood pressure at start of treatment and when the doses are increased.

Children and adolescents
Do not give this medicine to children aged below 1 year because it has not been studied in this age group. For children one year and older with a body weight below 40 kg, this medicine will be given as granules (instead of tablets).

Other medicines and Entresto
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. It may be necessary to change the dose, to take other precautions, or even to stop taking one of the medicines. This is particularly important for the following medicines:
- ACE inhibitors. Do not take Entresto with ACE inhibitors. If you have been taking an ACE inhibitor, wait 36 hours after taking the last dose of the ACE inhibitor before starting to take Entresto (see “Do not take Entresto”). If you stop taking Entresto, wait 36 hours after taking your last dose of Entresto before starting an ACE inhibitor.
- other medicines used to treat heart failure or lower blood pressure, such as angiotensin receptor blockers or aliskiren (see “Do not take Entresto”).
- some medicines known as statins that are used to lower high cholesterol levels (for example atorvastatin).
- sildenafil, tadalafil, vardenafil or avanafil, which are medicines used to treat erectile dysfunction or lung hypertension.
- medicines that increase the amount of potassium in the blood. These include potassium supplements, salt substitutes containing potassium, potassium-sparing medicines and heparin.

- painkillers of the type called non-steroidal anti-inflammatory medicines (NSAIDs) or selective cyclooxygenase-2 (Cox-2) inhibitors. If you are taking one of these, your doctor may want to check your kidney function when starting or adjusting treatment (see “Warnings and precautions”).
- lithium, a medicine used to treat some types of psychiatric illness.
- furosemide, a medicine belonging to the type known as diuretics, which are used to increase the amount of urine you produce.
- nitroglycerine, a medicine used to treat angina pectoris.
- some types of antibiotics (rifamycin group), ciclosporin (used to prevent rejection of transplanted organs) or antivirals such as ritonavir (used to treat HIV/AIDS).
- metformin, a medicine used to treat diabetes.
If any of the above applies to you, tell your doctor or pharmacist before you take Entresto.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy
You must tell your doctor if you think that you are (or might become) pregnant. Your doctor will normally advise you to stop taking this medicine before you become pregnant or as soon as you know you are pregnant, and will advise you to take another medicine instead of Entresto.

This medicine is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if it is used after the third month of pregnancy.

Breast-feeding
Entresto is not recommended for mothers who are breast-feeding. Tell your doctor if you are breast-feeding or about to start breast-feeding.

Driving and using machines
Before you drive a vehicle, use tools or operate machines, or carry out other activities that require concentration, make sure you know how Entresto affects you. If you feel dizzy or very tired while taking this medicine, do not drive a vehicle, cycle or use any tools or machines.

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

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Adults
You will usually start by taking a 24 mg/26 mg or 49 mg/51 mg tablet twice a day (one tablet in the morning and one tablet in the evening). Your doctor will decide your exact starting dose based on which medicines you have been taking previously and your blood pressure. Your doctor will then adjust the dose every 2-4 weeks depending on how you respond to the treatment until the best dose for you is found.

The usual recommended target dose is 97 mg/103 mg twice a day (one tablet in the morning and one tablet in the evening).

Children and adolescents (one year and older)
Your (or your child’s) doctor will decide the starting dose based on body weight and other factors including previously taken medicines. The doctor will adjust the dose every 2-4 weeks until the best dose is found.

Entresto should be given twice a day (one tablet in the morning and one tablet in the evening).

Entresto film-coated tablets are not meant to be used in children who weigh less than 40 kg. For these patients, Entresto granules are available.

Patients taking Entresto can develop low blood pressure (dizziness, light-headedness), a high level of potassium in the blood (which would be detected when your doctor performed a blood test) or decreased kidney function. If this happens, your doctor may reduce the dose of any other medicine you are taking, temporarily reduce the Entresto dose, or stop Entresto treatment completely.

Swallow the tablets with a glass of water. You can take Entresto with or without food. Splitting or crushing of the tablets is not recommended.

If you take more Entresto than you should
If you have accidentally taken too many Entresto tablets, or if someone else has taken your tablets, contact your doctor immediately. If you experience severe dizziness and/or fainting, tell your doctor as quickly as possible and lie down.

If you forget to take Entresto
It is advisable to take your medicine at the same time each day. However, if you forget to take a dose, you should simply take the next one at the scheduled time. Do not take a double dose to make up for a forgotten dose.

If you stop taking Entresto
Stopping your treatment with Entresto may cause your condition to get worse. Do not stop taking your medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects may be serious.
- Stop taking Entresto and seek immediate medical attention if you notice any swelling of the face, lips, tongue and/or throat, which may cause difficulties in breathing or swallowing. These may be signs of angioedema (an uncommon side effect which may affect up to 1 in 100 people).

Other possible side effects:
If any of the side effects listed below becomes severe, tell your doctor or pharmacist.

Very common (may affect more than 1 in 10 people)
- low blood pressure, which can cause symptoms of dizziness and light-headedness (hypotension)
- high level of potassium in the blood, shown in a blood test (hyperkalaemia)
- decreased kidney function (renal impairment)

Common (may affect up to 1 in 10 people)
- cough
- dizziness
- diarrhoea
- low level of red blood cells, shown in a blood test (anaemia)
- tiredness (fatigue)
- (acute) inability of the kidney to work properly (renal failure)
- low level of potassium in the blood, shown in a blood test (hypokalaemia)
- headache
- fainting (syncope)
- weakness (asthenia)
- feeling sick (nausea)
- low blood pressure (dizziness, light-headedness) when switching from sitting or lying to standing position
- gastritis (stomach pain, nausea)
- spinning sensation (vertigo)
- low level of sugar in the blood, shown in a blood test (hypoglycaemia)

Uncommon (may affect up to 1 in 100 people)
- allergic reaction with rash and itching (hypersensitivity)
- dizziness when switching from sitting to standing position (dizziness postural)
- low level of sodium in the blood, shown in a blood test (hyponatraemia)

Rare (may affect up to 1 in 1 000 people)
- seeing, hearing or feeling things that are not there (hallucinations)
- changes in sleeping pattern (sleep disorder)

Very rare (may affect up to 1 in 10 000 people)
- paranoia
- intestinal angioedema: a swelling in the gut presenting with symptoms like abdominal pain, nausea, vomiting and diarrhoea

Not known (frequency cannot be estimated from the available data)
- sudden involuntary muscle twitching (myoclonus)

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Entresto contains
- The active substances are sacubitril and valsartan.
o
Each 24 mg/26 mg film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartan sodium salt complex).
o
Each 49 mg/51 mg film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartan sodium salt complex).
o
Each 97 mg/103 mg film-coated tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartan sodium salt complex).
- The other ingredients in the tablet core are microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, talc and silica colloidal anhydrous (see end of section 2 under ‘Entresto contains sodium’).
- The 24 mg/26 mg and the 97 mg/103 mg tablet coatings contain hypromellose, titanium dioxide (E171), Macrogol (4000), talc, iron oxide red (E172) and iron oxide black (E172).
- The 49 mg/51 mg tablet coating contains hypromellose, titanium dioxide (E171), Macrogol (4000), talc, iron oxide red (E172) and iron oxide yellow (E172).

What Entresto looks like and contents of the pack
Entresto 24 mg/26 mg film-coated tablets are violet-white oval tablets with “NVR” on one side and “LZ” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm.
Entresto 49 mg/51 mg film-coated tablets are pale yellow oval tablets with “NVR” on one side and “L1” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm Entresto 97 mg/103 mg film-coated tablets are light pink oval tablets with “NVR” on one side and “L11” on the other side. Approximate tablet dimensions 15.1 mm x 6.0 mm.

The tablets are supplied in packs containing 14, 20, 28, 56, 168 or 196 tablets and in multipacks comprising 7 cartons, each containing 28 tablets. The 49 mg/51 mg and 97 mg/103 mg tablets are also supplied in multipacks comprising 3 cartons, each containing 56 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland

Manufacturer
Novartis Pharmaceutical Manufacturing LLC
Verovskova Ulica 57
1000 Ljubljana
Slovenia

Novartis Farma S.p.A
Via Provinciale Schito 131
80058 Torre Annunziata (NA)
Italy

LEK farmacevtska družba d. d., Poslovna enota PROIZVODNJA LENDAVA
Trimlini 2D
Lendava, 9220
Slovenia

Novartis Pharma GmbH
Sophie-Germain-Straße 10
90443 Nürnberg
Deutschland

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Lietuva
SIA Novartis Baltics Lietuvos filialas
Tel: +370 5 269 16 50

България
Novartis Bulgaria EOOD
Тел: +359 2 489 98 28

Luxembourg/Luxemburg
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Česká republika
Novartis s.r.o.
Tel: +420 225 775 111

Magyarország
Novartis Hungária Kft.
Tel.: +36 1 457 65 00
Danmark
Novartis Healthcare A/S
Tlf.: +45 39 16 84 00

Malta
Novartis Pharma Services Inc.
Tel: +356 2122 2872
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0

Nederland
Novartis Pharma B.V.
Tel: +31 88 04 52 111
Eesti
SIA Novartis Baltics Eesti filiaal
Tel: +372 66 30 810

Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12

Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00

Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 375 4888
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00

Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
Hrvatska
Novartis Hrvatska d.o.o.
Tel. +385 1 6274 220

România
Novartis Pharma Services Romania SRL
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55

Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439

Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200

Κύπρος
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690

Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00

Latvija
SIA Novartis Baltics
Tel: +371 67 887 070

This leaflet was last revised in

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu

Entresto is a heart medicine containing an angiotensin receptor neprilysin inhibitor. It delivers two active substances, sacubitril and valsartan.

Entresto is used to treat a type of long-term heart failure in children and adolescents (one year and older).

This type of heart failure occurs when the heart is weak and cannot pump enough blood to the lungs and the rest of the body. The most common symptoms of heart failure are breathlessness, fatigue, tiredness and ankle swelling.

Do not take Entresto
- if you (or your child) are allergic to sacubitril, valsartan or any of the other ingredients of this medicine (listed in section 6).
- if you (or your child) are taking another type of medicine called an angiotensin converting enzyme (ACE) inhibitor (for example enalapril, lisinopril or ramipril), which is used to treat high blood pressure or heart failure. If you have been taking an ACE inhibitor, wait for 36 hours after taking the last dose before you start to take Entresto (see “Other medicines and Entresto”).
- if you (or your child) have ever had a reaction called angioedema (rapid swelling under the skin in areas such as the face, throat, arms and legs which can be life threatening if throat swelling blocks the airway) when taking an ACE inhibitor or an angiotensin receptor blocker (ARB) (such as valsartan, telmisartan or irbesartan).
- if you (or your child) have a history of angioedema which is hereditary or for which the cause is unknown (idiopathic).
- if you (or your child) have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren (see “Other medicines and Entresto”).

- if you (or your child) have severe liver disease.
- if you (or your child) are more than 3 months pregnant (see “Pregnancy and breast-feeding”).
If any of the above applies to you, do not take Entresto and talk to your doctor.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before or when taking Entresto:
- if you (or your child) are being treated with an angiotensin receptor blocker (ARB) or aliskiren (see “Do not take Entresto”).
- if you (or your child) have ever had angioedema (see “Do not take Entresto” and section 4 “Possible side effects”).
- if you experience abdominal pain, nausea, vomiting or diarrhoea after taking Entresto. Your doctor will decide on further treatment. Do not stop taking Entresto on your own.
- if you (or your child) have low blood pressure or are taking any other medicines that reduce your blood pressure (for example, a medicine that increases urine production (diuretic)) or are suffering from vomiting or diarrhoea, especially if you are aged 65 years or more, or if you have kidney disease and low blood pressure.
- if you (or your child) have kidney disease.
- if you (or your child) are suffering from dehydration.
- if your (or your child’s) kidney artery has narrowed.
- if you (or your child) have liver disease.
- if you (or your child) experience hallucinations, paranoia or changes in sleeping pattern while taking Entresto.
- if you (or your child) have hyperkalaemia (high levels of potassium in the blood).
- if you (or your child) suffer from heart failure classified as NYHA class IV (unable to carry on any physical activity without discomfort and may have symptoms even when resting).

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

Your doctor may check the amount of potassium and sodium in your blood at regular intervals during Entresto treatment. In addition, your doctor may check your blood pressure at start of treatment and when the doses are increased.

Children (below one year of age)
Use in children below one year of age is not recommended. There is limited experience on use in children in this age group. Entresto film-coated tablets are available for children who weigh more than 40 kg.

Other medicines and Entresto
Tell your doctor, pharmacist or nurse if you (or your child) are taking, have recently taken or might take any other medicines. It may be necessary to change the dose, to take other precautions, or even to stop taking one of the medicines. This is particularly important for the following medicines:
- ACE inhibitors. Do not take Entresto with ACE inhibitors. If you have been taking an ACE inhibitor, wait 36 hours after taking the last dose of the ACE inhibitor before starting to take Entresto (see “Do not take Entresto”). If you stop taking Entresto, wait 36 hours after taking your last dose of Entresto before starting an ACE inhibitor.
- other medicines used to treat heart failure or lower blood pressure, such as angiotensin receptor blockers or aliskiren (see “Do not take Entresto”).
- some medicines known as statins that are used to lower high cholesterol levels (for example atorvastatin).
- sildenafil, tadalafil, vardenafil or avanafil, which are medicines used to treat erectile dysfunction or lung hypertension.
- medicines that increase the amount of potassium in the blood. These include potassium supplements, salt substitutes containing potassium, potassium-sparing medicines and heparin.

- painkillers of the type called non-steroidal anti-inflammatory medicines (NSAIDs) or selective cyclooxygenase-2 (Cox-2) inhibitors. If you are taking one of these, your doctor may want to check your kidney function when starting or adjusting treatment (see “Warnings and precautions”).
- lithium, a medicine used to treat some types of psychiatric illness.
- furosemide, a medicine belonging to the type known as diuretics, which are used to increase the amount of urine you produce.
- nitroglycerine, a medicine used to treat angina pectoris.
- some types of antibiotics (rifamycin group), ciclosporin (used to prevent rejection of transplanted organs) or antivirals such as ritonavir (used to treat HIV/AIDS).
- metformin, a medicine used to treat diabetes.
If any of the above applies to you, tell your doctor or pharmacist before you take Entresto.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy
You must tell your doctor if you think that you (or your child) are (or might become) pregnant. Your doctor will normally advise you to stop taking this medicine before you become pregnant or as soon as you know you are pregnant, and will advise you to take another medicine instead of Entresto.

This medicine is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if it is used after the third month of pregnancy.

Breast-feeding
Entresto is not recommended for mothers who are breast-feeding. Tell your doctor if you are breast-feeding or about to start breast-feeding.

Driving and using machines
Before you drive a vehicle, use tools or operate machines, or carry out other activities that require concentration, make sure you know how Entresto affects you. If you feel dizzy or very tired while taking this medicine, do not drive a vehicle, cycle or use any tools or machines.

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

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Your (or your child’s) doctor will decide the starting dose based on body weight and other factors including previously taken medicines. The doctor will adjust the dose every 2-4 weeks until the best dose is found.

Entresto should be given twice a day (once in the morning and once in the evening).

See the instructions for use for how to prepare and take Entresto granules.

Patients taking Entresto can develop low blood pressure (dizziness, light-headedness), a high level of potassium in the blood (which would be detected when your doctor performed a blood test) or decreased kidney function. If this happens, your doctor may reduce the dose of any other medicine you (or your child) are taking, temporarily reduce the Entresto dose, or stop Entresto treatment completely.

If you take more Entresto than you should
If you (or your child) have accidentally taken too many Entresto granules, or if someone else has taken your granules, contact your doctor immediately. If you (or your child) experience severe dizziness and/or fainting, tell your doctor as quickly as possible and lie down.

If you (or your child) forget to take Entresto
It is advisable to take your medicine at the same time each day. However, if you (or your child) forget to take a dose, you should simply take the next one at the scheduled time. Do not take a double dose to make up for a forgotten dose.

If you (or your child) stop taking Entresto
Stopping your treatment with Entresto may cause your condition to get worse. Do not stop taking your medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects may be serious.
- Stop taking Entresto and seek immediate medical attention if you (or your child) notice any swelling of the face, lips, tongue and/or throat, which may cause difficulties in breathing or swallowing. These may be signs of angioedema (an uncommon side effect which may affect up to 1 in 100 people).

Other possible side effects:
If any of the side effects listed below becomes severe, tell your doctor or pharmacist.

Very common (may affect more than 1 in 10 people)
- low blood pressure, which can cause symptoms of dizziness and light-headedness (hypotension)
- high level of potassium in the blood, shown in a blood test (hyperkalaemia)
- decreased kidney function (renal impairment)

Common (may affect up to 1 in 10 people)
- cough
- dizziness
- diarrhoea
- low level of red blood cells, shown in a blood test (anaemia)
- tiredness (fatigue)
- (acute) inability of the kidney to work properly (renal failure)
- low level of potassium in the blood, shown in a blood test (hypokalaemia)
- headache
- fainting (syncope)
- weakness (asthenia)
- feeling sick (nausea)
- low blood pressure (dizziness, light-headedness) when switching from sitting or lying to standing position
- gastritis (stomach pain, nausea)
- spinning sensation (vertigo)
- low level of sugar in the blood, shown in a blood test (hypoglycaemia)

Uncommon (may affect up to 1 in 100 people)
- allergic reaction with rash and itching (hypersensitivity)
- dizziness when switching from sitting to standing position (dizziness postural)
- low level of sodium in the blood, shown in a blood test (hyponatraemia)

Rare (may affect up to 1 in 1 000 people)
- seeing, hearing or feeling things that are not there (hallucinations)
- changes in sleeping pattern (sleep disorder)

Very rare (may affect up to 1 in 10 000 people)
- paranoia
- intestinal angioedema: a swelling in the gut presenting with symptoms like abdominal pain, nausea, vomiting and diarrhoea

Not known (frequency cannot be estimated from the available data)
- sudden involuntary muscle twitching (myoclonus)

Reporting of side effects
If you (or your child) get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Entresto contains
- The active substances are sacubitril and valsartan.
o
Each Entresto 6 mg/6 mg granules in capsule for opening (granules in capsule) contains four granules equivalent to 6.1 mg sacubitril and 6.4 mg valsartan (as sacubitril valsartan sodium salt complex).
o
Each Entresto 15 mg/16 mg granules in capsule for opening (granules in capsule) contains ten granules equivalent to 15.18 mg sacubitril and 16.07 mg valsartan (as sacubitril valsartan sodium salt complex).
- The other ingredients of the granules are microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate, silica colloidal anhydrous and talc.
- The ingredients of the film coat are basic butylated methacrylate copolymer, talc, stearic acid and sodium laurilsulfate (see end of section 2 under ‘Entresto contains sodium’).
- The ingredients of the capsule shell are hypromellose, titanium dioxide (E171), iron oxide (yellow) (E172) (Entresto 15 mg/16 mg only) and printing ink.
o
The ingredients of the printing ink are shellac, propylene glycol, iron oxide (red) (E172), ammonia solution (concentrated) and potassium hydroxide.

What Entresto looks like and contents of the pack
Entresto 6 mg/6 mg granules are white to slightly yellow in colour, round in shape, approximately 2 mm in diameter and provided in a capsule. The capsule consists of a white cap, marked “04” in red and a transparent body, marked “NVR” in red. An arrow is printed on both the body and the cap.
Entresto 15 mg/16 mg granules are white to slightly yellow in colour, round in shape, approximately 2 mm in diameter and provided in a capsule. The capsule consists of a yellow cap, marked “10” in red and a transparent body, marked “NVR” in red. An arrow is printed on both the body and the cap.

Entresto 6 mg/6 mg granules in capsules for opening and Entresto 15 mg/16 mg granules in capsules for opening are supplied in packs containing 60 capsules.

Marketing Authorisation Holder
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland

Manufacturer
Lek farmacevtska družba d.d.
Verovskova Ulica 57
1526 Ljubljana
Slovenia

Novartis Pharmaceutical Manufacturing LLC
Verovskova Ulica 57
1000 Ljubljana
Slovenia

Novartis Farmaceutica S.A.
Gran Via de les Corts Catalanes, 764
08013 Barcelona
Spain

Novartis Pharma GmbH
Sophie-Germain-Straße 10
90443 Nürnberg
Deutschland

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Lietuva
SIA Novartis Baltics Lietuvos filialas
Tel: +370 5 269 16 50

България
Novartis Bulgaria EOOD
Тел: +359 2 489 98 28

Luxembourg/Luxemburg
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Česká republika
Novartis s.r.o.
Tel: +420 225 775 111

Magyarország
Novartis Hungária Kft.
Tel.: +36 1 457 65 00

Danmark
Novartis Healthcare A/S
Tlf.: +45 39 16 84 00

Malta
Novartis Pharma Services Inc.
Tel: +356 2122 2872
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0

Nederland
Novartis Pharma B.V.
Tel: +31 88 04 52 111
Eesti
SIA Novartis Baltics Eesti filiaal
Tel: +372 66 30 810

Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12

Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
España
Novartis Farmacéutica, S.A.
Tel: +34 93 306 42 00

Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 375 4888
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00

Portugal
Novartis Farma - Produtos Farmacêuticos, S.A.
Tel: +351 21 000 8600
Hrvatska
Novartis Hrvatska d.o.o.
Tel. +385 1 6274 220

România
Novartis Pharma Services Romania SRL
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55

Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439

Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200

Κύπρος
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690

Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00

Latvija
SIA Novartis Baltics
Tel: +371 67 887 070

This leaflet was last revised in

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu

Instructions for use for Entresto 6 mg/6 mg granules in capsules for opening and Entresto 15 mg/16 mg granules in capsules for opening

To ensure that you use Entresto granules correctly for your child, it is important that you follow these instructions. Your doctor, pharmacist or nurse will show you how to do this. Ask one of them if you have any questions.

Entresto granules are contained within capsules and are available in two strengths: 6 mg/6 mg granules and 15 mg/16 mg granules. The capsules are packaged in blister cards. You may receive one or both strengths depending on the dose your child needs.

You can see the difference between the two strengths by the colour of the capsule cap and the imprint on it.
- The capsule containing the 6 mg/6 mg granules has a white cap with number 04 printed on it.
- The capsule containing the 15 mg/16 mg granules has a yellow cap with number 10 printed on it.

The capsules containing Entresto granules must be opened before use.

Do NOT swallow the whole capsule. Do NOT swallow the empty capsule shells.

If you use both strengths of Entresto granules, make sure you use the correct number of capsules of each strength as instructed by your doctor, pharmacist or nurse.

Step 1
- Wash and dry your hands

Step 2
- Place the following items on a clean flat surface:
o
A small bowl, cup or spoon with a small amount of soft food the child likes.
o
Blister card(s) with capsules containing Entresto granules.

• Check that you have the correct strength(s) of Entresto granules.

Step 3
- Push the blister(s) to remove the capsule(s).

Step 4
To open the capsule:
- Hold the capsule upright (with the coloured cap on top) so that the granules are in the bottom of the capsule.
- Hold the capsule over the soft food.
- Gently pinch the middle of the capsule and pull slightly to separate the two ends of the capsule. Take care not to spill the contents.

Step 5
- Empty all of the granules from the capsule onto the food.
- Make sure that you do not miss any granules.
Repeat steps 4 and 5 if you need more than one capsule to reach the prescribed dose.
Step 6
Feed the food with the granules to the child immediately, making sure your child eats all of it.

Make sure your child does not chew the granules to avoid change of taste.

Step 7
Throw away the empty shells of the capsule.

Neparvis is a heart medicine containing an angiotensin receptor neprilysin inhibitor. It delivers two active substances, sacubitril and valsartan.

Neparvis is used to treat a type of long-term heart failure in adults, children and adolescents (one year and older).

This type of heart failure occurs when the heart is weak and cannot pump enough blood to the lungs and the rest of the body. The most common symptoms of heart failure are breathlessness, fatigue, tiredness and ankle swelling.

Do not take Neparvis
- if you are allergic to sacubitril, valsartan or any of the other ingredients of this medicine (listed in section 6).
- if you are taking another type of medicine called an angiotensin converting enzyme (ACE) inhibitor (for example enalapril, lisinopril or ramipril), which is used to treat high blood pressure or heart failure. If you have been taking an ACE inhibitor, wait for 36 hours after taking the last dose before you start to take Neparvis (see “Other medicines and Neparvis”).
- if you have ever had a reaction called angioedema (rapid swelling under the skin in areas such as the face, throat, arms and legs which can be life threatening if throat swelling blocks the airway) when taking an ACE inhibitor or an angiotensin receptor blocker (ARB) (such as valsartan, telmisartan or irbesartan).
- if you have a history of angioedema which is hereditary or for which the cause is unknown (idiopathic).
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren (see “Other medicines and Neparvis”).

- if you have severe liver disease.
- if you are more than 3 months pregnant (see “Pregnancy and breast-feeding”).
If any of the above applies to you, do not take Neparvis and talk to your doctor.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before or when taking Neparvis:
- if you are being treated with an angiotensin receptor blocker (ARB) or aliskiren (see “Do not take Neparvis”).
- if you have ever had angioedema (see “Do not take Neparvis” and section 4 “Possible side effects”).
- if you experience abdominal pain, nausea, vomiting or diarrhoea after taking Neparvis. Your doctor will decide on further treatment. Do not stop taking Neparvis on your own.
- if you have low blood pressure or are taking any other medicines that reduce your blood pressure (for example, a medicine that increases urine production (diuretic)) or are suffering from vomiting or diarrhoea, especially if you are aged 65 years or more, or if you have kidney disease and low blood pressure.
- if you have kidney disease.
- if you are suffering from dehydration.
- if your kidney artery has narrowed.
- if you have liver disease.
- if you experience hallucinations, paranoia or changes in sleeping pattern while taking Neparvis.
- if you have hyperkalaemia (high levels of potassium in the blood).
- if you suffer from heart failure classified as NYHA class IV (unable to carry on any physical activity without discomfort and may have symptoms even when resting).

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

Your doctor may check the amount of potassium and sodium in your blood at regular intervals during Neparvis treatment. In addition, your doctor may check your blood pressure at start of treatment and when the doses are increased.

Children and adolescents
Do not give this medicine to children aged below 1 year because it has not been studied in this age group. For children one year and older with a body weight below 40 kg, this medicine will be given as granules (instead of tablets).

Other medicines and Neparvis
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. It may be necessary to change the dose, to take other precautions, or even to stop taking one of the medicines. This is particularly important for the following medicines:
- ACE inhibitors. Do not take Neparvis with ACE inhibitors. If you have been taking an ACE inhibitor, wait 36 hours after taking the last dose of the ACE inhibitor before starting to take Neparvis (see “Do not take Neparvis”). If you stop taking Neparvis, wait 36 hours after taking your last dose of Neparvis before starting an ACE inhibitor.
- other medicines used to treat heart failure or lower blood pressure, such as angiotensin receptor blockers or aliskiren (see “Do not take Neparvis”).
- some medicines known as statins that are used to lower high cholesterol levels (for example atorvastatin).
- sildenafil, tadalafil, vardenafil or avanafil, which are medicines used to treat erectile dysfunction or lung hypertension.
- medicines that increase the amount of potassium in the blood. These include potassium supplements, salt substitutes containing potassium, potassium-sparing medicines and heparin.

- painkillers of the type called non-steroidal anti-inflammatory medicines (NSAIDs) or selective cyclooxygenase-2 (Cox-2) inhibitors. If you are taking one of these, your doctor may want to check your kidney function when starting or adjusting treatment (see “Warnings and precautions”).
- lithium, a medicine used to treat some types of psychiatric illness.
- furosemide, a medicine belonging to the type known as diuretics, which are used to increase the amount of urine you produce.
- nitroglycerine, a medicine used to treat angina pectoris.
- some types of antibiotics (rifamycin group), ciclosporin (used to prevent rejection of transplanted organs) or antivirals such as ritonavir (used to treat HIV/AIDS).
- metformin, a medicine used to treat diabetes.
If any of the above applies to you, tell your doctor or pharmacist before you take Neparvis.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy
You must tell your doctor if you think that you are (or might become) pregnant. Your doctor will normally advise you to stop taking this medicine before you become pregnant or as soon as you know you are pregnant, and will advise you to take another medicine instead of Neparvis.

This medicine is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if it is used after the third month of pregnancy.

Breast-feeding
Neparvis is not recommended for mothers who are breast-feeding. Tell your doctor if you are breast-feeding or about to start breast-feeding.

Driving and using machines
Before you drive a vehicle, use tools or operate machines, or carry out other activities that require concentration, make sure you know how Neparvis affects you. If you feel dizzy or very tired while taking this medicine, do not drive a vehicle, cycle or use any tools or machines.

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

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Adults
You will usually start by taking a 24 mg/26 mg or 49 mg/51 mg tablet twice a day (one tablet in the morning and one tablet in the evening). Your doctor will decide your exact starting dose based on which medicines you have been taking previously and your blood pressure. Your doctor will then adjust the dose every 2-4 weeks depending on how you respond to the treatment until the best dose for you is found.

The usual recommended target dose is 97 mg/103 mg twice a day (one tablet in the morning and one tablet in the evening).

Children and adolescents (one year and older)
Your (or your child’s) doctor will decide the starting dose based on body weight and other factors including previously taken medicines. The doctor will adjust the dose every 2-4 weeks until the best dose is found.

Neparvis should be given twice a day (one tablet in the morning and one tablet in the evening).

Neparvis film-coated tablets are not meant to be used in children who weigh less than 40 kg. For these patients, Neparvis granules are available.

Patients taking Neparvis can develop low blood pressure (dizziness, light-headedness), a high level of potassium in the blood (which would be detected when your doctor performed a blood test) or decreased kidney function. If this happens, your doctor may reduce the dose of any other medicine you are taking, temporarily reduce the Neparvis dose, or stop Neparvis treatment completely.

Swallow the tablets with a glass of water. You can take Neparvis with or without food. Splitting or crushing of the tablets is not recommended.

If you take more Neparvis than you should
If you have accidentally taken too many Neparvis tablets, or if someone else has taken your tablets, contact your doctor immediately. If you experience severe dizziness and/or fainting, tell your doctor as quickly as possible and lie down.

If you forget to take Neparvis
It is advisable to take your medicine at the same time each day. However, if you forget to take a dose, you should simply take the next one at the scheduled time. Do not take a double dose to make up for a forgotten dose.

If you stop taking Neparvis
Stopping your treatment with Neparvis may cause your condition to get worse. Do not stop taking your medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects may be serious.
- Stop taking Neparvis and seek immediate medical attention if you notice any swelling of the face, lips, tongue and/or throat, which may cause difficulties in breathing or swallowing. These may be signs of angioedema (an uncommon side effect which may affect up to 1 in 100 people).

Other possible side effects:
If any of the side effects listed below becomes severe, tell your doctor or pharmacist.

Very common (may affect more than 1 in 10 people)
- low blood pressure, which can cause symptoms of dizziness and light-headedness (hypotension)
- high level of potassium in the blood, shown in a blood test (hyperkalaemia)
- decreased kidney function (renal impairment)

Common (may affect up to 1 in 10 people)
- cough
- dizziness
- diarrhoea
- low level of red blood cells, shown in a blood test (anaemia)
- tiredness (fatigue)
- (acute) inability of the kidney to work properly (renal failure)
- low level of potassium in the blood, shown in a blood test (hypokalaemia)
- headache
- fainting (syncope)
- weakness (asthenia)
- feeling sick (nausea)
- low blood pressure (dizziness, light-headedness) when switching from sitting or lying to standing position
- gastritis (stomach pain, nausea)
- spinning sensation (vertigo)
- low level of sugar in the blood, shown in a blood test (hypoglycaemia)

Uncommon (may affect up to 1 in 100 people)
- allergic reaction with rash and itching (hypersensitivity)
- dizziness when switching from sitting to standing position (dizziness postural)
- low level of sodium in the blood, shown in a blood test (hyponatraemia)

Rare (may affect up to 1 in 1 000 people)
- seeing, hearing or feeling things that are not there (hallucinations)
- changes in sleeping pattern (sleep disorder)

Very rare (may affect up to 1 in 10 000 people)
- paranoia
- intestinal angioedema: a swelling in the gut presenting with symptoms like abdominal pain, nausea, vomiting and diarrhoea

Not known (frequency cannot be estimated from the available data)
- sudden involuntary muscle twitching (myoclonus)

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Neparvis contains
- The active substances are sacubitril and valsartan.
o
Each 24 mg/26 mg film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as sacubitril valsartan sodium salt complex).
o
Each 49 mg/51 mg film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as sacubitril valsartan sodium salt complex).
o
Each 97 mg/103 mg film-coated tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as sacubitril valsartan sodium salt complex).
- The other ingredients in the tablet core are microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate, talc and silica colloidal anhydrous (see end of section 2 under ‘Neparvis contains sodium’).
- The 24 mg/26 mg and the 97 mg/103 mg tablet coatings contain hypromellose, titanium dioxide (E171), Macrogol (4000), talc, iron oxide red (E172) and iron oxide black (E172).
- The 49 mg/51 mg tablet coating contains hypromellose, titanium dioxide (E171), Macrogol (4000), talc, iron oxide red (E172) and iron oxide yellow (E172).

What Neparvis looks like and contents of the pack
Neparvis 24 mg/26 mg film-coated tablets are violet-white oval tablets with “NVR” on one side and “LZ” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm.
Neparvis 49 mg/51 mg film-coated tablets are pale yellow oval tablets with “NVR” on one side and “L1” on the other side. Approximate tablet dimensions 13.1 mm x 5.2 mm Neparvis 97 mg/103 mg film-coated tablets are light pink oval tablets with “NVR” on one side and “L11” on the other side. Approximate tablet dimensions 15.1 mm x 6.0 mm.

The tablets are supplied in packs containing 14, 20, 28 or 56 tablets and in multipacks comprising 7 cartons, each containing 28 tablets. The 49 mg/51 mg and 97 mg/103 mg tablets are also supplied in multipacks comprising 3 cartons, each containing 56 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland

Manufacturer
Novartis Pharmaceutical Manufacturing LLC
Verovskova Ulica 57
1000 Ljubljana
Slovenia

Novartis Farma S.p.A
Via Provinciale Schito 131
80058 Torre Annunziata (NA)
Italy

LEK farmacevtska družba d. d., Poslovna enota PROIZVODNJA LENDAVA
Trimlini 2D
Lendava, 9220
Slovenia

Novartis Pharma GmbH
Sophie-Germain-Strasse 10
90443 Nuremberg
Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Lietuva
SIA Novartis Baltics Lietuvos filialas
Tel: +370 5 269 16 50

България
Novartis Bulgaria EOOD
Тел: +359 2 489 98 28

Luxembourg/Luxemburg
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Česká republika
Novartis s.r.o.
Tel: +420 225 775 111

Magyarország
Novartis Hungária Kft.
Tel.: +36 1 457 65 00
Danmark
Novartis Healthcare A/S
Tlf.: +45 39 16 84 00

Malta
Novartis Pharma Services Inc.
Tel: +356 2122 2872
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0

Nederland
Novartis Pharma B.V.
Tel: +31 88 04 52 111
Eesti
SIA Novartis Baltics Eesti filiaal
Tel: +372 66 30 810

Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12

Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
España
Laboratorios Farmacéuticos ROVI, S.A.
Tel: +34 91 375 62 30

Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 375 4888
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00

Portugal
Servier Portugal - Especialidades Farmacêuticas,
Lda.
Tel: +351 21 312 2000

Hrvatska
Novartis Hrvatska d.o.o.
Tel. +385 1 6274 220

România
Novartis Pharma Services Romania SRL
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55

Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439

Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200

Κύπρος
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690

Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00

Latvija
SIA Novartis Baltics
Tel: +371 67 887 070

This leaflet was last revised in

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu

Neparvis is a heart medicine containing an angiotensin receptor neprilysin inhibitor. It delivers two active substances, sacubitril and valsartan.

Neparvis is used to treat a type of long-term heart failure in children and adolescents (one year and older).

This type of heart failure occurs when the heart is weak and cannot pump enough blood to the lungs and the rest of the body. The most common symptoms of heart failure are breathlessness, fatigue, tiredness and ankle swelling.

Do not take Neparvis
- if you (or your child) are allergic to sacubitril, valsartan or any of the other ingredients of this medicine (listed in section 6).
- if you (or your child) are taking another type of medicine called an angiotensin converting enzyme (ACE) inhibitor (for example enalapril, lisinopril or ramipril), which is used to treat high blood pressure or heart failure. If you have been taking an ACE inhibitor, wait for 36 hours after taking the last dose before you start to take Neparvis (see “Other medicines and Neparvis”).
- if you (or your child) have ever had a reaction called angioedema (rapid swelling under the skin in areas such as the face, throat, arms and legs which can be life threatening if throat swelling blocks the airway) when taking an ACE inhibitor or an angiotensin receptor blocker (ARB) (such as valsartan, telmisartan or irbesartan).
- if you (or your child) have a history of angioedema which is hereditary or for which the cause is unknown (idiopathic).
- if you (or your child) have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren (see “Other medicines and Neparvis”).

- if you (or your child) have severe liver disease.
- if you (or your child) are more than 3 months pregnant (see “Pregnancy and breast-feeding”).
If any of the above applies to you, do not take Neparvis and talk to your doctor.

Warnings and precautions
Talk to your doctor, pharmacist or nurse before or when taking Neparvis:
- if you (or your child) are being treated with an angiotensin receptor blocker (ARB) or aliskiren (see “Do not take Neparvis”).
- if you (or your child) have ever had angioedema (see “Do not take Neparvis” and section 4 “Possible side effects”).
- if you experience abdominal pain, nausea, vomiting or diarrhoea after taking Neparvis. Your doctor will decide on further treatment. Do not stop taking Neparvis on your own.
- if you (or your child) have low blood pressure or are taking any other medicines that reduce your blood pressure (for example, a medicine that increases urine production (diuretic)) or are suffering from vomiting or diarrhoea, especially if you are aged 65 years or more, or if you have kidney disease and low blood pressure.
- if you (or your child) have kidney disease.
- if you (or your child) are suffering from dehydration.
- if your (or your child’s) kidney artery has narrowed.
- if you (or your child) have liver disease.
- if you (or your child) experience hallucinations, paranoia or changes in sleeping pattern while taking Neparvis.
- if you (or your child) have hyperkalaemia (high levels of potassium in the blood).
- if you (or your child) suffer from heart failure classified as NYHA class IV (unable to carry on any physical activity without discomfort and may have symptoms even when resting).

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

Your doctor may check the amount of potassium and sodium in your blood at regular intervals during Neparvis treatment. In addition, your doctor may check your blood pressure at start of treatment and when the doses are increased.

Children (below one year of age)
Use in children below one year of age is not recommended. There is limited experience on use in children in this age group. Neparvis film-coated tablets are available for children who weigh more than 40 kg.

Other medicines and Neparvis
Tell your doctor, pharmacist or nurse if you (or your child) are taking, have recently taken or might take any other medicines. It may be necessary to change the dose, to take other precautions, or even to stop taking one of the medicines. This is particularly important for the following medicines:
- ACE inhibitors. Do not take Neparvis with ACE inhibitors. If you have been taking an ACE inhibitor, wait 36 hours after taking the last dose of the ACE inhibitor before starting to take Neparvis (see “Do not take Neparvis”). If you stop taking Neparvis, wait 36 hours after taking your last dose of Neparvis before starting an ACE inhibitor.
- other medicines used to treat heart failure or lower blood pressure, such as angiotensin receptor blockers or aliskiren (see “Do not take Neparvis”).
- some medicines known as statins that are used to lower high cholesterol levels (for example atorvastatin).
- sildenafil, tadalafil, vardenafil or avanafil, which are medicines used to treat erectile dysfunction or lung hypertension.
- medicines that increase the amount of potassium in the blood. These include potassium supplements, salt substitutes containing potassium, potassium-sparing medicines and heparin.

- painkillers of the type called non-steroidal anti-inflammatory medicines (NSAIDs) or selective cyclooxygenase-2 (Cox-2) inhibitors. If you are taking one of these, your doctor may want to check your kidney function when starting or adjusting treatment (see “Warnings and precautions”).
- lithium, a medicine used to treat some types of psychiatric illness.
- furosemide, a medicine belonging to the type known as diuretics, which are used to increase the amount of urine you produce.
- nitroglycerine, a medicine used to treat angina pectoris.
- some types of antibiotics (rifamycin group), ciclosporin (used to prevent rejection of transplanted organs) or antivirals such as ritonavir (used to treat HIV/AIDS).
- metformin, a medicine used to treat diabetes.
If any of the above applies to you, tell your doctor or pharmacist before you take Neparvis.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy
You must tell your doctor if you think that you (or your child) are (or might become) pregnant. Your doctor will normally advise you to stop taking this medicine before you become pregnant or as soon as you know you are pregnant, and will advise you to take another medicine instead of Neparvis.

This medicine is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if it is used after the third month of pregnancy.

Breast-feeding
Neparvis is not recommended for mothers who are breast-feeding. Tell your doctor if you are breast-feeding or about to start breast-feeding.

Driving and using machines
Before you drive a vehicle, use tools or operate machines, or carry out other activities that require concentration, make sure you know how Neparvis affects you. If you feel dizzy or very tired while taking this medicine, do not drive a vehicle, cycle or use any tools or machines.

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

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Your (or your child’s) doctor will decide the starting dose based on body weight and other factors including previously taken medicines. The doctor will adjust the dose every 2-4 weeks until the best dose is found.

Neparvis should be given twice a day (once in the morning and once in the evening).

See the instructions for use for how to prepare and take Neparvis granules.

Patients taking Neparvis can develop low blood pressure (dizziness, light-headedness), a high level of potassium in the blood (which would be detected when your doctor performed a blood test) or decreased kidney function. If this happens, your doctor may reduce the dose of any other medicine you

(or your child) are taking, temporarily reduce the Neparvis dose, or stop Neparvis treatment completely.

If you take more Neparvis than you should
If you (or your child) have accidentally taken too many Neparvis granules, or if someone else has taken your granules, contact your doctor immediately. If you (or your child) experience severe dizziness and/or fainting, tell your doctor as quickly as possible and lie down.

If you (or your child) forget to take Neparvis
It is advisable to take your medicine at the same time each day. However, if you (or your child) forget to take a dose, you should simply take the next one at the scheduled time. Do not take a double dose to make up for a forgotten dose.

If you (or your child) stop taking Neparvis
Stopping your treatment with Neparvis may cause your condition to get worse. Do not stop taking your medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects may be serious.
- Stop taking Neparvis and seek immediate medical attention if you (or your child) notice any swelling of the face, lips, tongue and/or throat, which may cause difficulties in breathing or swallowing. These may be signs of angioedema (an uncommon side effect which may affect up to 1 in 100 people).

Other possible side effects:
If any of the side effects listed below becomes severe, tell your doctor or pharmacist.

Very common (may affect more than 1 in 10 people)
- low blood pressure, which can cause symptoms of dizziness and light-headedness (hypotension)
- high level of potassium in the blood, shown in a blood test (hyperkalaemia)
- decreased kidney function (renal impairment)

Common (may affect up to 1 in 10 people)
- cough
- dizziness
- diarrhoea
- low level of red blood cells, shown in a blood test (anaemia)
- tiredness (fatigue)
- (acute) inability of the kidney to work properly (renal failure)
- low level of potassium in the blood, shown in a blood test (hypokalaemia)
- headache
- fainting (syncope)
- weakness (asthenia)
- feeling sick (nausea)
- low blood pressure (dizziness, light-headedness) when switching from sitting or lying to standing position
- gastritis (stomach pain, nausea)
- spinning sensation (vertigo)
- low level of sugar in the blood, shown in a blood test (hypoglycaemia)

Uncommon (may affect up to 1 in 100 people)
- allergic reaction with rash and itching (hypersensitivity)
- dizziness when switching from sitting to standing position (dizziness postural)
- low level of sodium in the blood, shown in a blood test (hyponatraemia)

Rare (may affect up to 1 in 1 000 people)
- seeing, hearing or feeling things that are not there (hallucinations)
- changes in sleeping pattern (sleep disorder)

Very rare (may affect up to 1 in 10 000 people)
- paranoia
- intestinal angioedema: a swelling in the gut presenting with symptoms like abdominal pain, nausea, vomiting and diarrhoea

Not known (frequency cannot be estimated from the available data)
- sudden involuntary muscle twitching (myoclonus)

Reporting of side effects
If you (or your child) get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.
Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Neparvis contains
- The active substances are sacubitril and valsartan.
o
Each Neparvis 6 mg/6 mg granules in capsule for opening (granules in capsule) contains four film-coated granules equivalent to 6.1 mg sacubitril and 6.4 mg valsartan (as sacubitril valsartan sodium salt complex).
o
Each Neparvis 15 mg/16 mg granules in capsule for opening (granules in capsule) contains ten film-coated granules equivalent to 15.18 mg sacubitril and 16.07 mg valsartan (as sacubitril valsartan sodium salt complex).
- The other ingredients of the granules are microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate, silica colloidal anhydrous and talc.
- The ingredients of the film coat are basic butylated methacrylate copolymer, talc, stearic acid and sodium laurilsulfate (see end of section 2 under ‘Neparvis contains sodium’).
- The ingredients of the capsule shell are hypromellose, titanium dioxide (E171), iron oxide (yellow) (E172) (Neparvis 15 mg/16 mg only) and printing ink.
o
The ingredients of the printing ink are shellac, propylene glycol, iron oxide (red) (E172), ammonia solution (concentrated) and potassium hydroxide.

What Neparvis looks like and contents of the pack
Neparvis 6 mg/6 mg granules are white to slightly yellow in colour, round in shape, approximately 2 mm in diameter and provided in a capsule. The capsule consists of a white cap, marked “04” in red and a transparent body, marked “NVR” in red. An arrow is printed on both the body and the cap.
Neparvis 15 mg/16 mg granules are white to slightly yellow in colour, round in shape, approximately 2 mm in diameter and provided in a capsule. The capsule consists of a yellow cap, marked “10” in red and a transparent body, marked “NVR” in red. An arrow is printed on both the body and the cap.

Neparvis 6 mg/6 mg granules in capsules for opening and Neparvis 15 mg/16 mg granules in capsules for opening are supplied in packs containing 60 capsules.

Marketing Authorisation Holder
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland

Manufacturer
Lek farmacevtska družba d.d.
Verovskova Ulica 57
1526 Ljubljana
Slovenia

Novartis Pharmaceutical Manufacturing LLC
Verovskova Ulica 57
1000 Ljubljana
Slovenia

Novartis Farmaceutica S.A.
Gran Via de les Corts Catalanes, 764
08013 Barcelona
Spain

Novartis Pharma GmbH
Sophie-Germain-Strasse 10
90443 Nuremberg
Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Lietuva
SIA Novartis Baltics Lietuvos filialas
Tel: +370 5 269 16 50

България
Novartis Bulgaria EOOD
Тел: +359 2 489 98 28

Luxembourg/Luxemburg
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11

Česká republika
Novartis s.r.o.
Tel: +420 225 775 111

Magyarország
Novartis Hungária Kft.
Tel.: +36 1 457 65 00

Danmark
Novartis Healthcare A/S
Tlf.: +45 39 16 84 00

Malta
Novartis Pharma Services Inc.
Tel: +356 2122 2872
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0

Nederland
Novartis Pharma B.V.
Tel: +31 88 04 52 111
Eesti
SIA Novartis Baltics Eesti filiaal
Tel: +372 66 30 810

Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12

Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
España
Laboratorios Farmacéuticos ROVI, S.A.
Tel: +34 91 375 62 30

Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 375 4888
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00

Portugal
Servier Portugal - Especialidades Farmacêuticas,
Lda.
Tel: +351 21 312 2000

Hrvatska
Novartis Hrvatska d.o.o.
Tel. +385 1 6274 220

România
Novartis Pharma Services Romania SRL
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55

Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439

Italia
Novartis Farma S.p.A.
Tel: +39 02 96 54 1
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200

Κύπρος
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690

Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00

Latvija
SIA Novartis Baltics
Tel: +371 67 887 070

This leaflet was last revised in

Other sources of information
Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu

Instructions for use for Neparvis 6 mg/6 mg granules in capsules for opening and Neparvis 15 mg/16 mg granules in capsules for opening

To ensure that you use Neparvis granules correctly for your child, it is important that you follow these instructions. Your doctor, pharmacist or nurse will show you how to do this. Ask one of them if you have any questions.

Neparvis granules are contained within capsules and are available in two strengths: 6 mg/6 mg granules and 15 mg/16 mg granules. The capsules are packaged in blister cards. You may receive one or both strengths depending on the dose your child needs.

You can see the difference between the two strengths by the colour of the capsule cap and the imprint on it.
- The capsule containing the 6 mg/6 mg granules has a white cap with number 04 printed on it.
- The capsule containing the 15 mg/16 mg granules has a yellow cap with number 10 printed on it.

The capsules containing Neparvis granules must be opened before use.

Do NOT swallow the whole capsule. Do NOT swallow the empty capsule shells.

If you use both strengths of Neparvis granules, make sure you use the correct number of capsules of each strength as instructed by your doctor, pharmacist or nurse.

Step 1
- Wash and dry your hands

Step 2
- Place the following items on a clean flat surface:
o
A small bowl, cup or spoon with a small amount of soft food the child likes.
o
Blister card(s) with capsules containing Neparvis granules.

• Check that you have the correct strength(s) of Neparvis granules.

Step 3
- Push the blister(s) to remove the capsule(s).

Step 4
To open the capsule:
- Hold the capsule upright (with the coloured cap on top) so that the granules are in the bottom of the capsule.
- Hold the capsule over the soft food.
- Gently pinch the middle of the capsule and pull slightly to separate the two ends of the capsule. Take care not to spill the contents.

Step 5
- Empty all of the granules from the capsule onto the food.
- Make sure that you do not miss any granules.
Repeat steps 4 and 5 if you need more than one capsule to reach the prescribed dose.
Step 6
Feed the food with the granules to the child immediately, making sure your child eats all of it.

Make sure your child does not chew the granules to avoid change of taste.

Step 7
Throw away the empty shells of the capsule.