Consumer medicine information

Perindopril Arginine Sandoz

Perindopril arginine

BRAND INFORMATION

Brand name

Perindopril Arginine Sandoz

Active ingredient

Perindopril arginine

Schedule

SUMMARY CMI

PERINDOPRIL ARGININE SANDOZ

Consumer Medicine Information (CMI) summary

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

1. Why am I using PERINDOPRIL ARGININE SANDOZ?

PERINDOPRIL ARGININE SANDOZ contains the active ingredient perindopril arginine. Perindopril belongs to a group of medicines called angiotensin converting enzyme (ACE) inhibitors. PERINDOPRIL ARGININE SANDOZ is used to lower high blood pressure, treat heart failure or coronary artery disease. For more information, see Section 1. Why am I using PERINDOPRIL ARGININE SANDOZ? in the full CMI.

2. What should I know before I use PERINDOPRIL ARGININE SANDOZ?

Do not use if you have ever had an allergic reaction to perindopril, any other ACE inhibitor 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 or plan to breastfeed.
For more information, see Section 2. What should I know before I use PERINDOPRIL ARGININE SANDOZ? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PERINDOPRIL ARGININE SANDOZ 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 use PERINDOPRIL ARGININE SANDOZ?

The dose of PERINDOPRIL ARGININE SANDOZ 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 use PERINDOPRIL ARGININE SANDOZ? in the full CMI.

5. What should I know while using PERINDOPRIL ARGININE SANDOZ?

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.
Driving or using machines	Take care when driving or operating machinery until you know how PERINDOPRIL ARGININE SANDOZ 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 in a cool dry place away from moisture, heat, and sunlight. Keep your tablets in the pack until it is time to take them. Keep out of reach of children. Keep the container tightly closed.

For more information, see Section 5. What should I know while using PERINDOPRIL ARGININE SANDOZ? 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 PERINDOPRIL ARGININE SANDOZ 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 PERINDOPRIL ARGININE SANDOZ. 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 PERINDOPRIL ARGININE SANDOZ – 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

PERINDOPRIL ARGININE SANDOZ

Active ingredient(s): perindopril arginine

Consumer Medicine Information (CMI)

This leaflet answers some common questions about PERINDOPRIL ARGININE SANDOZ. It does not contain all the available information. It does not take the place of talking to your doctor, pharmacist or nurse. If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

All medicines have risks and benefits. Your doctor has weighed the risks of taking PERINDOPRIL ARGININE SANDOZ against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor, pharmacist or nurse.

Keep this leaflet with the medicine. You may need to read it again.

Where to find information in this leaflet:

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

1. Why am I using PERINDOPRIL ARGININE SANDOZ?

The name of your medicine is PERINDOPRIL ARGININE SANDOZ.

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

PERINDOPRIL ARGININE SANDOZ is available only with a doctor's prescription.

PERINDOPRIL ARGININE SANDOZ 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. PERINDOPRIL ARGININE SANDOZ helps lower your blood pressure.

You may be prescribed PERINDOPRIL ARGININE SANDOZ 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.

PERINDOPRIL ARGININE SANDOZ 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 PERINDOPRIL ARGININE SANDOZ 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, PERINDOPRIL ARGININE SANDOZ has been shown to reduce some of the risks, including heart attacks.

2. What should I know before I use PERINDOPRIL ARGININE SANDOZ?

Warnings

There are some people who shouldn't take PERINDOPRIL ARGININE SANDOZ. Please read the list below. If you think any of these situations apply to you or you have any questions, please consult your doctor.

Do not use PERINDOPRIL ARGININE SANDOZ if:

You are allergic to perindopril, 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 use 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 PERINDOPRIL ARGININE SANDOZ, 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 have an intolerance to some sugars as PERINDOPRIL ARGININE SANDOZ contains lactose.
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 PERINDOPRIL ARGININE SANDOZ 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

PERINDOPRIL ARGININE SANDOZ can generally be used 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.

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

Some medications used to treat high blood pressure (including angiotensin receptor blockers), aliskiren (see also ‘Do not use PERINDOPRIL ARGININE SANDOZ 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 use PERINDOPRIL ARGININE SANDOZ 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 use PERINDOPRIL ARGININE SANDOZ 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 PERINDOPRIL ARGININE SANDOZ. Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking PERINDOPRIL ARGININE SANDOZ.

4. How do I use PERINDOPRIL ARGININE SANDOZ?

How much to take / use

The dose of PERINDOPRIL ARGININE SANDOZ 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 / use PERINDOPRIL ARGININE SANDOZ

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

If you forget to use PERINDOPRIL ARGININE SANDOZ

PERINDOPRIL ARGININE SANDOZ should be used 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.

How long to take it

PERINDOPRIL ARGININE SANDOZ helps control your blood pressure, or heart failure or coronary artery disease but does not cure it. Continue taking the tablets for as long as your doctor tells you.

If you use too much PERINDOPRIL ARGININE SANDOZ

If you think that you have used too much PERINDOPRIL ARGININE SANDOZ, you may need urgent medical attention.

Taking too much PERINDOPRIL ARGININE SANDOZ (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 using PERINDOPRIL ARGININE SANDOZ?

Things you should do

Take PERINDOPRIL ARGININE SANDOZ exactly as your doctor has prescribed. Otherwise you may not get the benefits from treatment.

Tell all healthcare professionals who are involved with your treatment that you are taking PERINDOPRIL ARGININE SANDOZ.

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 PERINDOPRIL ARGININE SANDOZ.

Angioedema (a severe allergic reaction) has been reported in patients treated with ACE inhibitors, including PERINDOPRIL ARGININE SANDOZ. 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 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

Things you should not do

Do not give PERINDOPRIL ARGININE SANDOZ to anyone else, even if they have the same condition as you.
Do not use PERINDOPRIL ARGININE SANDOZ to treat other complaints unless your doctor tells you to.
Do not stop taking PERINDOPRIL ARGININE SANDOZ 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 PERINDOPRIL ARGININE SANDOZ affects you.

Take care when driving or operating machinery until you know how PERINDOPRIL ARGININE SANDOZ 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

Heat and dampness can destroy some medicines.

Keep your tablets in the pack until it is time to take them.

Keep them in a cool, dry place where it stays below 30°C.

Do not store it in a bathroom, near a sink, in a car or on windowsills.

Keep the container tightly closed.

Keep it where children cannot reach it.

When to discard your medicine

Do not use this medicine after the expiry date.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking PERINDOPRIL ARGININE SANDOZ, 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 PERINDOPRIL ARGININE SANDOZ then tell your doctor or pharmacist as soon as possible.

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

PERINDOPRIL ARGININE SANDOZ helps most people with high blood pressure, heart failure or coronary artery disease, but it may have unwanted side effects in a few people. While these side effects when they occur are usually mild they can be serious.

Serious side effects

Serious side effects

What to do

Angioedema (a severe allergic reaction) has been reported in patients treated with ACE inhibitors, including PERINDOPRIL ARGININE SANDOZ. This may occur at any time during treatment. If you develop such symptoms described below you should tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital. These side effects are extremely rare but can become serious:
Respiratory and heart

Difficulty in breathing
A fast and irregular heartbeat

Skin

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

What to do

Gastrointestinal

Nausea, vomiting, taste disturbances, indigestion, diarrhoea, constipation, stomach pain or discomfort
Inflammation of the pancreas (pancreatitis)

Mouth

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

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

High levels in the blood of potassium, urea and/or creatine
Low sodium levels in the 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

Hypotension
Vasculitis
Flushing
Impaired peripheral circulation
Stroke
Discolouration, numbness and pain in fingers or toes (Raynaud's phenomenon)

Musculoskeletal

Muscle cramps
Chest pain
Aching muscles, muscle tenderness or weakness, not caused by exercise
Joint pain

Nervous system

Headache, dizziness, vertigo, pins and needles
Mood disturbance, sleep disturbances (difficulty sleeping, abnormal dreams), feeling sleepy or drowsy, fainting
Confusion or hallucinations

Skin

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

Vision disturbances
Tinnitus (persistent noise in the ears)
Runny or blocked nose, sneezing, facial pressure or pain
Nose bleeds

Reproductive system

Erectile dysfunction

General

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.

Consult your doctor, pharmacist or nurse if you experience any of these or notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them. Other uncommon side effects have been reported and you should ask your doctor, pharmacist or nurse if you want to know more.

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 PERINDOPRIL ARGININE SANDOZ contains

Active ingredient (main ingredient)	PERINDOPRIL ARGININE SANDOZ 2.5 contains 2.5 mg of perindopril arginine PERINDOPRIL ARGININE SANDOZ 5 contains 5 mg of perindopril arginine PERINDOPRIL ARGININE SANDOZ 10 contains 10 mg of perindopril arginine
Other ingredients (inactive ingredients)	Lactose monohydrate Magnesium stearate Maltodextrin Hydrophobic colloidal anhydrous silica Sodium starch glycollate (type A) Macrogol 6000 All tablet coatings include: Glycerol Hypromellose Titanium dioxide The inactive ingredient specific to: PERINDOPRIL ARGININE SANDOZ 5 is: premix for light-green colour coating [chlorophyllin-copper complex] PERINDOPRIL ARGININE SANDOZ 10 is: premix for green colour coating [chlorophyllin-copper complex]
Potential allergens	Lactose monohydrate

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

What PERINDOPRIL ARGININE SANDOZ looks like

PERINDOPRIL ARGININE SANDOZ 2.5 are white round convex film-coated tablets containing 2.5 mg of perindopril arginine.

(Tablet image not actual size)

PERINDOPRIL ARGININE SANDOZ 5 are light-green rod-shaped film-coated tablets engraved with a Servier logo on one face and scored on both edges containing 5 mg of perindopril arginine.

(Tablet image not actual size)

PERINDOPRIL ARGININE SANDOZ 10 are green round biconvex film-coated tablets with a Servier logo on one face and a heart on the other face containing 10 mg of perindopril arginine.

(Tablet image not actual size)

Thirty (30) tablets are supplied in a white bottle containing desiccants and equipped with a white child-resistant screw-on cap.

PERINDOPRIL ARGININE SANDOZ is registered on the Australian Register of Therapeutic Goods.

Australian Register Number:

PERINDOPRIL ARGININE SANDOZ 2.5: AUST R 407295

PERINDOPRIL ARGININE SANDOZ 5: AUST R 407296

PERINDOPRIL ARGININE SANDOZ 10: AUST R 407297

Who distributes PERINDOPRIL ARGININE SANDOZ

PERINDOPRIL ARGININE SANDOZ is distributed in Australia by:

Sandoz Pty Ltd
100 Pacific Highway
North Sydney NSW 2060
Phone: 1800 726 369

This leaflet was prepared in November 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Perindopril Arginine Sandoz

Active ingredient

Perindopril arginine

Schedule

Notes

Distributed by Sandoz Pty Ltd

1 Name of Medicine

Perindopril arginine.

2 Qualitative and Quantitative Composition

Perindopril Arginine Sandoz 2.5 mg.

Each tablet contains 2.5 mg perindopril arginine.

Perindopril Arginine Sandoz 5 mg.

Each tablet contains 5 mg perindopril arginine.

Perindopril Arginine Sandoz 10 mg.

Each tablet contains 10 mg perindopril arginine.

Excipient with known effect.

Contains sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Perindopril Arginine Sandoz 2.5 mg is a white, round, convex, film-coated tablet.
Perindopril Arginine Sandoz 5 mg is a light-green, rod-shaped, film-coated tablet engraved with a Servier logo on one face and scored on both edges.
Perindopril Arginine Sandoz 10 mg is a green, round, biconvex film-coated tablet with a Servier logo on one face and a heart logo on the other face.

4 Clinical Particulars

4.1 Therapeutic Indications

Perindopril Arginine Sandoz is indicated for:
the treatment of hypertension;
the treatment of heart failure. In such patients it is recommended that Perindopril Arginine Sandoz be given with a diuretic and/or digoxin under close medical supervision. (The safety and efficacy of Perindopril Arginine Sandoz 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) 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

Hypertension.

The usual starting dose is one Perindopril Arginine Sandoz 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 Sandoz 10 mg tablet once daily.
A starting dose of one Perindopril Arginine Sandoz 2.5 mg tablet once daily 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 Sandoz to patients under current treatment 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 Sandoz 2.5 mg tablet once daily, with titration to one Perindopril Arginine Sandoz 5 mg tablet once daily 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 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 Sandoz should be initiated under close medical supervision.
The usual starting dose is one Perindopril Arginine Sandoz 2.5 mg tablet once daily which should be given with a diuretic and/or digitalis. This is increased to one Perindopril Arginine Sandoz 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 Sandoz 5 mg tablet once daily for two weeks, and then increased to one Perindopril Arginine Sandoz 10 mg tablet once daily, depending on tolerance and renal function.
Elderly patients should receive one Perindopril Arginine Sandoz 2.5 mg tablet once daily for one week, then one Perindopril Arginine Sandoz 5 mg tablet once daily the next week, before increasing the dose up to one Perindopril Arginine Sandoz 10 mg tablet once daily depending on tolerance and renal function (see Patients with renal impairment, Table 1).

Elderly patients.

Patients with renal impairment.

In patients with renal failure, treatment should be initiated with one Perindopril Arginine Sandoz 2.5 mg tablet once daily. The dose should be adjusted as indicated below (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 Sandoz be taken before meals.

4.3 Contraindications

Perindopril Arginine Sandoz is contraindicated:
In patients with a history of previous hypersensitivity to the active ingredient perindopril, ACE-inhibitors or any of the excipient ingredients present in Perindopril Arginine Sandoz.
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 Sandoz 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.

Patients with 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 Sandoz (see Section 4.8 Adverse Effects (Undesirable Effects)). This may occur at any time during treatment. In such cases Perindopril Arginine Sandoz 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 Sandoz 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 Sandoz. If treatment with sacubitril/valsartan fixed dose combinations is stopped, Perindopril Arginine Sandoz 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 Sandoz with NEP inhibitors, mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus, everolimus, temsirolimus) 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 haemodyalysis.

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 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. polyacrylonitril membranes such as ''AN69'') are contraindicated. 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 medicines (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Anaphylactic reactions during desensitisation.

Patients treated with 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 re-challenge.

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 Sandoz 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 in 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 Sandoz 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 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 Sandoz and/or the diuretic is increased. In all high-risk patients it is advisable to initiate treatment with one Perindopril Arginine Sandoz 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 Sandoz. 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 Sandoz 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 Sandoz 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 medicines may be required in severe cases.

Proteinuria.

Perindopril Arginine Sandoz 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 Sandoz, 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 an ACE inhibitor. In patients with normal renal function and no other complicating factors, neutropaenia occurs rarely. Perindopril Arginine Sandoz should be used with extreme caution in patients with collagen vascular disease, immunosuppressant treatment, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing renal impairment. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic treatment. If Perindopril Arginine Sandoz 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 medicine 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 one to three 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 renin-angiotensin-aldosterone system (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 Sandoz 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 Sandoz may block angiotensin II formation secondary to compensatory renin release in patients undergoing major surgery or during anaesthesia with agents 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.

Lactose intolerance.

Perindopril Arginine Sandoz tablets contain lactose. Patients with an intolerance to lactose, rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 Sandoz 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 T_max) 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 with unilateral or bilateral renal artery stenosis, increases in blood urea, nitrogen and serum creatinine were observed in 20% of patients. Acute renal insufficiency may also 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 with 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 Sandoz 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 Sandoz 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 agent 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, combined use with potassium-sparing diuretics or high doses of other diuretics, limited cardiac reserve or treatment with a non-steroidal anti-inflammatory medicine (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 Sandoz to elderly patients. The initial dose of Perindopril Arginine Sandoz should always be one Perindopril Arginine Sandoz 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 Sandoz 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 renin-angiotensin-aldosterone-system (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 agent (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

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. polyacrylonitril 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 agent.

Sacubitril/valsartan.

The combined use of Perindopril Arginine Sandoz with sacubitril/valsartan fixed dose combinations 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 Sandoz. Perindopril Arginine Sandoz 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).

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 agent. 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 the combined use of lithium with ACE inhibitors. Combined 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 Sandoz 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 Combined medicines which require 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 Sandoz. Monitor blood pressure and adjust the dose of Perindopril Arginine Sandoz 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 Sandoz. 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 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 Sandoz 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 blocker), an anti-inflammatory medicine (NSAID or COX-2 inhibitor) and a thiazide diuretic 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 combined ACE inhibitor treatment including perindopril.

Antihypertensive medicines and vasodilators.

Combined use of these medicines may increase the hypotensive effects of perindopril. Combined 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 combined administration of a medicine with sympathetic activity and Perindopril Arginine Sandoz. 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 Sandoz should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Perindopril Arginine Sandoz 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.
The ACE inhibitor class has 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 mothers without diabetes 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 Sandoz should not be given to lactating women as the possible effect on the newborn is unknown. Alternative treatments with better established safety profiles during breast-feeding 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 agent 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)

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.
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. The following adverse effects (see Table 2) have been observed during clinical trials and/or post-marketing use with perindopril and ranked under the following frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000 and including isolated reports).

Withdrawals.

In total, 56 of 1,275 patients (4.4%) studied 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%).

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
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.

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 Sandoz 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 Sandoz 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 renin-angiotensin-aldosterone system (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 Sandoz may also inhibit the degradation of the potent vasodepressor peptide, bradykinin, and this action may contribute to its antihypertensive action. Perindopril Arginine Sandoz appears to reduce peripheral resistance and may influence arterial compliance.
Studies carried out in animal models of hypertension have shown that Perindopril Arginine Sandoz is a specific competitive angiotensin I converting enzyme inhibitor. The administration of Perindopril Arginine Sandoz 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 Sandoz 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 four to six 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 Sandoz 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 Sandoz is administered together with a thiazide-type diuretic, the antihypertensive activity of Perindopril Arginine Sandoz may be potentiated in some patients, and this effect is evident after four weeks of treatment. Perindopril Arginine Sandoz, like other ACE inhibitors, may compensate for thiazide-induced hypokalaemia.
In one study of 48 patients in which low-dose perindopril equivalent to Perindopril Arginine Sandoz 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 ten 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 four years. 12,218 patients aged over 18 were randomised: 6,110 patients to high dose perindopril, equivalent to Perindopril Arginine Sandoz 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 three months before screening, coronary revascularisation at least six 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. Patients randomised to perindopril were initiated on doses of perindopril equivalent to Perindopril Arginine Sandoz 2.5 mg or Perindopril Arginine Sandoz 5 mg for two weeks, and then titrated up to a dose of perindopril equivalent to Perindopril Arginine Sandoz 10 mg during the two following weeks. A dose of perindopril equivalent to Perindopril Arginine Sandoz 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 Sandoz 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 medicines 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 3.

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 Sandoz 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 three years of continuous treatment on perindopril.

5.2 Pharmacokinetic Properties

Absorption.

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

Distribution.

Peak plasma concentrations of perindoprilat occur three to four hours after oral administration of Perindopril Arginine Sandoz. Protein binding of perindoprilat is 20%, principally to angiotensin converting enzyme. When Perindopril Arginine Sandoz is administered chronically, steady-state perindoprilat concentration is reached within four days, and perindoprilat does not accumulate.

Metabolism.

Apart from perindoprilat, the administration of perindopril leads to the formation of five 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).

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.

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 two 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 the ACE inhibitor class to cause this effect in man is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when this occurs, it is considered as benign.

6 Pharmaceutical Particulars

6.1 List of Excipients

Perindopril Arginine Sandoz 2.5 mg.

The tablets contain hydrophobic colloidal silica anhydrous, lactose monohydrate, macrogol 6000, magnesium stearate, maltodextrin, sodium starch glycollate, glycerol, hypromellose, titanium dioxide.

Perindopril Arginine Sandoz 5 mg and Perindopril Arginine Sandoz 10 mg.

The tablets contain hydrophobic colloidal silica anhydrous, lactose monohydrate, macrogol 6000, magnesium stearate, maltodextrin, sodium starch glycollate, glycerol, hypromellose, titanium dioxide and chlorophyllin-copper complex.

6.2 Incompatibilities

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

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store in a dry place below 30°C.

6.5 Nature and Contents of Container

The tablets are supplied in a white HDPE bottle equipped with a white-induction sealed, and HDPE child resistant-closure and desiccant sachets.
Bottle of 30 tablets (all strengths).

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 active component of Perindopril Arginine Sandoz is perindopril arginine which has the chemical name, L-arginine (2S,3aS,7aS)-1-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino] propanoyl]octahydro-1H-indole-2-carboxylate. Perindopril is a dipeptide monoacid monoester with a perhydroindole group and no sulfydryl 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.

CAS number.

612548-45-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

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