Entresto 24/26

New Zealand - English - Medsafe (Medicines Safety Authority)

Active ingredient:
Sacubitril 24.3 mg (present as sacubitril/valsartan sodium hydrate complex);  ; Valsartan 25.7 mg (present as sacubitril/valsartan sodium hydrate complex);  
Available from:
Novartis New Zealand Ltd
INN (International Name):
Sacubitril/valsartan 50 mg (equivalent to 24.3mg sacubitril and 25.7 mg valsartan)
Dosage:
24.3 mg/25.7 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Sacubitril 24.3 mg (present as sacubitril/valsartan sodium hydrate complex)   Valsartan 25.7 mg (present as sacubitril/valsartan sodium hydrate complex)   Excipient: Colloidal silicon dioxide Crospovidone Hyprolose Basic coating premix, white Basic coating premix, red Basic coating premix, black Magnesium stearate Microcrystalline cellulose Purified talc Purified water
Prescription type:
Prescription
Manufactured by:
Novartis Pharma Stein AG
Therapeutic indications:
Entresto is indicated in adult patients for the treatment of chronic heart failure (NYHA Class II-IV) with reduced ejection fraction.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PVDC - 56 tablets - 36 months from date of manufacture stored at or below 25°C protect from moisture. The product manufactured at Novartis Farma SpA, Torre Annunziata, Italy. - Blister pack, PA/AL/PVC - 56 tablets - 36 months from date of manufacture stored at or below 30°C protect from moisture
Authorization number:
TT50-9938
Authorization date:
2016-02-18

Read the complete document

ENTRESTO

Entresto

®

24/26, 49/51, 97/103

sacubitril/valsartan

Consumer Medicine Information

What is in this leaflet

This leaflet answers some common

questions about Entresto.

It does not contain all the available

information. It does not take the

place of talking to your doctor, nurse

practitioner or pharmacist.

The information in this leaflet was

last updated on the date listed on the

final page. More recent information

on the medicine may be available.

You should ensure that you speak

to your pharmacist or doctor to

obtain the most up to date

information on the medicine. You

can also download the most up to

date leaflet from

www.novartis.com.au.

Those updates may contain important

information about the medicine and

its use of which you should be aware.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking this medicine

against the benefits they expect it

will provide.

If you have any concerns about this

medicine, ask your doctor, nurse

practitioner or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What Entresto is used

for

Entresto is used to treat a type of

long-term heart failure in adults. 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.

Entresto is an angiotensin receptor

neprilysin inhibitor (ARNI), which

contains sacubitril (a neprilysin

inhibitor), and valsartan (an

angiotensin receptor blocker or

ARB). Entresto works by blocking

the effects of neprilysin via sacubitril

and angiotensin-II receptor via

valsartan. As a result, blood vessels

relax and less water is retained by the

body which is beneficial to treat heart

failure.

Ask your doctor, nurse

practitioner or pharmacist if you

have any questions about why this

medicine has been prescribed for

you.

Your doctor may have prescribed it

for another reason.

This medicine is only available with

a doctor's prescription. It is not

addictive.

There is not enough information to

recommend this medicine for use in

children or adolescents under 18

years old.

Before you take

Entresto

When you must not take it

Do not take this medicine if you

have ever had an unusual or

allergic reaction to sacubitril,

valsartan or any other ingredients

listed at the end of this leaflet.

Ask your doctor for advice if you

think you may be allergic to this

medicine.

Your doctor will want to know if you

are prone to allergies.

Do not take this medicine if you

are taking another medicine for

treatment of your high blood

pressure or heart failure called an

Angiotensin Converting Enzyme

(ACE) Inhibitor.

Examples of ACE inhibitors are

perindopril (Coversyl, GenRx,

Perindo Combi), ramipril (Ramace,

Tritace), trandolapril (Gopten,

Dolapril, Tarka), lisinopril (Fibsol,

Liprace, Prinivil, Zestril), enalapril,

Auspril, Enalapril Sandoz, Renitec,

Zan-Extra), quinapril

(Accupril,Accuretic, Aquinafil,

Filpril, Qpril), fosinopril (Monace,

Monopril), captopril (Capoten,

Zedace) .

Do not start Entresto until 36

hours after taking the last dose of

medicines containing ACE

inhibitors.

ENTRESTO

Do not take this medicine if you

have ever had a reaction called

angioedema causing swelling of the

face, lips, tongue and/or throat,

with or without difficulties in

breathing while taking an ACE

inhibitor or an ARB in the past. Do

not take this medicine if you have

an inherited condition called

"hereditary angioedema", which

makes you prone to angioedema.

Do not take this medicine if you

have any of the following:

Type 2 diabetes (high level of

sugar in the blood) and high

blood pressure which is being

treated with a medicine called

aliskiren.

Severe liver disease.

Do not take this medicine if you

are pregnant or planning to

become pregnant.

Do not take this medicine if you

have very low blood pressure

(Systolic Blood pressure <

100mmHg). Your doctor will check

your blood pressure before you

start on Entresto.

Do not take this medicine after the

expiry date printed on the pack or

if the packaging is torn or shows

signs of tampering.

In that case, return it to your

pharmacist.

Before you start to take it

Tell your doctor, nurse

practitioner or pharmacist:

If you are already taking any

medicines containing an ACE

inhibitor, ARB or aliskiren to

treat your high blood pressure

or heart failure.

Ask your doctor or pharmacist if

you are unsure if you are being

treated with these other

medicines. ACE inhibitors and

ARBs are sold under many

different brand names in

Australia.

If you have ever experienced

angioedema

(swelling of the face, lips, tongue

and/or throat, difficulties in

breathing).

If you have low blood pressure or

are taking other medicines that

reduce your blood pressure such

as a diuretic (water pill) or are

suffering from vomiting or

diarrhoea, especially if you are

aged 75 years or more, or if you

have kidney disease and low

blood pressure.

If you have severe kidney

disease.

If you have liver disease.

If you are taking any medicines

that increase the amount of

potassium in your blood,

including potassium supplements,

salt substitutes that contain

potassium, potassium-sparing

medicines, or heparin.

Your doctor may need to check

the level of potassium in your

blood at regular intervals when

you are taking Entresto.

If your kidney artery has

narrowed.

If you are not sure whether any of the

above conditions apply to you, your

doctor can advise you.

Tell your doctor if you are

pregnant or intend to become

pregnant.

Entresto must not be taken during

pregnancy. You should stop taking

Entresto as soon as you become

pregnant during treatment and tell

your doctor.The medicine may harm

your unborn baby.

Females who might get pregnant

should use contraception while

taking Entresto and for 1 week after

the last dose. You should talk to your

doctor about treatment options if you

are planning to become pregnant.

Tell your doctor if you are breast-

feeding or plan to breast-feed.

Breast-feeding is not recommended

during treatment with Entresto.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

buy without a prescription from a

pharmacy, supermarket or health

food shop.

You may need to take different

amounts of your medicines or to take

different medicines while you are

taking Entresto. Your doctor and

pharmacist have more information.

This is particularly important with

the following medicines:

ACE inhibitors. You must not

take Entresto at the same time as

an ACE inhibitor. If you were

taking an ACE inhibitor, wait 36

hours after taking your last dose

of ACE inhibitor before starting

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 ARBs or

aliskiren.

Statins, such as atorvastatin,

which are medicines used to

lower high cholesterol levels.

Sildenafil, a medicine used to

treat erectile dysfunction or lung

hypertension

Medicines that increase the

amount of potassium in the blood,

including potassium supplements,

salt substitutes containing

potassium, and heparin. Your

doctor may check the level of

potassium in your blood

periodically.

Certain painkillers called non-

steroidal anti-inflammatory drugs

(NSAIDs) or selective cyclo-

oxygenase-2 inhibitors (COX-2

inhibitors). Your doctor may

check your kidney function when

starting or adjusting treatment.

Lithium, a medicine used to treat

some types of depression.

ENTRESTO

Frusemide, a medicine for fluid

retention.

Metformin, a medicine for

diabetes.

Some antibiotics (rifampicin

group), cyclosporin (a drug used

to protect against transplant

rejection), or ritonavir (an anti-

retroviral drug used to treat

HIV/AIDS infection). These

drugs may increase the effect of

valsartan.

Ask your doctor, nurse

practitioner or pharmacist if you

are not sure whether you are

taking any of the medicines listed

above.

If you have not told your doctor

about any of these things, tell

him/her before you start taking

this medicine.

How to take Entresto

Follow all directions given to you

by your doctor and pharmacist

carefully.

They may differ from the

information contained in this leaflet.

If you do not understand the

instructions on the label, ask your

doctor, nurse practitioner or

pharmacist for help.

How much to take

The usual recommended target dose

of Entresto is 97 mg/103 mg twice a

day (one tablet in the morning and

one tablet in the evening).

You will usually start by taking 24

mg/26 mg or 49 mg/51 mg twice a

day. Your doctor will decide your

exact starting dose based on which

medicines you have been taking

previously.

Your doctor will then adjust the dose

depending on how you respond to the

treatment until the best dose for you

is found.

Do not exceed the dose prescribed

by your doctor.

How to take it

Entresto is for oral use (taken by

mouth) only.

Swallow Entresto tablets whole.

The coated tablet should not be

broken or divided into parts.

When to take it

Take your medicine at about the

same time each day.

Taking it at the same time each day

will have the best effect. It will also

help you remember when to take it.

Entresto can be taken with or

without food.

How long to take it

Continue taking your medicine for

as long as your doctor tells you to.

Your doctor will check your progress

to make sure the medicine is working

and will discuss with you how long

your treatment should continue.

Do not stop taking Entresto unless

your doctor tells you to.

If you forget to take it

If it is almost time for your next

dose, skip the dose you missed and

take your next dose when you are

meant to.

Otherwise, take it as soon as you

remember, and then take the next

tablet at the usual time.

Do not take a double dose to make

up for the dose that you missed.

This may increase the chance of you

getting an unwanted side effect.

If you are not sure what to do, ask

your doctor or pharmacist.

If you have trouble remembering

when to take your medicine, ask

your pharmacist for some hints.

If you take too much

(overdose)

Immediately telephone your doctor

or the Poisons Information Centre

(telephone number: 13 11 26) (in

Australia) / National Poisons

Centre (telephone 0800 POISON

or 0800 764 766) (in New Zealand),

or go to Accident and Emergency

at your nearest hospital if you

think that you or anyone else may

have accidentally taken too much

Entresto. Do this even if there are

no signs of discomfort or

poisoning. Keep the telephone

numbers for these places handy.

You may need urgent medical

attention.

While you are taking

Entresto

Things you must do

If you experience swelling of the

face, lips, tongue and/or throat and

difficulty in breathing, stop taking

Entresto and contact your doctor

immediately.

If you become pregnant while

taking this medicine, stop taking

Entresto and tell your doctor

immediately.

Entresto must not be taken if you are

pregnant. The medicine may harm

your unborn baby.

Keep all of your doctor's

appointments so that your progress

can be checked.

Your doctor will do regular checks to

help prevent you from having side

effects from the medicine or

developing serious complications.

Tell your doctor if you become ill

or experience extra stress, injury,

fever, infection or need surgery.

Make sure you keep enough

medicine to last over weekends and

holidays.

Remind your doctor and

pharmacist that you are taking

ENTRESTO

Entresto if you are about to be

started on any new medicine.

Tell any other doctor, dentist or

pharmacist who treats you that

you are taking Entresto.

Things you must not do

Do not give this medicine to anyone

else, even if their condition seems

similar to yours.

Do not use it to treat any other

complaints unless your doctor tells

you to.

Side effects

Tell your doctor, pharmacist or

nurse practitioner as soon as

possible if you do not feel well

while you are taking Entresto even

if you do not think it is connected

with the medicine.

All medicines can have side effects.

Sometimes they are serious, most of

the time they are not. You may need

medical treatment if you get some of

the side effects.

Do not be alarmed by these lists of

possible side effects.

You may not experience any of

them.

Ask your doctor, pharmacist or

nurse practitioner if you have any

questions about these side effects.

Stop taking Entresto and tell your

doctor immediately or go to

Accident and Emergency if you

experience any of the following

which may signs of an allergic

reaction called angioedema:

swollen face, tongue, lips or

throat,

difficulty in swallowing,

rash, itching, hives, dizziness and

difficulties in breathing.

Tell your doctor if you notice any

of the following side effects and

they worry you:

low blood pressure (dizziness,

light-headedness)

your blood test shows an

abnormal (high or low) level of

potassium

kidney problems (signs of renal

impairment)

cough

dizziness

diarrhoea

low level of red blood cells

(shown in a blood test)

tiredness (fatigue)

severe kidney disorder (severe

renal failure)

headache

fainting

weakness

feeling sick (nausea)

low blood pressure or dizziness

when switching from sitting or

lying down to a standing position

gastritis (stomach pain, nausea)

spinning sensation

low level of sugar in the blood

(shown in a blood test)

Tell your doctor if you notice

anything else that is making you

feel unwell.

Some people may have other side

effects not yet known or mentioned

in this leaflet. Some side effects (e.g.

potassium levels in your blood) can

only be found by laboratory testing.

After using Entresto

Storage

Keep your medicine in the original

container until it is time to take it.

Store it in a cool dry place where

the temperature stays below 25°C.

Protect from moisture.

Do not store Entresto or any other

medicine in the bathroom or near a

sink.

Do not leave it in the car or on

window sills.

Keep the medicine where children

cannot reach it.

A locked cupboard at least one-and-

a-half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

tablets you have left over.

Product description

What it looks like

Entresto is supplied as film-coated

tablets and is available in 3 different

strengths of 24 mg/26 mg, 49 mg/51

mg and 97 mg/103 mg:

24 mg/26 mg: violet-white,

ovaloid biconvex film-coated

tablets with bevelled edges,

unscored, debossed with "NVR"

on one side and "LZ" on the other

side.

49 mg/51 mg: are pale yellow

ovaloid biconvex film-coated

tablets with bevelled edges,

unscored, debossed with "NVR"

on one side and "L1" on the other

side.

97 mg/103 mg: light pink ovaloid

biconvex film-coated tablets with

bevelled edges, unscored,

debossed with "NVR" on one side

and "L11" on the other side.

Entresto is packed in blister packs

containing 14 or 56 tablets per

carton.

Some pack sizes may not be

marketed.

Ingredients

The active substances of Entresto are

sacubitril and valsartan as a sodium

salt complex.

ENTRESTO

Each tablet also contains the

following inactive ingredients:

microcrystalline cellulose

hydroxypropylcellulose

crospovidone

magnesium stearate (of vegetable

origin)

colloidal anhydrous silica

purified talc

The film-coating on the tablets

contains:

hypromellose

macrogol 4000

purified talc

titanium dioxide

iron oxide red

iron oxide black (in the 24 mg/26

mg and 97 mg/103mg tablets

only)

iron oxide yellow (in the 49

mg/51mg tablets only)

Entresto does not contain lactose,

gluten, tartrazine or any other azo

dyes.

Sponsor

Entresto is supplied in Australia

NOVARTIS Pharmaceuticals

Australia Pty Limited

ABN 18 004 244 160

54 Waterloo Road

Macquarie Park NSW 2113

Telephone: 1 800 671 203

Web site: www.novartis.com.au

Entresto is supplied in New Zealand

Novartis New Zealand Limited

PO Box 99102

Newmarket

Auckland 1149

Telephone 0800 354 335

® = Registered Trademark

This leaflet was prepared in

September 2020

______________________________

(ent110920cNZ based on DS

ent110920iNZ)

Read the complete document

New Zealand Data sheet

Page

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30

1.

PRODUCT NAME

Entresto 24/26

film-coated tablets

Entresto 49/51

film-coated tablets

Entresto 97/103

film-coated tablets

(sacubitril/valsartan)

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Active ingredient:

A salt complex of the anionic forms of sacubitril and valsartan,

sodium cations and water molecules in the molar ratio of 1:1:3:2.5

respectively

Chemical name (IUPAC): Octadecasodium hexakis(4-{[(1

S

R

)-1-([1,1'-biphenyl]-4-

ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)

hexakis(

N

-pentanoyl-

N

-{[2'-(1H-tetrazol-1-id-5-yl)[1,1'-

biphenyl]-4-yl]methyl}-L-valinate)—water (1/15)

Structure (schematic 2-dimensional):

Molecular formula:

·15H

Relative molecular mass: 5748.0

CAS number:

936623-90-4

Following oral administration, the salt complex dissociates into:

Sacubitril (AAN)

Valsartan (AAN)

Chemical name

(IUPAC):

4-{[(1

S

,3R)-1-([1,1'-Biphenyl]-4-

ylmethyl)-4-ethoxy-3-methyl-4-

oxobutyl]amino}-4-oxobutanoic acid

N

-Pentanoyl-

N

-{[2'-(1

H

tetrazol-5-yl)[1,1'-biphenyl]-4-

yl]methyl}-L-valine

Molecular formula:

Molecular mass:

411. 5

435.5

New Zealand Data sheet

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30

Structural formula:

CAS number:

149709-62-6

137862-53-4

Entresto film-coated tablets are available in 3 strengths:

Each Entresto 24/26 film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan

(where both drug substances are combined as a sodium salt hydrate complex). This has been

rounded to 24 mg/26 mg throughout the document.

Each Entresto 49/51 film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan

(where both drug substances are combined as a sodium salt hydrate complex). This has been

rounded to 49 mg/51 mg throughout the document.

Each Entresto 97/103 film-coated tablet contains 97.3 mg sacubitril and 102.8 mg valsartan

(where both drug substances are combined as a sodium salt hydrate complex). This has been

rounded to 97 mg/103 mg throughout the document.

For the full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Film-coated tablet.

The sacubitril/valsartan sodium salt complex is a white to almost white powder with a

melting point of around 136°C (onset). It is freely soluble in water and the pH is 8.2. The

pKas for sacubitril (4.6) and valsartan (3.9 for the carboxylic group, and 4.7 for the tetrazole-

NH group) and partition coefficients [sacubitril: log D = 1.29 (n-octanol/phosphate buffer pH

6.8) and valsartan: log D = -1.49 (n-octanol/phosphate buffer pH 7.4)].

Entresto 24/26 (24.3 mg sacubitril/25.7 mg valsartan): Violet white, ovaloid, biconvex, film-

coated tablet with beveled edges; unscored, debossed with “NVR” on one side and “LZ” on

the other side.

Entresto 49/51 (48.6 mg sacubitril/51.4 mg valsartan): Pale yellow, ovaloid, biconvex, film-

coated tablet with beveled edges; unscored, debossed with “NVR” on one side and “L1” on

the other side.

Entresto 97/103 (97.3 mg sacubitril/102.8 mg valsartan): Light pink, ovaloid, biconvex, film-

coated tablet with beveled edges; unscored, debossed with “NVR” on one side and “L11” on

the other side.

New Zealand Data sheet

Page

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4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Entresto is indicated in adult patients for the treatment of chronic heart failure (NYHA Class

II-IV)

with reduced ejection fraction.

4.2

Dose and method of administration

Entresto is usually administered in conjunction with other heart failure therapies, in place of

an ACE inhibitor or other ARB.

Entresto should be initiated, and up-titration conducted, by a physician experienced with the

treatment of heart failure.

The recommended starting dose of Entresto is one tablet of 49 mg/51 mg twice daily, except

in the situations described below.

The dose of Entresto should be doubled after 2 to 4 weeks to the target maintenance dose of

one tablet of 97 mg/103 mg twice daily, as tolerated by the patient.

If patients experience tolerability issues (systolic blood pressure ≤95mmHg, symptomatic

hypotension, hyperkalaemia, renal dysfunction), consideration should be given to adjustment

of concomitant medications, or to temporary down–titration or discontinuation of Entresto.

Starting dose of Entresto of 24 mg/26 mg for some populations

A starting dose of Entresto of one tablet of 24 mg/26 mg taken twice daily is recommended

for patients not currently taking an ACE inhibitor or an ARB, or patients previously taking

low doses of these agents (see sections 5.1 and 4.2).

A starting dose of Entresto of one tablet of 24 mg/26 mg taken twice daily should be

considered for patients who have risk factors for hypotension, including patients ≥ 75 years

old and patients with low systolic blood pressure (SBP ≥100 to 110 mmHg) (see section 4.4).

The dose of Entresto should be doubled every 2-4 weeks to the target dose of one tablet of

Entresto 97 mg/103 mg twice daily, as tolerated by the patient.

See Special Populations

section below for further starting dose recommendations in Renal

insufficiency, Hepatic insufficiency and Geriatric patients.

Other important considerations for dosing

Entresto is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE)

inhibitor. Due to the potential risk of angioedema when used concomitantly with an ACE

inhibitor, Entresto must not be administered until 36 hours after the last dose of ACE

inhibitor therapy and similarly, at least 36 hours must elapse after the last dose of Entresto

before ACE inhibitor therapy is initiated (see section 4.3

)

Entresto should not be co-administered with an ARB due to the angiotensin II receptor

blocking activity of Entresto (see sections

4.4 and 4.5).

Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with

SBP <100 mmHg (see

section 4.4).

New Zealand Data sheet

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The valsartan contained within Entresto is more bioavailable than the valsartan in other

marketed tablet formulations;

New Zealand Data sheet

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30

Table 1

Doses of Sacubitril and Valsartan in Entresto and doses of valsartan in

other marketed formulations

Entresto dose

Amount of

Sacubitril

delivered from the

indicated Entresto

dose

Amount of

Valsartan

delivered from the

indicated Entresto

dose

Dose of valsartan in other

marketed formulations

delivering an equivalent

valsartan exposure (AUC)

as the indicated Entresto

dose

24mg/ 26 mg

24 mg

26 mg

40 mg

49mg/ 51 mg

49 mg

51 mg

80 mg

97mg/ 103 mg

97 mg

103 mg

160 mg

Special populations

Renal insufficiency

No dose adjustment is required in patients with mild (eGFR 60-90 mL/min/1.73 m

) to

moderate (eGFR 30-60 mL/min/1.73 m

) renal impairment.

A starting dose of Entresto 24 mg/26 mg twice daily is recommended in patients with severe

renal impairment (eGFR < 30 mL/min/1.73 m

). Caution is recommended when using

Entresto in these patients as there are no adequate data (see

section 5.2).

There is no experience in patients with end-stage renal disease and use of Entresto is not

recommended.

Hepatic insufficiency

No dose adjustment is required when administering Entresto to patients with mild hepatic

impairment (Child-Pugh A classification).

A starting dose of Entresto 24 mg/26 mg twice daily is recommended for patients with

moderate hepatic impairment (Child-Pugh B classification).

Patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child Pugh C

classification) should not take Entresto (see

sections 4.3 and 5.2).

Paediatric patients

The safety and efficacy of Entresto in paediatric patients aged below 18 years have not been

established.

Geriatric patients (older than 65 years)

No dose adjustment is required in patients over 65 years. However, Entresto has been studied

in a limited number of patients over 80 years.

In patients ≥ 75 years old, a starting dose of one

tablet of

Entresto 24 mg/26 mg

taken twice daily should be considered.

New Zealand Data sheet

Page

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Method of administration

For oral use. Entresto may be administered with or without food (see

section 5.2).

4.3

Contraindications

Hypersensitivity to the active substance, sacubitril, valsartan, or to any of the

excipients.

Concomitant use with ACE inhibitors. Do not administer Entresto within 36 hours of

switching from or to an ACE inhibitor (see sections 4.4, 4.2, and 4.5).

Known history of angioedema related to previous ACE inhibitor or ARB therapy.

Hereditary or idiopathic angioedema (see section 4.4).

Concomitant use with aliskiren in patients with Type 2 diabetes (see sections 4.4 and

4.5).

Severe hepatic impairment, biliary cirrhosis and cholestasis (see section 4.2).

Pregnancy (see section 4.4)

.

4.4

Special warnings and precautions for use

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

Entresto must not be administered with an ACE inhibitor due to the risk of angioedema.

Entresto must not be initiated until 36 hours after taking the last dose of ACE inhibitor

therapy. If treatment with Entresto is stopped, ACE inhibitor therapy must not be initiated

until 36 hours after the last dose of Entresto (see sections 4.3, 4.2, and 4.5).

Caution is required while co-administering Entresto with direct renin inhibitors such as

aliskiren (see sections 4.3 and 4.5). Entresto must not be administered with aliskiren in

patients with Type 2 diabetes (see section 4.3).

Entresto should not be co-administered with an ARB due to the angiotensin II receptor

blocking activity of Entresto (see sections 4.2 and 4.5).

Hypotension

Entresto lowers blood pressure and may cause symptomatic hypotension, especially in

patients ≥75 years old, patients with renal disease and patients with low systolic blood

pressure (<112 mmHg) (see section 4.8). Patients with systolic blood pressure <100 mmHg at

the time of initiation of Entresto have not been studied; use of Entresto in these patients is not

recommended. In the double-blind period of PARADIGM-HF, 18% of patients treated with

Entresto and 12% of patients treated with enalapril reported hypotension as an adverse event,

with hypotension reported as a serious adverse event in approximately 1.5% of patients in

both treatment arms.

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When initiating therapy or during dose titration with Entresto, blood pressure should be

monitored routinely. Patients with an activated renin-angiotensin system, such as volume-

and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at

greater risk.

If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and

treatment of other causes of hypotension (e.g. hypovolaemia) should be considered. If

hypotension persists despite such measures, the dosage of Entresto should be reduced or the

product should be temporarily discontinued (see section 4.2). Permanent discontinuation of

therapy is usually not required. Symptomatic hypotension is more likely to occur if the

patient has been volume-depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhea or

vomiting. Sodium and/or volume depletion should be corrected before starting treatment

with Entresto.

Impaired renal function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, the use of Entresto

may be associated with decreased renal function. In the double-blind period of PARADIGM-

HF, 5% of patients in both the Entresto and enalapril groups reported renal failure as an

adverse event (see section 4.8). The incidence of clinically relevant renal impairment was low

and associated treatment discontinuation was observed less frequently in patients receiving

Entresto (0.65%) compared to enalapril (1.28%). In patients whose renal function depends

upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe

congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists

has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and

death.

Use of Entresto should include appropriate assessment of renal function, before initiation of

therapy, and then during treatment, as appropriate. Closely monitor serum creatinine, and

down-titrate or interrupt Entresto in patients who develop a clinically significant decrease in

renal function (see section 5.2). As with all drugs that affect the RAAS, Entresto may

increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal

artery stenosis. In patients with renal artery stenosis, monitor renal function.

Patients with mild and moderate renal impairment are more at risk of developing

hypotension. There is very limited clinical experience in patients with severe renal

impairment (estimated GFR <30 ml/min/1.73m

) and these patients may be at greatest risk of

hypotension. Caution should be exercised when administering Entresto in patients with

severe renal impairment. There is no experience in patients with end-stage renal disease and

use of Entresto is not recommended (see sections 4.2 and 5.2).

Hyperkalaemia

Treatment should not be initiated if the serum potassium level is >5.4 mmol/l. Through its

action on the renin

angiotensin

aldosterone system, hyperkalaemia may occur with Entresto.

In the double-blind period of PARADIGM-HF, 12% of patients treated with Entresto and

14% of patients treated with enalapril reported hyperkalaemia as an adverse event (see

section 4.8). The incidence of clinically relevant hyperkalaemia was low, resulting in

treatment discontinuation in 0.26% of Entresto treated patients compared to 0.35% of

enalapril treated patients. Monitor serum potassium periodically and treat appropriately,

especially in patients with risk factors for hyperkalaemia such as severe renal impairment,

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diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of

Entresto may be required (see section 4.2). Medications known to raise potassium levels (e.g.

potassium-sparing diuretics, potassium supplements) should be used with caution when co-

administered with Entresto. If clinically significant hyperkalaemia occurs, measures such as

reducing dietary potassium, or adjusting the dose of concomitant medications should be

considered. In addition, if serum potassium level is >5.4 mmol/l, discontinuation of Entresto

should be considered.

Angioedema

Angioedema has been reported in 0.5% of patients treated with Entresto and 0.2% of patients

treated with enalapril. If angioedema occurs, Entresto should be immediately discontinued

and appropriate therapy and monitoring should be provided until complete and sustained

resolution of signs and symptoms has occurred. Entresto must not be re-administered. In

cases of confirmed angioedema where swelling has been confined to the face and lips, the

condition has generally resolved without treatment, although antihistamines have been useful

in relieving symptoms.

Angioedema associated with laryngeal edema may be fatal. Where there is involvement of

the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g.,

subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and/or measures

necessary to ensure a patent airway, should be promptly administered.

Patients with a prior history of angioedema were not studied. As they may be at higher risk

for angioedema, caution is recommended if Entresto is used in these patients. Entresto must

not be used in patients with a known history of angioedema related to previous ACE inhibitor

or ARB therapy or with hereditary or idiopathic angioedema (see section 4.3).

Black patients may have increased susceptibility to develop angioedema.

Patients with renal artery stenosis

Similar to other drugs that affect the renin-angiotensin-aldosterone system, Entresto may

increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal

artery stenosis. Caution is required in patients with renal artery stenosis and monitoring of

renal function is recommended.

Patients with NYHA functional classification IV

Caution should be exercised when initiating Entresto in patients with NYHA functional

classification IV due to limited clinical experience in this population.

Patients with hepatic impairment

There is limited clinical experience in patients with moderate hepatic impairment

(Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the

normal range. In these patients, exposure may be increased and safety is not established.

Caution is therefore recommended when using it in these patients (see sections 4.2 and 5.2).

Entresto is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or

cholestasis (Child-Pugh C classification) (see section 4.3).

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Effects on ability to drive and use machines

When driving vehicles or operating machines it should be taken into account that

occasionally dizziness or fatigue may occur.

Use in Pregnancy (Category D)

Drugs that act on the renin-angiotensin-aldosterone system (RAAS) can cause fetal and

neonatal morbidity and death when administered to pregnant women. Several dozen cases

have been reported in the world literature in patients who were taking angiotensin converting

enzyme inhibitors (a specific class of drugs acting on the RAAS).

As for other drugs that also act directly on the RAAS, Entresto must not be used during

pregnancy (see section 4.3) or in women planning to become pregnant. Valsartan exerts its

effects via angiotensin II antagonism. There have been reports of injury to the developing

fetus (e.g. spontaneous abortion, oligohydramnios and newborn renal dysfunction), when

pregnant women have taken valsartan. Physicians prescribing any agents acting on the RAAS

should counsel women of childbearing potential about the potential risk of these agents

during pregnancy. Patients should be advised to discontinue Entresto as soon as pregnancies

occur and to inform their physicians.

The use of drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) during

the second and third trimesters of pregnancy has been associated with fetal and neonatal

injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible

renal failure and death. Oligohydramnios has also been reported, presumably resulting from

decreased fetal renal function. Oligohydramnios in this setting has been associated with fetal

limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity,

intrauterine growth retardation and patent ductus arteriosus have also been reported, although

it is not clear whether these occurrences were due to exposure to the drug. In addition, in

retrospective data, first trimester use of ACE inhibitors has been associated with a potential

risk of birth defects.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be

closely observed for hypotension, oliguria and hyperkalaemia.

In animal studies, Entresto treatment during organogenesis resulted in increased embryo-fetal

lethality in rats at doses ≥ 49 mg sacubitril/51 mg valsartan/kg/day (≤ 0.06 [LBQ657

(sacubitrilat), the active metabolite] and 0.7 [valsartan]-fold the maximum recommended

human dose [MRHD] of 97 mg/103 mg twice-daily on the basis of the area under the plasma

drug concentration-time curve [AUC]) and rabbits at doses ≥ 5 mg sacubitril/5 mg

valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and sacubitrilat

AUC, respectively). Entresto is teratogenic based on a low incidence of fetal hydrocephaly,

associated with maternally toxic doses, which was observed in rabbits at a Entresto dose of ≥

5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of Entresto are

attributed to the angiotensin receptor antagonist activity.

Sacubitril

There are no data from the use of sacubitril in pregnant women. Studies in animals have

shown reproductive toxicity.

Entresto

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There are no data from the use of Entresto in pregnant women. Animal studies with Entresto

have shown reproductive toxicity.

Use in Lactation

It is not known whether Entresto is excreted in human milk. The components of Entresto,

sacubitril and valsartan, were excreted in the milk of lactating rats.

Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (1.1-

fold the MRHD on the basis of sacubitrilat AUC) and valsartan at doses up to 600 mg/kg/day

(0.9-fold the MRHD on the basis of AUC) indicate that treatment with Entresto during

organogenesis, gestation and lactation may affect pup development and survival.

Because of the potential risk for adverse drug reactions in breastfed newborns/infants,

Entresto is not recommended during breastfeeding. A decision should be made whether to

abstain from breast-feeding or to discontinue Entresto while breast-feeding, taking into

account the importance of Entresto to the mother.

Effects on Fertility

There are no available data on the effect of Entresto on human fertility.

Entresto did not show any effects on fertility or early embryonic development in male and

female rats up to a dose of 73 mg sacubitril/77 mg valsartan /kg/day (≤1.0 fold and ≤0.13 fold

the MRHD on the basis of valsartan and sacubitrilat AUC, respectively).

Females of child-bearing potential

Female patients of child-bearing potential should be advised about the consequences of

exposure to Entresto during pregnancy and to use contraception during treatment with

Entresto and for 1 week after their last dose.

Carcinogenicity

Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not

identify any carcinogenic potential for Entresto. The doses of sacubitril studied (high dose of

1200 and 400 mg/kg/day in mice and rats, respectively) were about 29 and 19 times,

respectively, the maximum recommended human dose (MRHD) on a mg/m

basis. The

doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats,

respectively) were about 4 and 10 times, respectively, the maximum recommended human

dose on a mg/m

basis.

Genotoxicity

Mutagenicity and clastogenicity studies conducted with Entresto, sacubitril, and valsartan did

not reveal any effects at either the gene or chromosome level.

Other preclinical safety findings, including amyloid-β findings

The effects of Entresto on amyloid-β concentrations in cerebrospinal fluid (CSF) and brain

tissue were assessed in young (2-4 years old) cynomolgus monkeys treated with Entresto (24

mg sacubitril/26 mg valsartan /kg/day) for 2 weeks. In this study, Entresto had a

pharmacodynamic effect on CSF Aβ clearance in cynomolgus monkeys, increasing CSF Aβ

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