Consumer medicine information

Entresto

Sacubitril; Valsartan

BRAND INFORMATION

Brand name

Entresto

Active ingredient

Sacubitril; Valsartan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Entresto.

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.

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 less than 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.
  • 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 Poisons Information Centre (telephone number: 13 11 26), 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 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 30°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, 28, 56 or 60 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.

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 by:

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

® = Registered Trademark

This leaflet was prepared in November 2017

Australian Registration Numbers:

Entresto 24 mg/26 mg tablets - AUST R 234219

Entresto 49 mg/51 mg tablets - AUST R 234222

Entresto 97 mg/103 mg tablets -AUST R 234218

Internal document code:

(ent231120c) based on PI (ent231120i)

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Entresto

Active ingredient

Sacubitril; Valsartan

Schedule

S4

 

1 Name of Medicine

Sacubitril and valsartan.

2 Qualitative and Quantitative Composition

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 List of Excipients.

3 Pharmaceutical Form

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.

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 administered 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.

Dosage.

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 ≤ 95 mmHg, symptomatic hypotension, hyperkalaemia, renal dysfunction), consideration should be given to adjustment of concomitant medications, or to temporary downtitration 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 Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration, Other important considerations for dosing).
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 Special Warnings and Precautions for Use, Hypotension).
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 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 Contraindications).
Entresto should not be coadministered with an ARB due to the angiotensin II receptor blocking activity of Entresto (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Treatment should not be initiated in patients with serum potassium level > 5.4 mmol/L or with SBP < 100 mmHg (see Section 4.4 Special Warnings and Precautions for Use).
The valsartan contained within Entresto is more bioavailable than the valsartan in other marketed tablet formulations (see Table 1).

Special populations.

Renal insufficiency.

No dose adjustment is required in patients with mild (eGFR 60-90 mL/min/1.73 m2) to moderate (eGFR 30-60 mL/min/1.73 m2) 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 m2). Caution is recommended when using Entresto in these patients as there are no adequate data (see Section 5.2 Pharmacokinetic Properties, Special populations).
There is no experience in patients with endstage 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 Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Special populations).

Method of administration.

For oral use. Entresto may be administered with or without food (see Section 5.2 Pharmacokinetic Properties, Absorption).

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 Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Known history of angioedema related to previous ACE inhibitor or ARB therapy.
Hereditary or idiopathic angioedema (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use with aliskiren in patients with type 2 diabetes (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Severe hepatic impairment, biliary cirrhosis and cholestasis (see Section 4.2 Dose and Method of Administration).
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

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 Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Caution is required while coadministering Entresto with direct renin inhibitors such as aliskiren (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Entresto must not be administered with aliskiren in patients with type 2 diabetes (see Section 4.3 Contraindications).
Entresto should not be coadministered with an ARB due to the angiotensin II receptor blocking activity of Entresto (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 Adverse Effects (Undesirable Effects)). 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.
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 Dose and Method of Administration). 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.

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 Adverse Effects (Undesirable Effects)). 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, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of Entresto may be required (see Section 4.2 Dose and Method of Administration). Medications known to raise potassium levels (e.g. potassium sparing diuretics, potassium supplements) should be used with caution when coadministered 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 in PARADIGM-HF. 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 readministered. 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 Contraindications).
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.

Use in hepatic impairment.

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

Use in renal impairment.

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 Adverse Effects (Undesirable Effects)). 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 downtitrate or interrupt Entresto in patients who develop a clinically significant decrease in renal function (see Section 5.2 Pharmacokinetic Properties, Special populations). 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/1.73 m2) 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 endstage renal disease and use of Entresto is not recommended (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Special populations).

Use in the elderly.

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.

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Anticipated interactions resulting in a contraindication.

ACE inhibitors.

The concomitant use of Entresto with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE inhibitor therapy may increase the risk of angioedema. Entresto must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Entresto (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).

Aliskiren.

The concomitant use of Entresto with aliskiren is contraindicated in patients with type 2 diabetes (see Section 4.3 Contraindications). Combination of Entresto with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure).

Anticipated interactions resulting in concomitant use not being recommended.

Entresto should not be coadministered with an ARB due to the angiotensin II receptor blocking activity of Entresto (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use with aliskiren should be avoided in patients with renal impairment (eGFR < 60 mL/min/1.73 m2) (see Section 4.4 Special Warnings and Precautions for Use).

Observed interactions to be considered.

Statins.

In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters. Entresto may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Coadministration of Entresto increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Therefore, caution should be exercised upon coadministration of Entresto with statins.

Sildenafil.

Addition of a single dose of sildenafil to Entresto at steady state in patients with hypertension was associated with greater BP reduction compared to administration of Entresto alone. Therefore, caution should be exercised when sildenafil or another PDE-5 inhibitor is initiated in patients treated with Entresto.

Anticipated interactions to be considered.

Potassium.

Concomitant use of potassium sparing diuretics (e.g. triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if Entresto is coadministered with these agents (see Section 4.4 Special Warnings and Precautions for Use).

Nonsteroidal anti-inflammatory agents (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors).

In elderly patients, volume depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of Entresto and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on Entresto who are taking NSAIDs concomitantly.

Lithium.

The potential for a drug interaction between Entresto and lithium has not been investigated. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use with Entresto. If a diuretic is also used, the risk of lithium toxicity may be increased further.

Frusemide.

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

Transporters.

The active metabolite of sacubitril (sacubitrilat) and valsartan are OATP1B1, OATP1B3 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, coadministration of Entresto with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampin, cyclosporine) or MRP2 (e.g. ritonavir) may increase the systemic exposure to sacubitrilat or valsartan, respectively. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.

Metformin.

Coadministration of Entresto with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with Entresto in patients receiving metformin, the clinical status of the patient should be evaluated.

No significant interactions.

No clinically meaningful drug-drug interaction was observed upon coadministration of Entresto and digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol, intravenous nitroglycerin or a combination of levonorgestrel/ ethinyloestradiol. No interaction is expected with atenolol, indomethacin, glyburide, or cimetidine.

CYP450 interactions.

In vitro metabolism studies indicate that the potential for CYP450 based drug interactions is low since there is limited metabolism of Entresto via the CYP450 enzymes. Entresto does not induce or inhibit CYP450 enzymes.

4.6 Fertility, Pregnancy and Lactation

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).
(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 Contraindications) 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 embryofetal lethality in rats at doses ≥ 49 mg sacubitril/51 mg valsartan/kg/day (≤ 0.06 [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 embryofetal 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.

There are no data from the use of Entresto in pregnant women. Animal studies with Entresto have shown reproductive toxicity.
 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 breastfeeding or to discontinue Entresto while breastfeeding, taking into account the importance of Entresto to the mother.

Females of childbearing potential.

Female patients of childbearing 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.

4.7 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.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

Summary of the safety profile.

PARADIGM-HF.

The safety of Entresto in patients with chronic heart failure was evaluated in the pivotal phase 3 study PARADIGM-HF, which compared patients treated twice daily with Entresto 97 mg/103 mg (n = 4203) or enalapril 10 mg (n = 4229). Patients randomised to Entresto received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3271 patients were treated for more than one year.
In the PARADIGM-HF study, patients were previously treated with ACE inhibitors and/or ARBs and also had to successfully complete sequential enalapril and Entresto run-in periods (median drug exposure of 15 and 29 days, respectively) prior to the randomised double blind period. During the enalapril run-in period, 1,102 patients (10.5%) permanently discontinued from the study, 5.6% because of an adverse reaction, most commonly renal dysfunction (1.7%), hyperkalaemia (1.7%) and hypotension (1.4%). During the Entresto run-in period, 10.4% of patients permanently discontinued, 5.9% because of an adverse reaction, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalaemia (1.3%). Due to discontinuations during the run-in period, the adverse reaction rates as presented in Table 2 may be lower than the adverse reaction rates expected in clinical practice.
Discontinuation of therapy due to an AE in the double blind period of the PARADIGM-HF trial occurred in 450 (10.71%) of Entresto treated patients and 516 (12.20%) of patients receiving enalapril. The events most commonly associated with dosage adjustment or treatment interruption were hypotension, hyperkalaemia and renal impairment. The overall incidence of adverse drug reactions (ADRs) of Entresto in heart failure patients was comparable to enalapril. The pattern of the ADRs is consistent with the pharmacology of Entresto and the patients underlying conditions.
The overall frequency of adverse reactions was not related to gender, age, or race.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions are ranked by system organ class and then by frequency with the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. See Tables 2 and 3.

Description of selected adverse reactions.

Angioedema.

In the PARADIGM-HF trial, the incidence of angioedema was 0.1% in both the enalapril and Entresto run-in periods. In the double blind period, the incidence of angioedema was higher in patients treated with Entresto than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in black patients was 2.4% with Entresto and 0.5% with enalapril (see Section 4.4 Special Warnings and Precautions for Use).

Hyperkalaemia and serum potassium.

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

Blood pressure.

In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (< 90 mmHg and decrease from baseline of > 20 mmHg) were reported in 17.6% and 4.76% of Entresto treated patients compared with 11.9% and 2.67% of enalapril treated patients, respectively. Orthostasis was reported in 2.1% of patients treated with Entresto compared to 1.1% of patients treated with enalapril during the double blind period of PARADIGM-HF. Falls were reported in 1.9% of patients treated with Entresto compared to 1.3% of patients treated with enalapril.

Renal impairment.

In PARADIGM-HF, renal impairment was reported in 10.1% of Entresto treated patients and 11.5% of enalapril treated patients.

Laboratory abnormalities.

Hemoglobin and hematocrit.

Decreases in hemoglobin/ hematocrit of > 20% were observed in approximately 5% of both Entresto and enalapril treated patients in the double blind period in PARADIGM-HF.

Serum creatinine.

In PARADIGM-HF, increases in serum creatinine of > 50% were observed in 1.4% of patients in the enalapril run-in period and 2.2% of patients in the Entresto run-in period. During the double blind period, approximately 16% of both Entresto and enalapril treated patients had increases in serum creatinine of > 50%.

Serum potassium.

In PARADIGM-HF, potassium concentrations > 5.5 mEq/L were observed in approximately 4% of patients in both the enalapril and Entresto run-in periods. During the double blind period, approximately 16% of both Entresto and enalapril treated patients had potassium concentrations > 5.5 mEq/L.
Adverse events leading to study drug discontinuation in the TITRATION study (see Section 5.1 Pharmacodynamic Properties, Clinical trials) are shown in Table 4.

Other Entresto studies.

PIONEER-HF.

The PIONEER-HF trial was a 8-week study comparing in-hospital initiation of Entresto versus enalapril in heart failure patients with reduced ejection fraction stabilised following hospitalisation for acute decompensated heart failure (ADHF) (see Section 5.1).
There was no significant difference in the overall occurrence of symptomatic hypotension in patients treated with Entresto (15.0%) compared to patients treated with enalapril (12.7%). Hyperkalaemia was comparable and did not differ significantly between Entresto-treated patients (11.6%) and enalapril-treated patients (9.3%). Worsening renal function was reported in 13.6% of Entresto-treated and 14.7% of enalapril-treated patients. 6 angioedema were reported in the enalapril group (1.4%, all Black patients) compared to 1 in the Entresto group (0.2%, Caucasian patient).

TRANSITION.

The TRANSITION trial was a 26-week study comparing pre- and post-discharge treatment initiation with Entresto in 1002 heart failure patients with reduced ejection fraction hospitalised for an acute decompensation event (ADHF) (see Section 5.1).
The safety profile of Entresto was similar in the pre-discharge and post-discharge groups.
In both studies, the safety profile of Entresto was consistent with the safety profile in PARADIGM-HF.

Post-marketing experience - adverse drug reactions from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from post-marketing experience with Entresto via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA (see Table 5).
Additional adverse event information for valsartan may be found in the Australian approved Diovan (valsartan) product information.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Limited data are available with regards to overdosage in human subjects with Entresto. In healthy volunteers, a single dose of Entresto 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated.
Hypotension is the most likely symptom of overdosage due to the blood pressure lowering effects of Entresto. Symptomatic treatment should be provided.
Entresto is unlikely to be removed by haemodialysis due to high protein binding.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

The pharmacodynamic effects of Entresto were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and RAAS blockade. In a 7 day valsartan controlled study in patients with reduced ejection fraction (HFrEF), administration of Entresto resulted in a significant nonsustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21 day study in HFrEF patients, Entresto significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1 compared to baseline. Entresto also blocked the AT1 receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, Entresto decreased plasma NT-proBNP and increased plasma BNP and urine cGMP compared with enalapril. While BNP is a neprilysin substrate, NT-proBNP is not. Therefore, NT-proBNP (but not BNP) is a suitable biomarker for monitoring of heart failure patients treated with Entresto.
In a thorough QTc clinical study in healthy male subjects, single doses of Entresto 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarisation.
In the mechanistic study PROVE-HF, Entresto demonstrated improvement of echocardiographic parameters of cardiac structural and functional remodeling (reduction of left atrial volume index [LAVi], left ventricular end systolic [LVESVi] and diastolic volume [LVEDVi] indices, mitral E/E' ratio and increase in left ventricular ejection fraction [LVEF]) compared to baseline at 1 year. Treatment with Entresto resulted in a clinically meaningful average LVEF increase of 9.4% compared to baseline after 12 months. Entresto also demonstrated improvement of biomarker parameters (reduction in NT-proBNP, high sensitivity Troponin T and soluble ST2), reflective of an improvement of the underlying pathophysiology of heart failure.
Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of Entresto 194 mg sacubitril/206 mg valsartan once daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 and 1-42. The clinical relevance of this finding is unknown.

Mechanism of action.

Entresto exhibits the novel mechanism of action of an angiotensin receptor neprilysin inhibitor (ARNI) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657 (sacubitrilat), the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type 1 (AT1) receptor via valsartan. The complementary cardiovascular benefits and renal effects of Entresto in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by sacubitrilat and the simultaneous inhibition of the deleterious effects of angiotensin II by valsartan. NPs exert their effects by activating membrane bound guanylyl cyclase coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), thereby promoting vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and antihypertrophic and antifibrotic effects. Sustained activation of the renin angiotensin aldosterone system results in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodeling. Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II dependent aldosterone release.

Clinical trials.

Dosing in clinical trials was based on the total amount of both components of Entresto, i.e. 24 mg/26 mg, 49 mg/51 mg and 97 mg/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.

PARADIGM-HF.

The PARADIGM-HF trial was a multinational, randomised, double blind trial comparing Entresto (sacubitril/valsartan) to enalapril in 8,442 adult patients with symptomatic chronic heart failure and reduced ejection fraction (left ventricular ejection fraction ≤ 40% amended later to ≤ 35%), in NYHA class II-IV, in addition to other heart failure therapy. Prior to study enrolment, patients were required to have a plasma B-type natriuretic peptide (BNP) ≥ 150 picogram/mL or N-terminal proBNP (NT-proBNP) ≥ 600 picogram/mL, or, if they had been hospitalised for heart failure in the last 12 months, a BNP ≥ 100 picogram/mL or a NT-proBNP ≥ 400 picogram/mL. Patients had to have been on an ACE inhibitor or ARB at a dose equivalent to at least 10 mg of enalapril daily for at least four weeks prior to screening, and on maximally tolerated doses of beta-blockers.
Patients with symptomatic hypotension, or having a systolic blood pressure of < 100 mmHg at screening were excluded. Patients with severe hepatic impairment, eGFR < 30 mL/min/1.73 m2 or serum potassium ≥ 5.2 mmol/L at baseline, or those with any history of angioedema were also excluded. The primary endpoint was the composite of cardiovascular (CV) death or hospitalisation for heart failure.
Prior to study participation, patients were well treated with standard of care therapy which included ACE inhibitors/ ARBs (> 99%), beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (83%). The median follow-up duration was 27 months and patients were treated for up to 4.3 years.
The population was 66% Caucasian, 18% Asian, and 5% black; the mean age was 64 years (19% of patients were 75 years or older); and 78% were male. At randomisation, 70% of patients were NYHA class II, 24% were NYHA class III, and 0.7% were NYHA class IV. The mean left ventricular ejection fraction was 29%. There were 11.4% of patients with a baseline left ventricular ejection fraction > 35 and ≤ 40%. Median NT-proBNP level at study enrollment was 1,629 picogram/mL for Entresto treated patients, and 1,593 picogram/mL for enalapril treated patients. Median BNP levels at study enrollment was 255 picogram/mL for Entresto treated patients, and 251 picogram/mL for enalapril treated patients. The underlying cause of heart failure was coronary artery disease in 60% of patients; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR < 60 mL/min/1.73 m2, and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Few patients had an implantable cardioverter defibrillator (ICD) or cardiac resynchronisation therapy defibrillator (CRT-D) (15%).
Patients were required to discontinue their existing ACE inhibitor or ARB therapy and entered a sequential single blind run-in period during which patients received treatment with enalapril 10 mg twice daily, followed by treatment with Entresto 49 mg/51 mg twice daily, increasing to Entresto 97 mg/103 mg twice daily. Patients were then randomised to the double blind period of the study to receive either Entresto 97 mg/103 mg or enalapril 10 mg twice daily [Entresto (n = 4209); enalapril (n = 4233)].
In the Entresto group, 76% of patients remained on the target dose of Entresto 97 mg/103 mg twice daily at the end of the study (mean daily dose of 375 mg). In the enalapril group, 75% of patients remained on the target dose of 10 mg twice daily at the end of the study (mean daily dose of 18.9 mg).
Entresto demonstrated clinically relevant and statistically significant superiority to enalapril, reducing the risk of cardiovascular death or heart failure hospitalisations by 20% (hazard ratio (HR): 0.80, 95% CI [0.73; 0.87], 1 sided p < 0.0001) versus enalapril. This effect was observed early and was sustained throughout the duration of the trial. The absolute risk reduction was 4.69%. A statistically significant reduction for CV death and first HF hospitalisation was observed (CV death, RRR 20%, HR 0.80; 95% CI [0.71, 0.89]; and hospitalisation for heart failure RRR 21%; HR 0.79; 95% CI [0.71, 0.89]) (see Table 6 and Figure 1). Sudden death accounted for 45% of cardiovascular deaths and was reduced by 20% in Entresto treated patients compared to enalapril treated patients (HR 0.80). Pump failure accounted for 26% of cardiovascular deaths and was reduced by 21% in Entresto treated patients compared to enalapril treated patients (HR 0.79).
This risk reduction was consistently observed across subgroups including: age, gender, race, geography, NYHA class, ejection fraction, renal function, history of diabetes or hypertension, prior heart failure therapy, and atrial fibrillation.
Entresto also significantly reduced all-cause mortality by 16% compared with enalapril (RRR 16%, HR 0.84; 95% CI [0.76 to 0.93], 1 sided p = 0.0005) (see Table 6). The absolute risk reduction was 2.84%.
The Kaplan-Meier presented in Figure 1 (top) shows time to first occurrence of the primary composite endpoint of CV death or heart failure hospitalisation. Entresto treatment effect was evident early and sustained for the duration of the study. The Kaplan-Meier figure presented in Figure 1 (bottom) shows the time to CV death endpoint.
Overall, there were fewer all-cause hospital admissions in patients treated with Entresto compared to enalapril, including a 12% relative risk reduction for the first hospitalisation (HR 0.88 [95% CI: 0.82, 0.94], p < 0.001), and a 16% relative rate reduction for total number of hospitalisations (RR 0.84 [95% CI: 0.78, 0.91], p < 0.001)].
A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. The results of the primary composite endpoint were consistent across the subgroups examined (see Figure 2).

TITRATION.

TITRATION was a 12 week safety and tolerability study in 538 patients with chronic heart failure (NYHA class II-IV) and systolic dysfunction (left ventricular ejection fraction ≤ 35%) naive to ACE inhibitor or ARB therapy or on varying doses of ACE inhibitors or ARBs prior to study entry. Patients initiated Entresto 24 mg/26 mg twice daily, were uptitrated to Entresto 49 mg/51 mg twice daily and then to the target dose of Entresto 97 mg/103 mg twice daily with either a 3 week or 6 week regimen.
Overall, 76% of patients achieved and maintained the target dose of Entresto 97 mg/103 mg twice daily without any dose interruption or downtitration over 12 weeks. More patients who were naive to previous ACE inhibitor or ARB therapy or on low dose therapy (equivalent to < 10 mg of enalapril/day) were able to achieve and maintain Entresto 97 mg/103 mg when uptitrated over 6 weeks versus 3 weeks.

Other Entresto studies.

PIONEER-HF.

PIONEER-HF was a 8-week multicenter, randomised, double-blind, parallel group, active-controlled study (n = 881) followed by a 4-week open label period to evaluate safety and tolerability of in-hospital initiation of Entresto compared to enalapril in HFrEF patients haemodynamically stabilised during hospitalisation for acute decompensated heart failure (ADHF). In PIONEER-HF, 52% of patients were not receiving an ACEi or ARB at the time of admission and 66% had history of HF prior to the index hospitalisation. Entresto significantly decreased NT-ProBNP vs. enalapril over 8 weeks of treatment (ratio of change with Entresto vs enalapril, 0.71, p < 0.001). Subgroup analysis of the primary endpoint defined according to demographic and clinical characteristics of interest reflected a consistently beneficial effect of Entresto compared to enalapril.

TRANSITION.

TRANSITION was a 26-week safety study aimed at exploring whether initiation and uptitration of Entresto in a wide range of HFrEF patients haemodynamically stabilised after an acute heart failure event, either in-hospital or shortly after discharge, is feasible, safe, and well tolerated. The study was a multicenter, randomised, open label, parallel group study (n = 1002) comparing pre-discharge and post-discharge treatment initiation with Entresto in heart failure patients with reduced ejection fraction hospitalised for an acute decompensation event (ADHF), due to deterioration of HF (71.1%) or newly diagnosed (de novo) HF (28.9%). The study demonstrated that there were no difference in treatment management between de novo ADHF and deterioration of HF, and between patients with (75.7%) and without (24.3%) prior ACEi or ARB therapy.
In a multivariable analysis, significant (p < 0.05) predictors of target-dose attainment within 10 weeks were age < 65 years, SBP ≥ 120 mmHg at baseline, history of hypertension, de novo HF, no atrial fibrillation at baseline, estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 at randomisation, and a Entresto starting dose of 49/51mg bid. Assignment to pre- or postdischarge initiation of Entresto was not significant (OR 1.21; 95% CI 0.93-1.59), nor was prior use of an ACEI or ARB a significant predictor of up-titration success (OR 1.04; 95% CI 0.75-1.45).

5.2 Pharmacokinetic Properties

The valsartan contained within Entresto is more bioavailable than the valsartan in other marketed tablet formulations (see Table 1).

Absorption.

Following oral administration, Entresto dissociates into sacubitril, which is further metabolised to sacubitrilat, and valsartan, which reach peak plasma concentrations in 0.5 hours, 3 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be ≥ 60% and 23%, respectively.
Following twice daily dosing of Entresto, steady-state levels of sacubitril, sacubitrilat, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate significantly, while sacubitrilat accumulates by 1.6-fold. Entresto administration with food has no clinically significant impact on the systemic exposures of sacubitril, sacubitrilat and valsartan. Although there is a decrease in exposure to valsartan when Entresto is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect. Entresto can therefore be administered with or without food.

Distribution.

Entresto is highly bound to plasma proteins (94%-97%). Based on the comparison of plasma and CSF exposures, sacubitrilat does cross the blood brain barrier to a limited extent (0.28%). Entresto has an apparent volume of distribution ranging from 75 L to 103 L.

Metabolism.

Sacubitril is readily converted to sacubitrilat by esterases; sacubitrilat is not further metabolised to a significant extent. Valsartan is minimally metabolised, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (< 10%). Since CYP450 enzyme mediated metabolism of sacubitril and valsartan is minimal, coadministration with drugs that impact CYP450 enzymes is not expected to impact the pharmacokinetics.

Excretion.

Following oral administration, 52-68% of sacubitril (primarily as sacubitrilat) and ~ 13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as sacubitrilat), and 86% of valsartan and its metabolites are excreted in faeces.
Sacubitril, sacubitrilat, and valsartan are eliminated from plasma with a mean elimination half-life (T1/2) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.

Linearity/ nonlinearity.

The pharmacokinetics of sacubitril, sacubitrilat, and valsartan are linear in the dose range tested (24 mg sacubitril/26 mg valsartan - 194 mg sacubitril/206 mg valsartan).

Special populations.

Elderly patients (aged over 65 years).

The exposures of sacubitrilat and valsartan are increased in elderly subjects by 42% and 30%, respectively, compared to younger subjects. However, this is not associated with clinically relevant effects and therefore no dosage adjustment is necessary in patients over 65 years. In patients ≥ 75 years old, a lower starting dose of Entresto 24 mg/26 mg should be considered (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Paediatric patients (aged below 18 years).

Entresto has not been studied in paediatric patients.

Impaired renal function.

A correlation was observed between renal function and systemic exposure to sacubitrilat, but not to valsartan. In patients with mild (60 mL/min/1.73 m2 ≤ eGFR < 90 mL/min/1.73 m2) to moderate (30 mL/min/1.73 m2 ≤ eGFR < 60 mL/min/1.73 m2) renal impairment, the AUC for sacubitrilat was up to 2-fold higher. No dosage adjustment is required in patients with mild or moderate renal impairment. A 2.7-fold higher AUC for sacubitrilat was observed in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2). A starting dose of Entresto 24 mg/26 mg twice daily is recommended in patients with severe renal impairment. Caution is recommended when administering Entresto to these patients due to limited data.
No studies have been performed in patients undergoing dialysis. However, sacubitrilat and valsartan are highly bound to plasma protein and, therefore, unlikely to be effectively removed by dialysis.

Impaired hepatic function.

In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5 and 3.4-fold, sacubitrilat increased by 1.5 and 1.9-fold, and valsartan increased by 1.2-fold and 2.1-fold, respectively, compared to matching healthy subjects. No dosage adjustment is recommended when administering Entresto to patients with mild hepatic impairment (Child-Pugh A classification) including patients with biliary obstructive disorders. A starting dose of Entresto 24 mg/26 mg twice daily is recommended in patients with moderate hepatic impairment (Child-Pugh B classification). Entresto has not been studied in patients with severe hepatic impairment. Therefore, its use is not recommended in patients with severe hepatic impairment.

Ethnic group.

The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are comparable across different race and ethnic groups (Caucasians, Blacks, Asians, Japanese and others).

Gender.

The pharmacokinetics of Entresto (sacubitril, sacubitrilat and valsartan) are similar between male and female subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity and clastogenicity studies conducted with Entresto, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level.

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/m2 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/m2 basis.

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 1-40, 1-42, and 1-38 levels; there was no corresponding increase in Aβ levels in the brain. Increases in CSF Aβ 1-40 and 1-42 were not observed in a 2 week healthy volunteer study in humans (see Section 5.1 Pharmacodynamic Properties). Additionally, in a toxicology study in cynomolgus monkeys treated with Entresto at 146 mg sacubitril/154 mg valsartan/kg/day for 39 weeks, there was no amyloid-β plaque accumulation in the brain. The clinical relevance of these findings is not known. Studies in heart failure patients will investigate the potential effects of Entresto on cognitive function and brain amyloid-β deposition.

6 Pharmaceutical Particulars

6.1 List of Excipients

All tablets also contain microcrystalline cellulose-, hydroxypropylcellulose, crospovidone, magnesium stearate (vegetable origin), purified talc, colloidal anhydrous silica, hypromellose, titanium dioxide, macrogol 4000 and iron oxide red.
The Entresto 24/26 and Entresto 97/103 tablets also contain iron oxide black while the Entresto 49/51 tablets also contain iron oxide yellow.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Protect from moisture.
Store in the original package. Keep out of the reach and sight of children.

6.5 Nature and Contents of Container

PA/Al/PVC/Al blister packs. Blister packs contain 14, 28 or 56 or 60 tablets.
Not all packs sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

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)].

Chemical structure.


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-{[(1S,3R)-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).
Molecular formula: C288H330N36O48N18, 15H2O.
Relative molecular mass: 5748.0.

CAS number.

936623-90-4.
Following oral administration, the salt complex dissociates into:

Sacubitril.

Chemical name (IUPAC): 4-{[(1S,3R)-1-([1,1'-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoic acid.
Molecular formula: C24H29NO5.
Molecular mass: 411.5.
Structural formula:

CAS number.

149709-62-6.

Valsartan.

Chemical name (IUPAC): N-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl}-L-valine.
Molecular formula: C24H29N5O3.
Molecular mass: 435.5.
Structural formula:

CAS number.

137862-53-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine Only.

Summary Table of Changes