Consumer medicine information

APO-Perindopril Arginine

Perindopril arginine

BRAND INFORMATION

Brand name

APO-Perindopril Arginine

Active ingredient

Perindopril arginine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Perindopril Arginine.

SUMMARY CMI

APO-PERINDOPRIL ARGININE

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or pharmacist.

1. Why am I taking APO-PERINDOPRIL ARGININE?

APO-PERINDOPRIL ARGININE contains the active ingredient perindopril arginine. Perindopril arginine belongs to a group of medicines called angiotensin converting enzyme (ACE) inhibitors. APO-PERINDOPRIL ARGININE is used to lower high blood pressure, treat heart failure or coronary artery disease.

For more information, see Section 1. Why am I taking APO-PERINDOPRIL ARGININE? in the full CMI.

2. What should I know before I take APO-PERINDOPRIL ARGININE?

Do not take if you have ever had an allergic reaction to perindopril arginine or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take APO-PERINDOPRIL ARGININE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-PERINDOPRIL ARGININE and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take APO-PERINDOPRIL ARGININE?

The dose of APO-PERINDOPRIL ARGININE you may need each day will be decided and adjusted by your doctor. This will normally be 2.5 mg, 5 mg or 10 mg once daily for high blood pressure and coronary artery disease; or 2.5 mg to 5 mg once daily for heart failure. Swallow your tablet(s) with water, preferably in the morning before a meal. More instructions can be found in Section 4. How do I take APO-PERINDOPRIL ARGININE? in the full CMI.

5. What should I know while taking APO-PERINDOPRIL ARGININE?

Things you should do
  • Take this medicine exactly as prescribed and remind any healthcare professional you are taking it.
  • Make sure you drink enough water during exercise and hot weather especially if you sweat a lot. This will help you avoid any dizziness or light-headedness caused by a sudden drop in blood pressure.
  • Tell your doctor straight away if you have excessive vomiting or diarrhoea while taking this medicine.
Things you should not do
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take this medicine to treat other complaints unless your doctor tells you to.
  • Do not stop taking this medicine or change the dosage, without checking with your doctor.
  • Do not stop taking your tablets because you are feeling better, unless advised by your doctor.
Driving or using machines
  • Take care when driving or operating machinery until you know how this medicine affects you.
  • Dizziness or weakness due to low blood pressure may occur in certain patients. If you have any of these symptoms do not drive or operate machinery.
Looking after your medicine
  • Store below 25°C. Protect from moisture.

For more information, see Section 5. What should I know while taking APO-PERINDOPRIL ARGININE? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. Sometimes they are serious, most of the time they are not. If you do not feel well while you are taking APO-PERINDOPRIL ARGININE then tell your doctor or pharmacist as soon as possible.

Angioedema (a severe allergic reaction) has been reported in patients treated with ACE inhibitors, including APO-PERINDOPRIL ARGININE. This may occur at any time during treatment. If you develop swelling of your limbs, hands or feet, lips, face, mouth, tongue or throat, a fast and irregular heartbeat, purple spots with occasional blisters on the front of your arms and legs and/or around your neck and ears (a rare condition known as Stevens-Johnson Syndrome), difficulty in breathing, severe blisters, skin rash, itching, erythema multiforme or other allergic reactions after taking APO-PERINDOPRIL ARGININE - please seek urgent medical attention. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APO-PERINDOPRIL ARGININE

Active ingredient: Perindopril arginine

Consumer Medicine Information (CMI)

This leaflet provides important information about taking APO-PERINDOPRIL ARGININE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking APO-PERINDOPRIL ARGININE.

Where to find information in this leaflet:

1. Why am I taking APO-PERINDOPRIL ARGININE?
2. What should I know before I take APO-PERINDOPRIL ARGININE?
3. What if I am taking other medicines?
4. How do I take APO-PERINDOPRIL ARGININE?
5. What should I know while taking APO-PERINDOPRIL ARGININE?
6. Are there any side effects?
7. Product details

1. Why am I taking APO-PERINDOPRIL ARGININE?

APO-PERINDOPRIL ARGININE contains the active ingredient perindopril arginine. Perindopril arginine belongs to a group of medicines called angiotensin converting enzyme (ACE) inhibitors.

APO-PERINDOPRIL ARGININE lowers high blood pressure, a condition which doctors call hypertension.

Everyone has blood pressure. This pressure helps get your blood all around the body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have high blood pressure when your blood pressure stays higher than is needed, even when you are calm or relaxed.

There are usually no symptoms of high blood pressure. The only way of knowing that you have it is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems. You may feel fine and have no symptoms, but eventually it can cause stroke, heart disease and kidney failure. APO-PERINDOPRIL ARGININE helps lower your blood pressure.

You may be prescribed APO-PERINDOPRIL ARGININE for heart failure. Heart failure means that the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops working.

Some people develop heart failure after having had a heart attack. However, there are also other causes of heart failure.

Heart failure may start off with no symptoms, but as the condition progresses, you may feel short of breath or may get tired easily after light physical activity such as walking. You may wake up short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet. In severe heart failure, symptoms may occur even at rest.

APO-PERINDOPRIL ARGININE helps to treat heart failure. If you follow your doctor's advice, your ability to perform daily activities may improve. You may breathe more easily, feel less tired, and have less swelling.

You may also have been prescribed APO-PERINDOPRIL ARGININE if you have coronary artery disease. Coronary artery disease is narrowing of the vessels carrying blood to the heart. In patients with coronary artery disease, APO-PERINDOPRIL ARGININE has been shown to reduce some of the risks, including heart attacks.

2. What should I know before I take APO-PERINDOPRIL ARGININE?

Warnings

Do not take APO-PERINDOPRIL ARGININE if:

  • You are allergic to perindopril arginine, any other ACE inhibitor or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can take this medicine.
  • You have experienced symptoms such as wheezing, swelling of the face, tongue, lips or throat, intense itching or severe skin rashes with previous ACE inhibitor treatment or if you or a member of your family have had these symptoms either spontaneously or in response to another medicine in the past (a rare condition called angioedema).
  • You are pregnant or trying to become pregnant.
  • You are breastfeeding or plan to breastfeed.
  • You undergo treatments where your blood is treated outside of the body (also known as extracorporeal treatments) that may increase your risk of allergic reactions, treatments such as:
    - renal dialysis or haemofiltration using polyacrylonitrile membranes
    - low-density lipoprotein (LDL) apheresis, a technique where LDL is 'filtered' out of the blood, using dextran sulphate.
  • You are treated with a blood pressure lowering medicine containing aliskiren and have diabetes or impaired kidney function.
  • You have kidney problems where the blood supply to your kidneys is reduced (renal artery stenosis).
  • You are treated with sacubitril/ valsartan a medicine used to treat long-term heart failure as the risk of angioedema (rapid swelling under the skin in an area such as the throat) is increased (see also ‘Tell your doctor straight away if’ and ‘What if I am taking other medicines’ sections).
  • The packaging is damaged or shows sign of tampering.
  • The expiry date (EXP) on the pack has passed.

Tell your doctor straight away if:

  • You are pregnant or become pregnant while taking APO-PERINDOPRIL ARGININE, as it may cause serious harm to your baby.
  • You are undergoing desensitisation treatment or have had an allergic reaction during previous desensitisation treatment (e.g. treatments using bee, wasp or ant venom).
  • You are undergoing, or you are intending to undergo treatments where your blood is treated outside of the body (also known as extracorporeal treatments).
  • You are to undergo anaesthesia and/or surgery.
  • You have recently suffered from diarrhoea or vomiting or are dehydrated.
  • You are on a salt restricted diet or use salt substitutes which contain potassium.
  • You are taking lithium (used to treat mania or depression).
  • You are taking any of the following medicines used to treat high blood pressure:
    - An 'angiotensin II receptor blocker' (also known as ARBs or sartans - for example valsartan, telmisartan, irbesartan), in particular if you have diabetes-related kidney problems.
    - Aliskiren.
    - Sacubitril (available as fixed-dose combination with another medicine valsartan), used to treat long-term heart failure.
  • You have any other health problems, including:
    - Kidney disease, or if you are on renal dialysis.
    - Aortic stenosis (narrowing of the main blood vessel leading from the heart).
    - Liver disease.
    - High or low levels of potassium, or other problems with salt balance.
    - Diabetes.
    - Low blood pressure.
    - Heart disease, including hypertrophic cardiomyopathy (heart muscle disease).
    - Systemic lupus erythematous or scleroderma (a disease affecting the skin, joints and kidneys).
    - Are of African origin since you may have a higher risk of angioedema and this medicine is less effective in lowering your blood pressure.
    - Have abnormally increased levels of a hormone called aldosterone in your blood (primary aldosteronism).

If you think any of these situations apply to you, or you have any doubts or questions about taking APO-PERINDOPRIL ARGININE consult your doctor or pharmacist.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

It is important to tell your doctor if you are pregnant or intend to become pregnant, or if you are breastfeeding or intend to breastfeed.

For older people or children

APO-PERINDOPRIL ARGININE can generally be taken safely by elderly people. However reduced kidney function is often found in elderly people and in this case, the starting dose should always be 2.5 mg.

APO-PERINDOPRIL ARGININE is not recommended for children.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Taking APO-PERINDOPRIL ARGININE may change the effect of some medicines, and some medicines may affect how well APO-PERINDOPRIL ARGININE works. You may need different amounts of your medication or to take different medicines. The medicines that may interact with APO-PERINDOPRIL ARGININE include the following:

  • Some medications used to treat high blood pressure (including angiotensin receptor blockers), aliskiren (see also ‘Do not take APO-PERINDOPRIL ARGININE if’ and ‘Tell your doctor straight away if’ sections), diuretics (sometimes called 'fluid' or 'water' tablets because they increase the amount of urine passed each day).
  • Some treatments where your blood is treated outside of the body, also known as extracorporeal treatments (see also ‘Do not take APO-PERINDOPRIL ARGININE if’ and ‘Tell your doctor straight away if’ sections).
  • Some antibiotics and medicines used to treat infections.
  • Some anti-inflammatory drugs (including high dose aspirin, ibuprofen) for pain relief.
  • Medicines used to treat mood swings and some types of depression (lithium, tricyclic antidepressants, antipsychotics).
  • Potassium-sparing diuretics, sources of potassium, like potassium tablet and salt substitutes containing potassium, other drugs which can increase potassium in your body (such as heparin, a medicine used to thin blood to prevent clots; co-trimoxazole also known as trimethoprim/sulfamethoxazole for infections caused by bacteria; and ciclosporin, an immunosuppressant medicine used to prevent organ transplant rejection).
  • Immunosuppressants (medicines which reduces the activity of the body's natural defences).
  • Vasodilators including nitrates.
  • Medicines used to treat diabetes (tablets and insulin).
  • Medicines which may affect the blood cells, such as allopurinol, procainamide.
  • Baclofen (a medicine used to treat muscle stiffness in diseases such as multiple sclerosis).
  • Medicines used for the treatment of low blood pressure, shock or asthma (e.g. ephedrine, noradrenaline or adrenaline).
  • Gold salts, especially with intravenous administration (used to treat symptoms of rheumatoid arthritis).
  • Medicines which may increase the risk of angioedema (a severe allergic reaction) such as
    - Mammalian target of rapamycin (mTOR) inhibitors used to avoid rejection of transplanted organs (e.g. temsirolimus, sirolimus, everolimus).
    - Sacubitril (available as fixed-dose combination with valsartan), used to treat long-term heart failure (see also ‘Do not take APO-PERINDOPRIL ARGININE if’ and ‘Tell your doctor straight away if’ sections).
    - Gliptins used to treat diabetes (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin, alogliptin).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APO-PERINDOPRIL ARGININE.

4. How do I take APO-PERINDOPRIL ARGININE?

How much to take

The dose of APO-PERINDOPRIL ARGININE you may need each day will be decided and adjusted by your doctor. This will normally be 2.5 mg, 5 mg or 10 mg once daily for high blood pressure and for people with coronary artery disease or 2.5 mg to 5 mg once daily for heart failure.

When to take APO-PERINDOPRIL ARGININE

  • Swallow your tablet(s) with water, preferably in the morning before a meal.

If you forget to take APO-PERINDOPRIL ARGININE

APO-PERINDOPRIL ARGININE should be taken regularly at the same time each day.

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 go back to taking it as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you take too much APO-PERINDOPRIL ARGININE

If you think that you have taken too much APO-PERINDOPRIL ARGININE, you may need urgent medical attention.

Taking too much APO-PERINDOPRIL ARGININE (an overdose) may cause low blood pressure (also known as hypotension). The most likely effect in case of overdose is low blood pressure which can make you feel dizzy or faint. If this happens, lying down with the legs elevated can help. Other effects like sickness, cramps, sleepiness, confusion, kidney problems, salt and water disturbances are possible. You may require urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking APO-PERINDOPRIL ARGININE?

Things you should do

Take APO-PERINDOPRIL ARGININE exactly as your doctor has prescribed. Otherwise, you may not get the benefits from treatment. Tell all doctors, dentists and pharmacists who are involved with your treatment that you are taking APO-PERINDOPRIL ARGININE.

Make sure you drink enough water during exercise and hot weather especially if you sweat a lot. This will help you avoid any dizziness or light-headedness caused by a sudden drop in blood pressure.

Tell your doctor straight away if you have excessive vomiting or diarrhoea while taking APO-PERINDOPRIL ARGININE.

Angioedema (a severe allergic reaction) has been reported in patients treated with ACE inhibitors, including APO-PERINDOPRIL ARGININE. This may occur at any time during treatment.

Call your doctor straight away if you develop such symptoms described below

  • Swelling of your extremities (limbs, hands or feet), lips, face, mouth, tongue or throat.
  • A fast irregular heartbeat.
  • Purple spots with occasional blisters on the front of your arms and legs and/or around your neck and ears (a rare condition known as Stevens-Johnson Syndrome).
  • Difficulty in breathing.
  • Severe blisters, skin rash, itching, erythema multiforme or other allergic reactions.

Remind any doctor, dentist or pharmacist you visit that you are taking APO-PERINDOPRIL ARGININE.

Things you should not do

  • Do not give APO-PERINDOPRIL ARGININE to anyone else, even if they have the same condition as you.
  • Do not take APO-PERINDOPRIL ARGININE to treat other complaints unless your doctor tells you to.
  • Do not stop taking APO-PERINDOPRIL ARGININE or change the dosage, without checking with your doctor.
  • Do not stop taking your tablets because you are feeling better, unless advised by your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-PERINDOPRIL ARGININE affects you.

Take care when driving or operating machinery until you know how APO-PERINDOPRIL ARGININE affects you.

Dizziness or weakness due to low blood pressure may occur in certain patients. If you have any of these symptoms `do not drive or operate machinery.

Looking after your medicine

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Store below 25°C. Protect from moisture.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Do not take this medicine after the expiry date.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking APO-PERINDOPRIL ARGININE, or the tablets have passed their expiry date, return any leftover tablets to your pharmacist for disposal.

6. Are there any side effects?

If you do not feel well while you are taking APO-PERINDOPRIL ARGININE then tell your doctor or pharmacist as soon as possible.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Serious side effects

Serious side effectsWhat to do
Respiratory and heart related:
  • Difficulty in breathing.
  • A fast and irregular heartbeat.
Skin related:
  • Purple spots with occasional blisters on the front of your arms and legs and/or around your neck and ears (a rare condition known as Stevens-Johnson Syndrome).
  • Severe blisters, skin rash, itching, erythema multiforme or other allergic reactions.
  • Swelling of your extremities (limbs, hands or feet), lips, face, mouth, tongue or throat.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal related:
  • Nausea, vomiting, taste disturbances, indigestion, diarrhoea, constipation, stomach pain or discomfort.
  • Inflammation of the pancreas (pancreatitis).
Mouth related:
  • Dry mouth.
  • Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing.
Kidney and liver related:
  • Kidney problems.
  • Elevation of bilirubin levels in the blood, increases in liver enzymes.
  • Kidney disease.
  • Problems with production or passing of urine.
  • Concentrated urine (dark in colour), feel or are sick, have muscle cramps, confusion and fits which may be due to inappropriate anti-diuretic hormone (ADH) secretion can occur with ACE inhibitors. If you have these symptoms contact your doctor as soon as possible.
  • Hepatitis.
Respiratory and heart related:
  • Cough, often described as dry and irritating, shortness of breath, discomfort on exertion.
  • Changes in the rhythm or rate of the heartbeat, fast or irregular heartbeat.
  • Difficulty breathing or wheezing.
  • Eosinophilic pneumonia.
  • Myocardial infarction, angina pectoris (a feeling of tightness, pressure or heaviness in the chest).
  • Changes in the rhythm or rate of the heartbeat.
Blood and investigations related:
  • High levels in the blood of potassium, urea and/or creatine, low sodium levels in blood.
  • Increase in some white blood cells.
  • Decreased blood sugar levels.
  • Bleeding or bruising more easily than normal caused by a low blood platelet count, frequent infections such as fever, severe chills, sore throat or mouth ulcers caused by a lack of white blood cells, pancytopenia (a rare type of anaemia).
  • Illnesses resulting from a lack of red blood cells.
Vascular disorders related:
  • Hypotension.
  • Vasculitis.
  • Flushing.
  • Impaired peripheral circulation.
  • Stroke.
  • Discolouration, numbness and pain in fingers or toes (Raynaud's phenomenon).
Musculoskeletal related:
  • Muscle cramps.
  • Chest pain.
  • Aching muscles, muscle tenderness or weakness, not caused by exercise.
  • Joint pain.
Nervous system related:
  • Headache, dizziness, vertigo, pins and needles.
  • Mood disturbance, sleep disturbances (difficulty sleeping, abnormal dreams), feeling sleepy or drowsy, fainting.
  • Confusion and hallucinations.
Skin related:
  • Rash, pruritus (itching).
  • Excessive sweating.
  • Increased sensitivity of the skin to sun, skin rash or inflammation of the skin often including blisters that weep and become crusted.
  • Worsening of psoriasis.
  • Red, often itchy spots, similar to the rash of measles, which starts on the limbs and sometimes on the face and the rest of the body.
  • Swelling of hands, ankles or feet.
Eye, ear and nose related:
  • Vision disturbances.
  • Tinnitus (persistent noise in the ears).
  • Runny or blocked nose, sneezing, facial pressure or pain.
  • Nose bleeds.
Reproductive system related:
  • Erectile dysfunction.
General related:
  • Feeling tired, lethargic or weak.
  • Fever or high temperature.
  • Generally feeling unwell.
  • Falls.
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What APO-PERINDOPRIL ARGININE contains

Active ingredient
(main ingredient)		Perindopril arginine
Other ingredients
(inactive ingredients)
  • Isomalt
  • Colloidal anhydrous silica
  • Magnesium stearate
  • Hypromellose
  • Hydroxypropyl cellulose
  • Macrogol 8000
  • Titanium dioxide
  • 5 mg and 10 mg tablets contain brilliant blue FCF aluminium lake and iron oxide yellow.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What APO-PERINDOPRIL ARGININE looks like

2.5 mg Tablets*

White coloured, round shaped, biconvex, film coated tablets, with engraved "APO" on one side and "2.5" on the other side.

Blister pack of 30 or 100 tablets*. AUST R 184819.

5 mg Tablets*

Light green coloured, capsule-shaped, biconvex, film coated tablets, with notch and engraved "APO" on one side and "P 5" on the other side.

Blister pack of 30 or 100 tablets*. AUST R 184814.

10 mg Tablets*

Green coloured, round shaped, biconvex, film coated tablets, with engrave "APO" on one side and "P 10" on the other side.

Blister pack of 30 or 100 tablets*. AUST R 184809.

*Not all strengths and pack sizes may not be available.

Who distributes APO-PERINDOPRIL ARGININE

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St
Cremorne VIC 3121
www.arrotex.com.au

This leaflet was prepared in October 2024.

Published by MIMS January 2025

BRAND INFORMATION

Brand name

APO-Perindopril Arginine

Active ingredient

Perindopril arginine

Schedule

S4

 

1 Name of Medicine

Perindopril arginine.

2 Qualitative and Quantitative Composition

Each tablet contains 2.5 mg, 5 mg or 10 mg perindopril arginine, as the active ingredient.

3 Pharmaceutical Form

2.5 mg tablets.

White coloured, round shaped, biconvex, film coated tablets, with engraved "APO" on one side and "2.5" on the other side.

5 mg tablets.

Light green coloured, capsule-shaped, biconvex, film coated tablets, with notch and engraved "APO" on one side and "P 5" on the other side.

10 mg tablets.

Green coloured, round shaped, biconvex, film coated tablets, with engraved "APO" on one side and "P 10" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

The treatment of hypertension.
The treatment of heart failure. In such patients it is recommended that perindopril arginine be given with a diuretic and/or digoxin under close medical supervision. (The safety and efficacy of perindopril arginine has not been demonstrated for New York Heart Association Category IV patients); and
Patients with established coronary artery disease (see Section 5.1 Pharmacodynamic Properties, Clinical trials) who are stable on concomitant therapy and have no heart failure, to reduce the risk of non-fatal myocardial infarction or cardiac arrest.

4.2 Dose and Method of Administration

Perindopril arginine tablets are intended for oral administration.

Hypertension.

The usual starting dose is one perindopril arginine 5 mg tablet once daily, taken in the morning.
Optimum control of blood pressure is achieved by increasing the dose, titrating it against the blood pressure to a maximum of one perindopril arginine 10 mg tablet once daily.
A starting dose of one perindopril arginine 2.5 mg tablet per day is recommended in the following patients who may be at risk of ACE inhibitor-induced hypotension:

Combination with a diuretic.

The administration of perindopril arginine to patients currently treated with a diuretic may induce hypotension and sometimes, but more rarely, acute renal failure, at the beginning of the treatment. Monitoring of plasma creatinine is recommended during the first month of treatment.

Elderly patients with hypertension.

Elderly patients with hypertension should start treatment with one perindopril arginine 2.5 mg tablet daily, with titration to one perindopril arginine 5 mg tablet if necessary. It is recommended that renal function be assessed before starting treatment.

Other patients who may be at risk of ACE inhibitor-induced hypotension.

Patients with renovascular hypertension, salt and/or volume depletion, or cardiac decompensation may have a strongly activated renin angiotensin aldosterone system (RAAS). These patients may experience an excessive drop in blood pressure following the first dose of an ACE inhibitor.

Congestive heart failure.

Treatment of congestive heart failure with perindopril arginine should be initiated under close medical supervision.
The usual starting dose is one perindopril arginine 2.5 mg tablet once daily, which should be given with a diuretic and/or digitalis. This is increased to one perindopril arginine 5 mg tablet once daily for maintenance.
Patients with severe hepatic or renal impairment and/or severe salt/volume depletion are particularly sensitive to ACE inhibitors. Doses in these patients should be carefully titrated as no pharmacokinetic and dose titration studies have been conducted.

Reduction of risk of cardiovascular events.

For stable coronary artery disease, the starting dose is one perindopril arginine 5 mg tablet once daily for two weeks, and then increased to one perindopril arginine 10 mg tablet once daily, depending on tolerance and renal function.
Elderly patients should receive one perindopril arginine 2.5 mg tablet once daily for one week, then one perindopril arginine 5 mg tablet once daily the next week, before increasing the dose up to one perindopril arginine 10 mg tablet once daily depending on tolerance and renal function (see Patients with renal impairment, Table 1).

Elderly patients.

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril arginine to elderly patients. The initial dose of perindopril arginine should always be one perindopril arginine 2.5 mg tablet once daily and patients should be monitored closely during the initial stages of treatment (see Section 4.4 Special Warnings and Precautions for Use).
Particular care should be taken in elderly patients with congestive heart failure who have renal and/or hepatic insufficiency.

Patients with renal impairment.

In patients with renal failure, treatment should begin with one perindopril arginine 2.5 mg tablet daily. The dose should be adjusted as indicated (see Table 1) according to creatinine clearance. Creatinine and potassium levels should be closely monitored.

Patients with hepatic impairment.

The small changes in the kinetics of perindoprilat do not justify the need to change the usual dose in most patients with hepatic failure (see Section 4.4 Special Warnings and Precautions for Use).

Food.

Food intake may reduce hepatic biotransformation of perindopril to perindoprilat. Whilst this effect has not been shown to be clinically significant, it is recommended that perindopril arginine should be taken before meals.

4.3 Contraindications

Perindopril arginine tablets are contraindicated:
In patients with a history of previous hypersensitivity to the active ingredient perindopril, ACE inhibitors or any of the excipient ingredients present in this perindopril arginine.
During pregnancy and for lactating women.
In patients with bilateral or unilateral renal artery stenosis (see Section 4.4 Special Warnings and Precautions for Use).
In patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous ACE inhibitor treatment (see Section 4.4 Special Warnings and Precautions for Use).
In patients receiving extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitrile membranes such as "AN69") and low density lipoprotein apheresis with dextran sulfate due to increased risk of severe anaphylactoid reactions following treatment with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive medicines or alternative membranes (e.g. cuprophane or polysulfone PSF) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Combined use with aliskiren-containing products in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m2) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Combined use with sacubitril/valsartan fixed dose combinations - perindopril arginine must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Precautions.

Hyperkalaemia.

Since ACE inhibitors reduce angiotensin II formation resulting in decreased production of aldosterone, increases in serum potassium have been observed in some patients treated with ACE inhibitors including perindopril. The effect is usually not significant in patients with normal renal function. Serum electrolytes (including sodium potassium and urea) should be measured from time to time when ACE inhibitors are given and especially in combination with diuretics.
Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age (> 70 years), diabetes, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and combined use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other medicines associated with increases in serum potassium (e.g. heparin, other ACE-inhibitors, angiotensin receptor blocker, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors and other non-selective NSAIDS, immunosuppressant agents such as ciclosporin or tacrolimus, co-trimoxazole also known as trimethoprim/sulfamethoxazole). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored. Combined use of the above-mentioned medicines should be used with caution in combination with ACE inhibitors. Frequent monitoring of serum potassium is needed (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In some patients, hyponatraemia may co-exist with hyperkalaemia.

Diabetes.

Glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor in patients with diabetes treated with oral medicines or insulin (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Lithium.

The combination of lithium and perindopril is generally not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Potassium sparing medicines, potassium supplements or potassium-containing salt substitutes.

The combination of perindopril and potassium sparing medicines, potassium supplements or potassium-containing salt substitutes is generally not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Angioedema.

Patients with a history of angioedema unrelated to ACE inhibitor treatment may be at increased risk of angioedema while treated with an ACE inhibitor (see Section 4.3 Contraindications).
Life-threatening angioedema has been reported with most ACE inhibitors. The overall incidence is approximately 0.1%-0.2%. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually the angioedema is non-pitting oedema of the skin mucous membrane and subcutaneous tissue.
Angioedema of the face, extremities, lips, tongue, mucous membranes, glottis and/or larynx has been reported in patients treated with ACE inhibitors and has been reported uncommonly with perindopril arginine (see Section 4.8 Adverse Effects (Undesirable Effects)). This may occur at any time during treatment. In such cases perindopril arginine should be promptly discontinued and the patient carefully observed until the swelling disappears.
Where such cases have been described with other ACE inhibitors and swelling has been confined to the face and lips, the condition has generally resolved without treatment although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal or near fatal. In most cases symptoms occurred during the first week of treatment and the incidence appears to be similar in both sexes or those with heart failure or hypertension.
Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction, appropriate treatment (e.g. adrenaline (epinephrine) and oxygen) should be given promptly. Treatment of progressive angioedema should be aggressive and failing a rapid response to medical treatment, mechanical methods to secure an airway should be undertaken before massive oedema complicates oral or nasal intubation.
Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.
The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months.
Patients may have multiple episodes of angioedema with long symptom-free intervals.
Angioedema may occur with or without urticaria.
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
ACE inhibitors should not be reintroduced in patients who have a history of angioedema due to rare reports of recurrence.
The combined use of perindopril arginine with sacubitril/valsartan fixed dose combinations is contraindicated due to the increased risk of angioedema (see Section 4.3 Contraindications).
Sacubitril/valsartan fixed dose combinations must not be initiated until 36 hours after taking the last dose of perindopril arginine. If treatment with sacubitril/valsartan fixed dose combinations is stopped, perindopril arginine must not be initiated until 36 hours after the last dose of sacubitril/valsartan fixed dose combination (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The combined use of perindopril arginine with NEP inhibitors, mammalian target of rapamycin (mTOR) inhibitor (e.g. temsirolimus, sirolimus, everolimus) and gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin, alogliptin) may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Caution should be used when commencing treatment with these above-mentioned medicines in a patient already taking an ACE inhibitor.

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis and haemodialysis.

Rarely, patients treated with ACE inhibitors during LDL apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy treatment prior to each apheresis.
Anaphylactoid reactions have been reported in patients dialysed with high flux membranes, who are treated with an ACE inhibitor. Extracorporeal treatments leading to contact of blood with negatively charged surfaces (e.g. polyacrylonitrile membranes such as "AN69") are contraindicated. If such treatment is required, consideration should be given to use a different type of dialysis membrane (e.g. cuprophane or polysulfone PSF) or a different class of antihypertensive medicines (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Anaphylactic reactions during desensitisation.

Patients receiving ACE inhibitors during desensitisation treatment (e.g. Hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Hypotension.

Hypotension has been reported in patients commencing treatment with ACE inhibitors. Symptomatic hypotension is rarely seen in uncomplicated hypertension but is a potential consequence of perindopril arginine use in patients with salt/volume-depletion, for example, in patients vigorously treated with diuretics, in patients on dialysis, with impaired renal function, following severe diarrhoea or vomiting, in patients on dietary restrictions or those with severe renin-dependent hypertension (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Administration of perindopril arginine 2.5 mg to patients with mild-moderate heart failure was not associated with any significant reduction in blood pressure. In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is more likely to occur in those patients with severe heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. This may be associated with syncope, neurological deficits, oliguria and/or progressive increase in blood nitrogen, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, treatment should be started at low doses under very close supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose is increased, or the diuretic treatment is commenced or increased.
Patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident should be closely followed for the first two weeks of treatment and whenever the dose of perindopril arginine and/or diuretic is increased. In all high-risk patients it is advisable to initiate treatment with one perindopril arginine 2.5 mg tablet once daily.
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with perindopril arginine. This is anticipated and is usually not a reason to discontinue treatment. If symptomatic hypotension occurs, a reduction of dose or discontinuation of perindopril arginine may be necessary.
If hypotension occurs the patient should be placed in a supine position and if necessary infused with normal saline. A transient hypotensive response is not a contraindication to further doses, which can usually be given without difficulty when blood pressure has increased following volume expansion.

Renovascular hypertension.

If renovascular hypertension is also present, treatment should be started under close medical supervision with low doses and careful dose titration. There is an increased risk of severe hypotension and renal insufficiency. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of perindopril treatment. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.

Kidney transplantation.

There is no experience regarding the administration of perindopril arginine in patients with a recent kidney transplantation.

Hepatic failure.

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients treated with ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up (see Section 4.8 Adverse Effects (Undesirable Effects)).

Ethnicity.

ACE inhibitors cause a higher rate of angioedema in patients of indigenous African origin than in patients of other racial origin. As with other ACE inhibitors, perindopril may be less effective in lowering blood pressure in people of indigenous African origin than in people of other racial origin, possibly because of a higher prevalence of low-renin states in this population. It is unknown if the same observations have been made in patients of indigenous Australian origin.

Cough.

A persistent dry (non-productive) irritating cough has been reported with most of the ACE inhibitors. The frequency of reports has been increasing since cough was first recognised as a class-effect of ACE inhibitor treatment with the incidence of cough varying between 2%-15% depending upon the medicine, dose and duration of use.
The cough is often worse when lying down or at night, and has been reported more frequently in women (who account for two-thirds of the reported cases). Patients who cough may have increased bronchial reactivity compared with those who do not. The observed higher frequency of this side-effect in non-smokers may be due to a higher level of tolerance of smokers to cough.
The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins, which accumulate because of ACE inhibition. Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor; the reaction may recur but this is not invariably the case. A change to another class of drugs may be required in severe cases.

Proteinuria.

Perindopril arginine treatment has occasionally been associated with mild or transient proteinuria (< 1 gram/per 24 hours). However in the majority of patients with pre-existing proteinuria treated with perindopril arginine, proteinuria disappeared or remained stable. ACE inhibitors have potential to delay the progression of nephropathy in patients with diabetes, or hypertension.

Neutropaenia/agranulocytosis/thrombocytopenia/anaemia.

Neutropaenia, agranulocytosis, thrombocytopenia and anaemia have been reported in patients treated with ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropaenia occurs rarely. Perindopril arginine should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic treatment. If perindopril arginine is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever).

Dermatological reactions.

Dermatological reactions characterised by maculo-papular pruritic rashes and sometimes photosensitivity have been reported with another ACE inhibitor. Rare and sometimes severe skin reactions (lichenoid eruptions, psoriasis, pemphigus like rash, rosacea, Stevens-Johnson syndrome etc.) have been reported following administration of perindopril and may therefore occur. A causal relationship is difficult to assess.
Patients who develop a cutaneous reaction with one ACE inhibitor might not when switched to another drug of the same class, but there are reports of cross-reactivity.

Taste disturbances (dysgeusia).

Taste disturbances were reported to be common (prevalence up to 12.5%) with high doses of one ACE inhibitor. The actual incidence of taste disturbance is probably low (< 0.5%) but data are scarce and difficult to interpret.
Taste disturbances with ACE inhibitors have been described as suppression of taste or a metallic sensation in the mouth. Dysgeusia usually occurs in the first weeks of treatment and may disappear in most cases within 1-3 months.

Medicines causing renin release.

The effects of perindopril may be enhanced by concomitant administration of antihypertensive medicines which cause renin release.

Dual blockade of the RAAS.

As a consequence of inhibiting the RAAS, hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicines that affect this system. Dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If dual blockade therapy is considered absolutely necessary, this should be limited to individually defined cases under specialist supervision with frequent close monitoring of renal function, electrolytes and blood pressure.
The combination of perindopril arginine with aliskiren is contraindicated in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m2) (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
ACE inhibitors and angiotensin receptor blockers should not be used in combination in patients with diabetic nephropathy.

Surgery and anaesthesia.

Perindopril arginine may block angiotensin II formation secondary to compensatory renin release in patients undergoing major surgery or during anaesthesia with medicines that produce hypotension, and cause further reduction in blood pressure. Treatment should be discontinued one day prior to the surgery. Perioperative hypotension can be corrected with volume expansion.

Aortic or mitral valve stenosis/ hypertrophic cardiomyopathy.

There has been some concern on theoretical grounds that patients with mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or with hypertrophic cardiomyopathy might be at particular risk of decreased coronary perfusion when treated with vasodilators, including ACE inhibitors. Vasodilators may tend to drop diastolic pressure, and hence coronary perfusion pressure, without producing the concomitant reduction in myocardial oxygen demand that normally accompanies vasodilatation. The true clinical importance of this concern is uncertain.

Stable coronary artery disease.

If an episode of unstable angina pectoris, regardless of severity, occurs during the first month of perindopril treatment, a careful appraisal of the benefits/risks of continuing treatment should be performed.

Primary aldosteronism.

Patients with primary hyperaldosteronism will generally not respond to antihypertensive medicines acting through inhibition of the renin-angiotensin system. Therefore, treatment with perindopril arginine is not recommended.

Use in hepatic impairment.

Biotransformation of perindopril to perindoprilat mainly occurs in the liver. Studies in patients with hepatic impairment have shown that kinetic parameters of perindopril were not modified by hepatic failure. With the exception of bioavailability, which was increased, kinetic parameters of perindoprilat (including Tmax) were also unchanged. The increase in bioavailability could be due to inhibition of the formation of perindopril metabolites other than perindoprilat (see Section 5.2 Pharmacokinetic Properties). The administration of perindopril leads to the formation of a glucuronoconjugate derivative of perindoprilat by a hepatic first-pass effect. The kinetic parameters of perindoprilat glucuronide are not modified by hepatic failure. The small changes in the kinetics of perindoprilat do not justify the need to change the usual dose in most patients with hepatic failure.

Use in renal impairment.

As a consequence of inhibiting the RAAS, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on RAAS activity, treatment with ACE inhibitors may be associated with oliguria and/or progressive increase in blood nitrogen, and rarely with acute renal failure and/or death.
In patients with symptomatic heart failure, hypotension following the initiation of treatment with ACE inhibitors may lead to further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
ACE inhibitors should be avoided in patients with known or suspected renal artery stenosis (see Section 4.3 Contraindications).
In clinical studies in patients with hypertension and unilateral or bilateral renal artery stenosis, increases in blood urea, nitrogen and serum creatinine were observed in 20% of patients. Acute renal insufficiency may occur. These increases are usually reversible upon discontinuation. Renal function may also be reduced in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces the pressure in the afferent glomerular arteriole, and transglomerular hydrostatic pressure is then maintained by angiotensin II-induced constriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration pressure falls, and renal failure may result. ACE inhibitors can lead to the thrombotic occlusion of a stenosed renal artery.
Some patients with hypertension and no apparent pre-existing renovascular disease have developed increases in blood urea, nitrogen and serum creatinine, which are usually minor and transient, particularly when perindopril arginine has been given in combination with a diuretic. However, increases in blood urea, nitrogen and serum creatinine are more likely to occur in patients with pre-existing renal impairment or in those on diuretics. Dose reduction of the ACE inhibitor and/or discontinuation of the diuretic may be required.
Renal function should always be assessed (see Section 4.2 Dose and Method of Administration). In the case of renal impairment, the initial perindopril arginine dose should be adjusted according to the patient's creatinine clearance (see Section 4.2 Dose and Method of Administration). Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see Section 4.2 Dose and Method of Administration). If a deterioration in renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by another and in these patients use of another class of antihypertensive medicine would be preferable. Patients with unilateral renal artery disease present a special problem as deterioration of function may not be apparent from measurement of blood urea and serum creatinine.
Some ACE inhibitors have been associated with the occurrence of proteinuria (up to 0.7%) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium-sparing diuretics or high doses of other diuretics, limited cardiac reserve, or treatment with a non-steroidal anti-inflammatory drug (NSAID).
Perindopril is dialysable with a clearance of 70 mL/min.

Use in the elderly.

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril arginine to elderly patients. The initial dose in the elderly should always be one perindopril arginine 2.5 mg tablet once daily and patients should be monitored closely during the initial stages of treatment (see Section 4.2 Dose and Method of Administration).
In a study of 91 elderly patients with a mean age of 71.9 years, a 6% increase in serum potassium occurred in the first month of treatment and subsequently remained stable. There was no change in the group in blood urea, creatinine or creatinine clearance.
Particular care should be taken in elderly patients with congestive heart failure who have renal and/or hepatic insufficiency.

Paediatric use.

Use of perindopril arginine in children is not recommended as no data establishing safety or effectiveness in children are available.

Effects on laboratory tests.

Increases in blood urea and plasma creatinine, hyperkalaemia reversible on discontinuation may occur, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension. Elevation of liver enzymes and serum bilirubin have been reported rarely.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting medicine (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Combined use which is contraindicated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Aliskiren.

Patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m2), may be at risk of hypotension, syncope, stroke, hyperkalaemia and changes in renal function (including acute renal failure).

Extracorporeal treatments.

Extracorporeal treatments leading to contact of blood with negatively charged surfaces such as dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitrile membranes such as "AN69") and low density lipoprotein apheresis with dextran sulfate are contraindicated due to increased risk of severe anaphylactoid reactions (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use). If such treatment is required, consideration should be given to using a different type of dialysis membrane (e.g. cuprophane or polysulfone PSF) or a different class of antihypertensive medicine.

Sacubitril/valsartan.

The combined use of perindopril arginine with sacubitril/valsartan fixed dose combination is contraindicated as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema. Sacubitril/valsartan fixed dose combinations must not be started until 36 hours after taking the last dose of perindopril arginine. Perindopril arginine must not be started until 36 hours after the last dose of sacubitril/valsartan fixed dose combination (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Combined use not recommended (see Section 4.4 Special Warnings and Precautions for Use).

Aliskiren.

Patients other than those with diabetes or renal impairment may be at risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity, and an increase in mortality (see Section 4.3 Contraindications).

Combined use with ACE inhibitor and angiotensin-receptor blocker.

It is reported in the literature that in patients with established atherosclerosis, heart failure, or diabetes with end organ damage, combined use with an ACE inhibitor and an angiotensin-receptor blocker is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal function (including acute renal failure) as compared to use of a single RAAS medicine. Dual blockade (e.g. by combining an ACE-inhibitor with an angiotensin receptor blocker) should be limited to individually defined cases with close monitoring of renal function, serum potassium, and blood pressure.

Co-trimoxazole (trimethoprim/sulfamethoxazole).

Patients on combined treatment with co-trimoxazole (trimethoprim/sulfamethoxazole) may be at increased risk of hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use).

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. Use of perindopril with lithium is not recommended, but if the combination is necessary, careful monitoring of serum lithium levels should be performed (see Section 4.4 Special Warnings and Precautions for Use).

Potassium sparing diuretics (e.g. triamterene, amiloride, potassium salts).

The combined use of perindopril arginine and potassium sparing diuretics may result in potentially lethal hyperkalaemia especially in patients with renal impairment (additive hyperkalaemic effects). The combination of perindopril with the above-mentioned medicines is not recommended (see Section 4.4 Special Warnings and Precautions for Use). If the combination is required, it should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone and eplerenone in heart failure, see paragraph under 'Combined use which requires special care'.

Combined use which requires special care.

Medicines to treat diabetes (e.g. insulin, oral hypoglycaemic medicines).

Reported with captopril and enalapril. ACE inhibitors may add to the glucose lowering effect, with risk of hypoglycaemia, in patients with diabetes who are treated with insulin or with oral hypoglycaemic medicines. Hypoglycaemia is very rare and appears to be more likely to occur during the first weeks of combined treatment, and in patients with renal impairment.

Baclofen.

Baclofen may increase the antihypertensive effect of perindopril arginine. Monitor blood pressure and adjust the dose of perindopril arginine if necessary.

Non-potassium-sparing diuretics.

Patients treated with diuretics, especially those who are volume and/or salt depleted, may experience excessive reduction in blood pressure after initiation of treatment with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic or by increasing volume or salt intake prior to commencing treatment with low and progressive doses of perindopril arginine. If it is not possible to discontinue the diuretic, the starting dose of the ACE inhibitor should be reduced. The patient should be closely observed for several hours following the initial dose of the ACE inhibitor and until the blood pressure has stabilised. In arterial hypertension, when prior diuretic treatment has caused salt/volume depletion, the diuretic must be discontinued before commencing treatment with the ACE inhibitor. A non-potassium-sparing diuretic can then be reintroduced, or the ACE inhibitor can be commenced at a low dose and progressively increased. In diuretic-treated congestive heart failure, the ACE inhibitor should be initiated at a very low dose, possibly after reducing the dose of the associated non-potassium-sparing diuretic.
In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE inhibitor treatment.

Potassium-sparing diuretics (eplerenone, spironolactone).

As the combination of perindopril and potassium sparing medicines (e.g. eplerenone and spironolactone), potassium supplements or potassium-containing salt substitutes is general not recommended:
Ensure patients do not have hyperkalaemia or renal impairment before commencing treatment with this combination.
There is a risk of potentially lethal hyperkalaemia with this combination in patients treated for NYHA Class II-IV heart failure with a reduced ejection fraction, who have been previously treated with ACE inhibitors and loop diuretics. This risk is particularly high when recommendations for use of this combination have not been followed.
Weekly monitoring of serum potassium and creatinine levels is recommended in the first month of the treatment and, monthly thereafter.

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including acetylsalicylic acid ≥ 3 g/day.

Medicines with prostaglandin synthetase inhibitor properties (e.g. indometacin) or an NSAID (i.e. acetylsalicylic acid at anti-inflammatory dose regimens, non-selective NSAIDs or COX-2 inhibitors) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors. However, clinical studies have not demonstrated any interaction between perindopril arginine and indometacin or other NSAIDs. Combination use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after commencing treatment with the combination, and periodically thereafter.

Ciclosporin.

Hyperkalaemia may occur during the combined use of ACE inhibitors with ciclosporin. Frequent monitoring of serum potassium is recommended.

Heparin.

Hyperkalaemia may occur during the combined use of ACE inhibitors with heparin. Frequent monitoring of serum potassium is recommended.

Combination use of ACE inhibitors, anti-inflammatory medicines and thiazide diuretics.

The combined use of an ACE inhibiting medicine (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products. The combination of medicines from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at initiation.

Mammalian target of rapamycin (mTOR) inhibitor (e.g. temsirolimus, sirolimus, everolimus).

Patients on combined treatment with an ACE inhibitor and an mTOR inhibitor may be at increased risk of angioedema (see Section 4.4 Special Warnings and Precautions for Use).

Gliptins (e.g. linagliptin, saxagliptin, sitagliptin, vildagliptin, alogliptin).

When an ACE inhibitor and a gliptin are used in combination, there is an increased risk of angioedema due to the decreased activity of the dipeptidyl peptidase IV (DPP-IV).

Combined use which requires some care.

Gold.

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients treated with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including perindopril.

Antihypertensive medicines and vasodilators.

Concomitant use of these medicines may increase the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

Tetracycline and other medicines that interact with magnesium.

The simultaneous administration of tetracycline with an ACE inhibitor may significantly reduce the absorption of tetracycline, possibly due to the magnesium content in the ACE inhibitor tablets. This interaction should be considered if co-prescribing an ACE inhibitor and tetracycline or other medicines that interact with magnesium.

Medicines affecting sympathetic activity.

As the sympathetic nervous system plays an important part in physiological blood pressure regulation, caution should be exercised with concomitant administration of a medicine with sympathetic activity and perindopril arginine. Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Tricyclic antidepressants/antipsychotics/anaesthetics.

Combined use of certain anaesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of perindopril arginine on fertility have not been investigated. Studies in rats showed no impairment of male or female fertility at oral perindopril erbumine doses up to 10 mg/kg/day.
(Category D)
The use of ACE inhibitors is contraindicated during pregnancy (see Section 4.3 Contraindications).
As with all ACE inhibitors, perindopril arginine should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with perindopril arginine and avoided during the treatment. Unless continued treatment with an ACE inhibitor is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment. If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
Perindopril or its metabolites have been shown to cross the placenta and distribute to the foetus in pregnant animals. There are no adequate and well-controlled studies of ACE inhibitors in pregnant women, but foetotoxicity is well documented in animal models. Data, however, show that ACE inhibitors cross the human placenta. Post marketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded.
A historical cohort study in over 29,000 infants born to non-diabetic mothers has shown 2.7 times higher risk for congenital malformations in infants exposed to ACE inhibitors during the first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02) respectively, compared to no exposure.
When ACE inhibitors have been used during the second and third trimesters of pregnancy, there have been reports of foetal and neonatal toxicity, hypotension, hyperkalaemia, renal failure, skull hypoplasia, oligohydramnios and death.
Oligohydramnios has been reported, presumably resulting from decreased foetal renal function; oligohydramnios has been associated with foetal limb contractures, craniofacial deformities, hypoplastic lung development and intra-uterine growth retardation. Prematurity and patent ductus arteriosus have been reported, however it is not clear whether these events were due to ACE inhibitor exposure or to the mother's underlying disease.
Infants exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalaemia. Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. If such complications arise, appropriate medical treatment should be initiated to support blood pressure and renal perfusion.
 Animal studies have shown that perindopril and its metabolites are excreted in milk during lactation, but there are no human data. It is therefore recommended that perindopril arginine should not be given to lactating women as the possible effect on the newborn is unknown. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on Ability to Drive and Use Machines

The antihypertensive effect in individual cases may be symptomatic. Treatment with any blood pressure lowering medicine may, therefore, affect the ability to drive, cross the road safely or operate machinery, especially at the start of treatment or when changing over from other preparations, or during combined use of alcohol.

4.8 Adverse Effects (Undesirable Effects)

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors. The most frequent adverse events reported in clinical trials and observed with perindopril are: dizziness, headache, paraesthesia, vertigo, visual disturbances, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, diarrhoea, dysgeusia, dyspepsia, nausea, vomiting, pruritus, rash, muscle cramps, and asthenia.
Adverse events that have been observed during clinical trials and/or post-marketing use of perindopril and ranked under the following frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000 and including isolated reports).

Blood and lymphatic system disorders.

Uncommon: eosinophilia#.
Very rare: decreases in haemoglobin and haematocrit, thrombocytopenia, leukopenia/neutropenia, agranulocytosis or pancytopenia. An unexplained change in prothrombin ratio was reported in one patient. Haemolytic anaemia has been reported in patients with congenital G-6PDH deficiency (see Section 4.4 Special Warnings and Precautions for Use).

Endocrine disorders.

Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders.

Uncommon: hypoglycaemia# (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), hyperkalaemia#, reversible on discontinuation (see Section 4.4 Special Warnings and Precautions for Use), hyponatraemia#.

Psychiatric disorders.

Uncommon: mood disturbances, sleep disorder (insomnia, dream abnormality).
Uncommon: depression#.

Nervous system disorders.

Common: headache, dizziness, drowsiness, vertigo, paresthaesia.
Uncommon: syncope#, somnolence#.
Very rare: confusion, hallucinations.

Eye disorders.

Common: vision disturbance.

Ear and labyrinth disorders.

Common: tinnitus.

Cardiac disorders.

Common: palpitations.
Uncommon: tachycardia#.
Very rare: arrhythmia, angina pectoris (see Section 4.4 Special Warnings and Precautions for Use), myocardial infarction - possibly secondary to excessive hypotension in high-risk patients (see Section 4.4 Special Warnings and Precautions for Use).

Vascular disorders.

Common: hypotension (and effects related to hypotension), vasculitis, flushing, impaired peripheral circulation.
Very rare: stroke - possibly secondary to excessive hypotension in high risk patients (see Section 4.4 Special Warnings and Precautions for Use).
Not known: Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders.

Common: cough, dyspnoea, epistaxis, discomfort on exertion.
Uncommon: bronchospasm.
Very rare: eosinophilic pneumonia, rhinitis.

Gastrointestinal disorders.

Common: nausea, vomiting, abdominal pain, dysgeusia, diarrhoea, dyspepsia, constipation.
Uncommon: dry mouth.
Very rare: pancreatitis.

Hepatobiliary disorders.

Very rare: hepatitis, either cytolytic or cholestatic (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Common: rash, pruritus.
Uncommon: urticaria (see Section 4.4 Special Warnings and Precautions for Use), angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see Section 4.4 Special Warnings and Precautions for Use), hyperhidrosis, photosensitivity reactions#, pemphigoid#, eczema#.
Rare: psoriasis aggravation#.
Very rare: erythema multiforme.

Musculoskeletal and connective tissue disorders.

Common: muscle cramps.
Uncommon: arthralgia#, myalgia#.

Renal and urinary disorders.

Uncommon: renal insufficiency.
Rare: acute renal failure#, anuria/oliguria#.

Reproductive system and breast disorders.

Uncommon: erectile dysfunction.

General disorders and administration site conditions.

Common: asthenia.
Uncommon: sweating, chest pain#, atypical chest pain, malaise#, oedema peripheral#, pyrexia#.

Investigations.

Uncommon: blood urea increased#, blood creatinine increased#.
Rare: blood bilirubin elevation, hepatic enzyme increases.

Injury, poisoning and procedural complications.

Uncommon: fall#.
# Frequency of these adverse events detected from spontaneous reports is calculated from clinical trial data.

Withdrawals.

In total, 56 of 1275 patients studied (4.4%) stopped treatment because of adverse reactions. In a specific study of 632 patients, in which 36 patients (5.7%) withdrew because of adverse events, a plausible or probable relationship with perindopril treatment was considered to exist in 19 cases (3%).

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 http://www.tga.gov.au/reporting-problems and to also contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Limited data are available for overdose in humans. Symptoms associated with overdose of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. The recommended treatment of overdose is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with intravenous catecholamines may also be considered. Perindopril may be removed from the general circulation by haemodialysis (see Section 4.4 Special Warnings and Precautions for Use). Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Perindopril (prodrug), following hydrolysis to perindoprilat, inhibits angiotensin converting enzyme (ACE) both in vitro and in vivo. It is thought that ACE inhibitors reduce blood pressure by inhibiting the enzyme which catalyses the conversion of angiotensin I to angiotensin II. Decreased plasma angiotensin II leads to increased plasma renin activity and a decrease in aldosterone. In addition to its effects on circulating ACE, perindopril arginine binds to and inhibits tissue converting enzyme, predominantly in the kidney and vascular wall. The contribution of this mechanism to the overall antihypertensive effect of perindopril arginine is unknown. Animal studies have demonstrated reversal of vascular hypertrophy and an improvement in the ratio of elastin to collagen in the vessel wall. Studies in man have demonstrated an improvement in the visco-elastic properties of large vessels and in compliance. Studies in animals and humans suggest that specific and competitive suppression of the RAAS is the main mechanism by which blood pressure is reduced. However, antihypertensive activity has also been observed in patients with low renin activity. Perindopril arginine may also inhibit the degradation of the potent vasodepressor peptide, bradykinin, and this action may contribute to its antihypertensive action. Perindopril arginine appears to reduce peripheral resistance and may influence arterial compliance.
Studies carried out in animal models of hypertension have shown that perindopril arginine is a specific competitive angiotensin I converting enzyme inhibitor. The administration of perindopril arginine to patients with essential hypertension results in a reduction in supine and standing blood pressure without any significant effect on heart rate. Abrupt withdrawal of perindopril arginine has not been associated with a rebound rise in blood pressure. Single dose studies have demonstrated that peak inhibition of ACE activity and peak reduction in blood pressure occurs 4-6 hours after administration. The durations of these effects are dose related and at the recommended dose range, both effects have been shown to be maintained over a 24-hour period.
In haemodynamic studies carried out in animal models of hypertension, blood pressure reduction after perindopril arginine administration was accompanied by a reduction in peripheral arterial resistance and improved arterial wall compliance. In studies carried out in patients with essential hypertension the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no change, or a small increase in renal blood flow and no change in glomerular filtration rate. An increase in the compliance of large arteries was also observed. When perindopril arginine is administered together with a thiazide-type diuretic, the antihypertensive activity of perindopril arginine may be potentiated in some patients, and this effect is evident after four weeks of treatment. Perindopril arginine, like other ACE inhibitors, may compensate for thiazide-induced hypokalaemia.
In one study of 48 patients where low-dose perindopril, equivalent to perindopril arginine 2.5 mg, was compared with correspondingly low doses of enalapril (2.5 mg) or captopril (6.25 mg) in patients with congestive heart failure, significantly different blood pressure responses were noted. Blood pressure fell significantly with captopril and enalapril following the first dose. However, whilst perindopril inhibited plasma ACE comparably with enalapril, the blood pressure changes were insignificant and similar to placebo for up to 10 hours of regular observation. Data regarding possibility of a late hypotensive response are not available for perindopril.

Clinical trials.

Patients with stable coronary artery disease.

The effects of perindopril were compared to placebo in patients with stable coronary artery disease with no clinical signs of heart failure. The EUROPA (European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) study was a multicentre, international, randomised, double blind, placebo-controlled clinical trial lasting 4 years. 12,218 patients aged over 18 were randomised: 6,110 patients to high dose perindopril, equivalent to perindopril arginine 10 mg and 6,108 patients to placebo.
The primary endpoint was the composite of cardiovascular mortality, non-fatal myocardial infarction, and/or cardiac arrest with successful resuscitation.
The trial population had evidence of coronary artery disease documented by previous myocardial infarction at least 3 months before screening, coronary revascularisation at least 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain.
Study medication was added to conventional treatment, including medication used for the management of hyperlipidaemia, hypertension and diabetes mellitus. Patients randomised to perindopril were initiated on doses of perindopril equivalent to perindopril arginine 2.5 mg or perindopril arginine 5 mg for 2 weeks, and then titrated up to a dose of perindopril equivalent to perindopril arginine 10 mg during the 2 following weeks. A dose of perindopril equivalent to perindopril arginine 10 mg was then maintained for the whole duration of the study. If this dose was not well tolerated, it could be reduced to a dose of perindopril equivalent to perindopril arginine 5 mg once daily.
Most of the patients also received platelet inhibitors, lipid-lowering medicines and beta-blockers. At the end of the study, the proportions of patients treated with a combination of these medications were 91%, 69% and 63% respectively.
The results of the EUROPA study, specifically the primary endpoint and its components (cardiovascular mortality, non-fatal myocardial infarction or resuscitated cardiac arrest) for the intention-to-treat (ITT) population are presented in Table 2.
The reduction in the primary composite endpoint was mainly due to a reduction in the number of non-fatal myocardial infarctions. There was no significant reduction in the rate of cardiovascular mortality or total mortality in patients taking perindopril compared to those taking placebo.
After a mean follow-up of 4.2 years, treatment with a dose of perindopril equivalent to perindopril arginine 10 mg once daily resulted in a significant relative risk reduction of 20% (95% CI: 9-29) in the primary combined endpoint: 488 patients (8.0%) reported events in the perindopril group compared to 603 patients (9.9%) in the placebo group (p = 0.0003). Improvements in the primary composite endpoint achieved statistical significance after 3 years of continuous treatment on perindopril.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, perindopril arginine is rapidly absorbed with bioavailability of 24%. Elimination is rapid, occurring predominantly via the urine. Plasma half-life is approximately 1 hour. Bioavailability of the active metabolite perindoprilat is approximately 27%.

Distribution.

Peak plasma concentrations of perindoprilat occur 3 to 4 hours after oral administration of perindopril arginine. Protein binding of perindoprilat is 20%, principally to angiotensin converting enzyme. When perindopril arginine is administered chronically, steady state of perindoprilat is reached within 4 days, and perindoprilat does not accumulate.

Metabolism.

Apart from perindoprilat, the administration of perindopril leads to the formation of 5 other metabolites, all of which are inactive and exist in very low quantities. One of these is the glucuronoconjugate of perindoprilat, which is formed by a hepatic first-pass effect. This effect does not appear to have any influence on the kinetics of perindoprilat. Food intake may reduce hepatic biotransformation to perindoprilat.

Excretion.

Perindoprilat binds to plasma and tissue ACE, and free perindoprilat is eliminated through the urine. The terminal half-life of the unbound fraction is approximately 17 hours.
The elimination of perindoprilat is reduced in elderly patients and in patients with cardiac and renal failure (see Section 4.2 Dose and Method of Administration).
In a study comparing this product with the reference product, the two products were shown to be bioequivalent. The 90% confidence intervals for the ratio of AUC0-t and Cmax were found to be between 0.98-1.06 and 0.93-1.15 respectively for perindopril; 0.96-1.02 (AUC72) and 0.91-1.04 per perindoprilat.

5.3 Preclinical Safety Data

Genotoxicity.

Results from a broad set of assays for gene mutation and chromosomal damage with perindopril arginine suggest no genotoxic potential at clinical doses.

Carcinogenicity.

Carcinogenicity studies have not been conducted with perindopril arginine.
No evidence of carcinogenic activity was observed in mice and rats when perindopril erbumine was administered via drinking water at levels up to 7.5 mg/kg/day for 2 years. At least one ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential of ACE inhibitors to cause this effect in man is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when it does occur, it is considered to be benign.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains the following inactive ingredients: isomalt; colloidal anhydrous silica; magnesium stearate; hypromellose; hyprolose; macrogol 8000; titanium dioxide; 5 mg and 10 mg tablets contain brilliant blue FCF aluminium lake and 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 25°C. Protect from moisture.

6.5 Nature and Contents of Container

APO-Perindopril Arginine tablets.

2.5 mg tablets.

Blister packs (aluminium/aluminium) of 30 and 100 tablets (AUST R 184819).

5 mg tablets.

Blister packs (aluminium/aluminium) of 30 and 100 tablets (AUST R 184814).

10 mg tablets.

Blister packs (aluminium/aluminium) of 30 and 100 tablets (AUST R 184809).
Not all strengths, pack types and/or pack sizes may be available.
APO is a registered trade mark of Apotex Inc.

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

Perindopril is a dipeptide monoacid monoester with a perhydroindole group and no sulphydryl radical. Perindopril arginine is a white powder, readily soluble in purified water, slightly soluble in 95% ethanol and practically insoluble in chloroform. Perindopril has five asymmetric centres and is synthesised stereoselectively so that it is a single enantiomer (all S stereochemistry).

Chemical structure.


Chemical Name: (2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1- [Ethoxycarbonyl)butyl]amino]propanoyl] octahydro-1H-indole-2- carboxylic acid, L-arginine salt.
Molecular Formula: C19H32N2O5, C6H14N4O2.
Molecular Weight: 542.669.

CAS number.

612548-45-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes