Consumer medicine information

Perindopril and Indapamide-GH 4/1.25

Perindopril erbumine; Indapamide hemihydrate

BRAND INFORMATION

Brand name

Perindopril and Indapamide-GH 4/1.25

Active ingredient

Perindopril erbumine; Indapamide hemihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Perindopril and Indapamide-GH 4/1.25.

What is in this leaflet

This leaflet answers some common questions about Perindopril and Indapamide-GH 4/1.25 mg tablets. It does not contain all the available information about this medicine. Reading this leaflet does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Perindopril and Indapamide-GH 4/1.25 mg tablets against the expected benefits for you.

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

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

What Perindopril and Indapamide-GH 4/1.25 is used for

The name of your medicine is Perindopril and Indapamide-GH 4/1.25 mg tablets. The medicine contains the active ingredients perindopril erbumine and indapamide hemihydrate. Perindopril belongs to a group of medicines called angiotensin converting enzyme (ACE) inhibitors. Indapamide belongs to a group of medicines called diuretics (a type of “water” tablet).

You have been prescribed Perindopril and Indapamide-GH 4/1.25 mg tablets for high blood pressure.

Perindopril and Indapamide-GH 4/1.25 mg tablets are available only with a doctor's prescription.

There is no evidence that Perindopril and Indapamide-GH 4/1.25 mg tablets are addictive.

Why Perindopril and Indapamide-GH 4/1.25 mg tablets 4/1.25 mg is used for high blood pressure

Everyone has blood pressure. This pressure helps to circulate blood all around the body. Your blood pressure may be different at different times of the day, depending on how busy or stressed you are.

You have high blood pressure (also known as hypertension) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

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 and Indapamide-GH 4/1.25 mg tablets help to lower your blood pressure.

Ask your doctor if you have any questions about why Perindopril and Indapamide-GH 4/1.25 mg tablets has been prescribed for you.

Before you take Perindopril and Indapamide-GH 4/1.25

There are some people who should not take Perindopril and Indapamide-GH 4/1.25 mg tablets. Please read the lists below. If you think any of these situations apply to you, or you have any questions, please consult your doctor or pharmacist.

Do not take Perindopril and Indapamide-GH 4/1.25 mg tablets if:

  • You are allergic to perindopril, indapamide, or any of the other ingredients of Perindopril and Indapamide-GH 4/1.25 mg tablets listed at the end of this leaflet.
  • You are allergic to sulphonamide (sulpha) antibiotics, or to thiazide diuretics (a type of fluid" or "water" tablet).
  • You are allergic to another angiotensin converting enzyme (ACE) inhibitor.
  • You are pregnant or trying to become pregnant.
  • You are breastfeeding or plan to breastfeed.
  • You undergo treatments where your blood pressure 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 a patient’s 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 suffering from decreases in the amount, or absence of, urine produced by the kidney.
  • You have narrowing of the main blood vessel leading from the heart and/or heart valve.
  • You have low blood potassium.
  • You have severe liver disease or suffer from a condition called hepatic encephalopathy (degenerative disease of the brain that occurs as a result of liver disease).
  • You have experienced serious swelling of the face, tongue, lips or throat either suddenly or in response to another medicine in the past (a rare allergic condition known as angioedema).
  • You are treated with sacubitril/valsartan a medicine used to treat long-term heart failure (see also 'Tell Your Doctor Straight Away' and 'Taking Other Medicines' sections).
  • The packaging is damaged or shows signs of tampering, or the tablets do not look quite right.
  • The expiry date (EXP) on the pack has passed.

Before you start to take it

Tell your doctor straight away if:

  • You are pregnant or become pregnant while taking Perindopril and Indapamide-GH 4/1.25 mg tablets, as it may cause serious harm to your unborn baby.
  • You have a severe allergic reaction with swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (angioedema). This may occur at any time during treatment. If you develop such symptoms, you should stop taking Perindopril and Indapamide-GH 4/1.25 mg tablets and see a doctor immediately (see also 'Side Effects' section).
  • You are undergoing desensitisation treatment, or have had an allergic reaction during previous desensitisation treatment (eg. 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 undergoing anaesthesia and/or surgery.
  • You are undergoing a medical test that requires injection of an iodinated contrast agent (a substance that makes organs like the kidney or stomach visible on an X-ray).
  • 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 and Indapamide-GH 4/1.25 mg contains lactose.
  • You are of African origin since you may have a higher risk of angioedema and this medicine is less effective in lowering your blood pressure.
  • 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;
    - sacubitril (available as fixed-dose combination with another medicine valsartan), used to treat long-term heart failure;
    - aliskiren.
  • You have any other health problems, including:
    - Kidney disease or if you are on renal dialysis.
    - Liver disease.
    - High or low levels of potassium, sodium, or other problems with salt balance.
    - Diabetes.
    - Gout.
    - Heart disease.
    - Hardening of the arteries.
    - Hyperparathyroidism (overactive parathyroid gland).
    - Photosensitivity reactions (increased sensitivity of the skin to sun).
    - Systemic lupus erythematosus or scleroderma (a disease affecting the skin, joints and kidneys).
    - Abnormally increased levels of a hormone called aldosterone in your blood (primary aldosteronism).
    - If you experience a decrease in vision or eye pain. These could be symptoms of fluid accumulation in the vascular layer of the eye or an increase of pressure in your eye and can happen within hours to a week of taking Perindopril and Indapamide-GH 4/1.25 mg tablets. This can lead to permanent vision loss, if not treated.
    - If you earlier have had a penicillin or sulphonamide allergy, you can be at higher risk of developing this.
    - Muscle disorders including muscle pain, tenderness, weakness or cramps.

Taking other medicines

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

Taking Perindopril and Indapamide-GH 4/1.25 mg tablets may change the effect of some medicines, and some medicines may affect how well Perindopril and Indapamide-GH 4/1.25 mg tablets work. You may need different amounts of your medication or to take different medicines. The medicines that may interact with Perindopril and Indapamide-GH 4/1.25 mg tablets include the following:

  • Some steroid medicines.
  • Diuretics (sometimes called 'fluid' or 'water' tablets because they increase the amount of urine passed each day, eg. amiloride, spironolactone, triamterene).
  • Medicines used for heart rhythm problems (eg. quinidine, hydroquinidine, disopyramide, amiodarone, sotalol, flecainide).
  • Some medications used to treat high blood pressure (including angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers), aliskiren (see also “Do not take Perindopril and IndapamideGH 4/1.25 mg tablets if” and “Tell you doctor straight away” sections),
  • Some treatments where your blood is treated outside of the body, also known as extracorporeal treatments (see also “Do not take Perindopril and Indapamide-GH 4/1.25 mg tablets if” and “Tell you doctor straight away” sections).
  • Some antibiotic and medicines used to treat infections (eg. trimethoprim, moxifloxacin).
  • Medicines used to treat fungal disease (eg. Amphotericin B by injection, fluconazole).
  • Tetracosactide (to treat Crohn's disease).
  • Some anti-inflammatory medicines (including high dose aspirin, ibuprofen) for pain relief.
  • Some anaesthetic medicines.
  • Medicines used to treat mental illnesses such as some medicines for epilepsy, anxiety, schizophrenia and some other antidepressants (eg. lithium, tricyclic antidepressants, antipsychotics, drugs, neuroleptics such as: droperidol, haloperidol, chlorpromazine, trifluoperazine, amisulpride, sulpiride, psychoanaleptics).
  • Antiparasitic medicines used to treat certain types of malaria (eg. chloroquine).
  • Pentamidine (a medicine used to treat certain types of pneumonia).
  • Antihistamines used to treat allergic reactions, such as hay fever.
  • Medicines used to treat nausea and vomiting (eg. ondansetron, domperidone).
  • Medicines used to treat gastrointestinal problems (eg. cisapride, papaverine).
  • Potassium-sparing diuretics (eg. spironolactone, triamterene), sources of potassium, like potassium tablet and salt substitutes containing potassium, other drugs which can increase potassium in your body (such as heparin and cotrimoxazole also known as trimethoprim/ sulfamethoxazole).
  • Medicines used to treat cancer (eg. vandetanib, oxaliplatin) or to suppress the immune system (eg. cyclosporin, tacrolimus).
  • Non-steroidal anti-inflammatory drugs for pain relief (eg. ibuprofen) or high doses of aspirin.
  • Vasodilators including nitrates.
  • Medicines used to treat diabetes (eg. metformin, gliptins and insulin).
  • 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 (eg. ephedrine, noradrenaline or adrenaline).
  • Gold salts, especially with intravenous administration (used to treat symptoms of rheumatoid arthritis).
  • Medicines which may affect the blood cells, such as allopurinol, procainamide.
  • 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 (eg. temsirolimus, sirolimus, everolimus).
    - Sacubitril (available as fixed-dose combination with valsartan), used to treat long-term heart failure (see also 'Do Not Take Perindopril and Indapamide-GH 4/1.25 mg tablets if' and 'Tell Your Doctor Straight Away' sections).
  • Iodinated contrast agent used in certain medical tests.
  • Methadone (a medicine used to treat severe pain or opioid addiction).
  • Digoxin or other cardiac glycosides (for the treatment of heart problems).
  • Calcium supplements.
  • Stimulant laxatives (eg. senna).
  • Medicines used to treat bacterial infections (eg. moxifloxacin, ciprofloxacin, clarithromycin.
  • Allopurinol (a medicine used to treat gout).
  • Cilostazol (used to treat cramp like pain in the legs when you walk).

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Perindopril and Indapamide-GH 4/1.25 mg tablets.

For older people or children

  • Elderly people can generally use Perindopril and Indapamide-GH 4/1.25 mg tablets safely. However, some older people have reduced kidney function - in which case additional care may be required.
  • Perindopril and Indapamide-GH 4/1.25 mg tablet is not recommended for use in children and adolescents.

How to take Perindopril and Indapamide-GH 4/1.25

Follow all directions given to you by your doctor and pharmacist carefully. If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

Your doctor will select a dose when they prescribe Perindopril and Indapamide-GH 4/1.25 mg tablets for you. The usual dose is one tablet once daily.

How to take it

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

How long to take it

Perindopril and Indapamide-GH 4/1.25 mg tablets can help to control your blood pressure, but cannot cure this condition. Perindopril and Indapamide-GH 4/1.25 mg tablets treatment is usually for life -so you should keep taking the tablets regularly unless advised otherwise by your doctor.

If you forget to take it

  • If your next usual dose is less than 6 hours away, just leave out the dose that you missed. Take the next dose at the usual time and continue as normal.
  • If your next dose is more than 6 hours away, take the dose you have missed as soon as you realise. Then take the next dose at the usual time and continue as normal.

Do not try to make up for missed doses by taking more than one dose at a time.

If you take too much (overdose)

Taking too much Perindopril and Indapamide -GH 4/1.25 mg tablets (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. If this happens, lying down with the legs elevated can help. Other effects like, nausea, vomiting, cramps, sleepiness, confusion, changes in the amount of urine produced by the kidney are possible. You may require urgent medical attention.

If you think that you or anyone else may have taken too much Perindopril and Indapamide-GH 4/1.25 mg tablets then act immediately: Telephone your doctor or the Poisons Information Centre (13 11 26 in Australia; 0800 764 766 in New Zealand), or go to the Accident and Emergency department at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

While you are taking Perindopril and Indapamide-GH 4/1.25

Things you must do

Take Perindopril and Indapamide-GH 4/1.25 mg tablets 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 Perindopril and Indapamide-GH 4/1.25 mg tablets.

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 and Indapamide-GH 4/1.25 mg tablets.

Things you must not do

Do not give this medicine to anyone else, even if they have the same condition as you. Do not use Perindopril and Indapamide-GH 4/1.25 mg tablets to treat any other complaints unless your doctor tells you to.

Do not stop taking Perindopril and Indapamide-GH 4/1.25 mg tablets or change the dose, without checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how Perindopril and Indapamide-GH 4/1.25 mg tablets affects you. You may feel light-headed or dizzy when you begin to take Perindopril and Indapamide-GH 4/1.25 mg tablets. This is because your blood pressure is falling. If you have these symptoms when standing up or getting out of bed then getting up more slowly can help. This allows your body to get used to the change in position and blood pressure.

If you have these symptoms and they don't get better in a short time then talk to your doctor.

Side effects

If you do not feel well while you are taking Perindopril and Indapamide-GH 4/1.25 mg tablets 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 and Indapamide-GH 4/1.25 mg tablets help most people with high blood pressure, but it may sometimes have unwanted side effects in few people. While these side effects when they occur are usually mild they can be serious.

Stop taking Perindopril and Indapamide-GH 4/1.25 mg tablets and see a doctor immediately, if you experience any of the following side effects that can be serious:

  • Dizziness becoming severe or fainting induced by low blood pressure.
  • Difficulty breathing or wheezing, tightening of the chest. (Uncommon).
  • Angioedema (a severe allergic reaction) has been reported in patients treated with ACE inhibitors, including Perindopril and Indapamide-GH 4/1.25 mg tablets. 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. Swelling of your extremities (limbs, hands or feet), lips, face, mouth, tongue or throat. (Uncommon).
  • 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) (Very rare).
  • Painful red areas, developing large blisters and peeling of layers of skin. This is accompanied by fever and chills (a condition known as Toxic Epidermal Necrolysis or TEN). (Very rare).
  • 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 (a condition known as Erythema Multiforme). (Very rare).
  • Stroke (signs include weakness of arms or legs or problems speaking). (Very rare).
  • Heart disorders such as a fast and irregular heartbeat, heart attack, angina pectoris (a feeling of tightness, pressure or heaviness in the chest). (Very rare).
  • Inflammation of the pancreas (Pancreatitis). (Very rare).
  • Liver disease (Hepatitis) characterised by yellowing of the skin or eyes (jaundice). (Very rare).
  • Life-threatening irregular heart beat (Torsades de pointes). (Frequency not known).
  • Disease of the brain caused by liver illness (Hepatic encephalopathy) (Frequency not known).
  • Muscle spasms, tenderness, pain or weakness and particularly, if at the same time, you feel unwell or have a high temperature it may be caused by an abnormal muscle breakdown (frequency not known).

The above side effects are categorised into the following frequencies:

  • Common - may affect up to 1 in 10 people
  • Uncommon - may affect up to 1 in 100 people
  • Rare - may affect up to 1 in 1,000 people
  • Very rare - may affect up to 1 in 10,000 people
  • Not known - frequency cannot be estimated from the data available.

Talk to your doctor or pharmacist or nurse if you notice any of the following side effects, some of which are usually only identified after blood tests:

Common (may affect up to 1 in 10 people) side effects can include:

  • Cough, often described as dry and irritating, shortness of breath, discomfort on exertion.
  • Nosebleeds.
  • Headache, dizziness, vertigo, pins and needles.
  • Feeling tired or weak.
  • Tinnitus (persistent noise in the ears), vertigo, vision impairment.
  • Low blood pressure (and related effects), flushing, impaired peripheral circulation, vasculitis.
  • Nausea, vomiting, taste disturbances, indigestion, diarrhoea, constipation, stomach pain or discomfort.
  • Dry mouth.
  • Decreased appetite.
  • Muscle spasms.
  • Muscle tenderness or weakness.
  • Rash, pruritus (itching), red raised skin rash.
  • Hypersensitivity reactions, mainly skin reactions, in patients with allergies and asthmatic reactions.

Uncommon (may affect up to 1 in 100 people) side effects can include:

  • High levels in the blood of potassium, urea and/or creatine.
  • Low sodium (salt) levels in the blood.
  • Altered mood, sleep disorder (difficulty sleeping, abnormal dreams), feeling sleepy or drowsy, fainting.
  • Anxiety.
  • Bronchitis, upper respiratory tract infection.
  • Back pain.
  • Gastrointestinal inflammation.
  • Excessive sweating.
  • Increased sensitivity of the skin to sun, skin rash or inflammation of the skin often including blisters that weep and become crusted.
  • Pemphigoid - a skin disease usually affecting older people.
  • Increase in some white blood cells.
  • Erectile dysfunction, libido disorder.
  • Fever or high temperature.
  • Chest pain.
  • Fast heartbeat.
  • Palpitations (awareness of your heartbeat).
  • Abnormal ECG heart tracing.
  • Abnormal kidney function.
  • Polyuria - increased urination.
  • Cystitis - an infection of the bladder.
  • Decreased blood sugar levels.
  • Worsening of pre-existing Lupus Erythematosus.
  • Aching muscles, not caused by exercise, Joint pain.
  • Generally feeling unwell or lethargic.
  • Falls.
  • Vasculitis (inflammation of blood cells).
  • Impaired peripheral circulation.
  • Syncope - fainting not associated with seizures or trauma.

Rare (may affect up to 1 in 1,000 people) side effects can include:

  • Elevation of bilirubin levels in the blood, increases in liver enzymes.
  • Elevated calcium levels in the blood.
  • Worsening of psoriasis.

Very rare (may affect up to 1 in 10,000 people) side effects can include:

  • Abnormal liver function.
  • Kidney failure.
  • Eosinophilic pneumonia.
  • Runny or blocked nose, sneezing, facial pressure or pain.
  • 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.
  • Changes in the rhythm or rate of the heartbeat.
  • Confusion, depression or hallucinations.

Not known (frequency cannot be estimated from the data available):

  • Myopia, blurred vision.
  • Low potassium levels.
  • Blood glucose increased.
  • Blood uric acid increased.
  • Discolouration, numbness and pain in fingers or toes (Raynaud’s phenomenon).
  • Decrease in vision or pain in your eyes due to high pressure (possible signs of fluid accumulation in the vascular layer of the eye or acute angle closure glaucoma).

Other:

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.

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

Most of these side effects are mild when they occur. 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.

Changes may occur in your laboratory parameters (blood tests) and your doctor may need to give you blood tests to check your condition. The following changes in laboratory tests may occur low potassium in the blood, low sodium in the blood (that may lead to dehydration and low blood pressure), increase in uric acid (a substance which may cause or worsen gout), increase in blood glucose levels in diabetic patients, increased levels of liver enzymes.

After taking Perindopril and Indapamide-GH 4/1.25

Storage

Keep your Perindopril and Indapamide-GH 4/1.25 mg tablets where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your tablets in the pack until it is time to take them. Perindopril and Indapamide-GH 4/1.25 mg tablets will not keep as well outside its blister packaging.

Heat and dampness can destroy some medicines.

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

Do not store medicines in a bathroom or near a sink.

Do not leave them in a car or on a windowsill.

Disposal

If your doctor tells you to stop taking Perindopril and Indapamide-GH 4/1.25 mg tablets, or the tablets have passed their expiry date, return any leftover tablets to your pharmacist for disposal.

Product description

What it looks like

Perindopril erbumine and Indapamide hemihydrate tablets 4 mg/1.25 mg are white to off-white; capsule shaped uncoated tablets, plain on both sides containing.

Perindopril erbumine Ph Eur 4.0 mg and Indapamide Ph Eur 1.22 mg equal to Indapamide hemihydrate 1.25mg.

Perindopril and Indapamide-GH 4/1.25 mg tablets come in a blister strip. Each box contains 30 tablets.

Ingredients

Active ingredient

Each tablet of Perindopril and Indapamide-GH 4/1.25 mg tablets contains:

  • 4 mg of perindopril erbumine; and
  • 1.25 mg of indapamide hemihydrate.

Other ingredients

  • microcrystalline cellulose;
  • lactose monohydrate;
  • magnesium stearate; and
  • hydrophobic colloidal silica anhydrous.

Australian Registration Numbers

Perindopril and Indapamide-GH 4/1.25 mg tablets:
AUST R 147149.

Distributor

Generic Health Pty Ltd
Suite 2, Level 2
19-23 Prospect Street
Box Hill, VIC, 3128
Australia

Email: [email protected]
Telephone: +61 3 9809 7900
Website: www.generichealth.com.au

This leaflet was prepared in July 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

Perindopril and Indapamide-GH 4/1.25

Active ingredient

Perindopril erbumine; Indapamide hemihydrate

Schedule

S4

 

Notes

Distributed by Generic Health Pty Ltd

1 Name of Medicine

Perindopril erbumine and indapamide hemihydrate.

2 Qualitative and Quantitative Composition

Perindopril and Indapamide GH 4/1.25 mg tablets containing perindopril erbumine 4 mg and indapamide hemihydrate 1.25 mg.

List of excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Perindopril and Indapamide GH 4/1.25 mg tablets are white to off-white; capsule shaped uncoated tablets, plain on both sides.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypertension.

Treatment should not be initiated with this combination.

4.2 Dose and Method of Administration

Note that Perindopril and Indapamide-GH is not available in a 2/0.625 mg strength. Other brands should be used if this dose strength is required.
One Perindopril and Indapamide GH 4/1.25 tablet per day as a single dose, preferably to be taken in the morning.

Elderly patients.

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril-containing medicines to elderly hypertensive patients.
The initial dose in the elderly should always be one tablet of the perindopril 2 mg/indapamide 0.625 mg fixed dose combination product daily, and patients should be monitored closely during the initial stages of treatment.
Particular care should be taken in elderly patients with congestive heart failure who have renal and/or hepatic insufficiency (see Section 4.4 Special Warnings and Precautions for Use).

Patients with renal insufficiency.

In cases of severe renal insufficiency (creatinine clearance below 30 mL/min), the treatment is contraindicated.
In patients with moderate renal insufficiency (creatinine clearance 30-60 mL/min), the maximum dose should be one tablet of the perindopril 2 mg/indapamide 0.625 mg fixed dose combination product per day.
In patients with a creatinine clearance greater than or equal to 60 mL/min, no dose adaptation is required.
Normal medical practice includes periodic control for creatinine and potassium.

Patients with hepatic impairment.

In severe hepatic impairment, treatment is contraindicated. In patients with moderate hepatic impairment, no dose modification is required.

4.3 Contraindications

Perindopril and Indapamide GH 4/1.25 is contraindicated:

Relating to Perindopril and Indapamide GH 4/1.25.

In patients with a history of previous hypersensitivity to either of the active ingredients, perindopril or indapamide, or excipient ingredients present in Perindopril and Indapamide GH 4/1.25 mg tablets.
During pregnancy and for lactating women.
In patients with severe renal insufficiency (creatinine clearance below 30 mL/min).
Due to the lack of sufficient therapeutic experience, perindopril and indapamide tablets should not be used in:
patients with severe untreated decompensated heart failure;
patients on dialysis.

Related to perindopril component.

In patients with a history of previous hypersensitivity to the active ingredient perindopril, or to ACE inhibitor.
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 sulphate 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 polysulphone PSF) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In combination 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).
In combination with sacubitril/valsartan fixed dose combinations (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Related to indapamide component.

In patients with a history of hypersensitivity to indapamide or any other sulphonamide derivatives.
In patients with severe renal impairment.
In patients with anuria.
In patients with progressive and severe oliguria.
In patients in a hepatic coma.
In patients with hepatic encephalopathy.
In patients with severe hepatic impairment.
In patients with hypokalaemia.
In combination with non-antiarrhythmic agents causing Torsades de pointes.

4.4 Special Warnings and Precautions for Use

Related to perindopril and indapamide 4/1.25 mg tablets.

Specific precautions relating to the use of perindopril and indapamide 4/1.25 mg tablets are the same as those which apply to the separate components of the combination. Consequently, caution should be observed when it is administered in patients with renal impairment and the risk of hypotension and electrolyte imbalance should be borne in mind (see precautions specific to perindopril and indapamide; see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use). Due to the possibility of an increased risk of idiosyncratic reactions following the combined use of two antihypertensives, careful monitoring of patients is recommended.

Use in renal impairment.

Use of perindopril and indapamide 4/1.25 mg tablets are contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
Perindopril and indapamide 4/1.25 mg tablets are not recommended in patients with bilateral renal artery stenosis or a single functioning kidney.
Treatment with perindopril and indapamide 4/1.25 mg tablets should be stopped and possibly restarted with either one tablet of perindopril 2 mg/ indapamide 0.625 mg fixed dose combination or with either indapamide or perindopril only in hypertensive patients whose blood tests show functional renal insufficiency. In these patients usual medical follow-up should include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal failure including renal artery stenosis.

Fluid and electrolyte imbalance.

Patients should be monitored for signs and symptoms of fluid or electrolyte imbalance; namely hyponatraemia, hypochloraemia, hyperuricaemia, hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use) and hypokalaemia (see Section 4.4 Special Warnings and Precautions for Use). Plasma, urea and uric acid levels should also be monitored during treatment. Gout has been reported rarely. Tendency for gout attacks may be increased in patients with hyperuricaemia. The clinical features of electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, gastrointestinal disturbances such as nausea and vomiting, tachycardia and ECG changes.

Potassium levels.

The combination of perindopril and indapamide does not prevent the onset of hypokalaemia particularly in patients with diabetes or in patients with renal failure. As with any antihypertensive agent in combination with a diuretic, regular monitoring of plasma potassium levels should be carried out.

Lactose intolerance.

Perindopril and indapamide 4/1.25 mg tablets contain lactose. Patients with an intolerance to lactose, rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Hypotension and water and electrolyte depletion.

As there is a risk of sudden hypotension in the presence of pre-existing sodium depletion, particularly in those with renal artery stenosis, routine monitoring for clinical signs of water and electrolyte depletion which may occur concurrently with diarrhoea or vomiting is recommended. Regular monitoring of plasma electrolytes should be carried out in such patients.

Marked hypotension may require an intravenous infusion of isotonic saline.

Treatment with perindopril and indapamide 4/1.25 mg tablets should be stopped in patients with transient hypotension and possibly restarted, following re-establishment of a satisfactory blood volume and blood pressure, with either one tablet of perindopril 2 mg/ indapamide 0.625 mg fixed dose combination or with either perindopril or indapamide only.

Lithium.

The combination of lithium with perindopril or indapamide is not recommended. Diuretics should not be given with lithium because they reduce its renal clearance and add a high risk of lithium toxicity (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Related to perindopril component.

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. Serum electrolytes (including sodium, potassium and urea) should be measured from time to time when ACE inhibitors are given, 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 with potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, 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, aspirin ≥ 3 g/day, COX-2 inhibitors and other non-selective NSAIDS, immunosuppressant agents such as cyclosporine or tacrolimus, co-trimoxazole also known as trimethoprim/sulfamethoxazole). Combined use of the above-mentioned medicines should be used with caution in combination with ACE inhibitors. Frequent monitoring of serum potassium (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In some patients, hyponatraemia may coexist 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). Patients with insulin-dependent diabetes mellitus (spontaneous tendency for hyperkalaemia) should be monitored closely during the initial stages of treatment. Treatment should be initiated with a reduced dose.

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 not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Angioedema.

ACE inhibitors should not be used in patients with a history of angioedema related to any other medicine as patients with a history of angioedema unrelated to ACE inhibitor treatment may be at increased risk of angioedema while receiving 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 with ACE inhibitors and has been reported uncommonly with perindopril (see Section 4.8 Adverse Effects (Undesirable Effects)). This may occur at any time during treatment. In such cases treatment 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 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, ultrasound or during 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.
Patients on combined treatment with a Mammalian target of rapamycin (mTOR) inhibitor (e.g. temsirolimus, sirolimus, everolimus) may be at 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).
The combination of perindopril and indapamide 4/1.25 mg tablets 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 and indapamide 4/1.25 mg tablets. If treatment with sacubitril/valsartan fixed dose combinations is stopped, perindopril and indapamide 4/1.25 mg tablets 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 combination of other NEP inhibitors and perindopril and indapamide 4/1.25 mg tablets may also increase the risk of angioedema (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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

Rarely, patients treated with ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate 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. polyacrylonitrile 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 polysulphone PSF) or a different class of antihypertensive medicine (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 use in patients with salt/volume depletion, for example, in patients vigorously treated with diuretics, on dialysis, with renal impairment, following severe diarrhoea or vomiting, on dietary restrictions, or in those with severe renin-dependent hypertension (see Section 4.8 Adverse Effects (Undesirable Effects)).
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.
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 is increased. In all high risk patients it is advisable to initiate treatment with one tablet of the perindopril 2 mg/indapamide 0.625 mg fixed dose combination product.
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with perindopril. This is anticipated and is usually not a reason to discontinue treatment. If symptomatic hypotension occurs, a reduction of dose or discontinuation 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.

Use in renal impairment.

As a consequence of inhibiting the renin-angiotensin-aldosterone system (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 impairment may also occur. These increases are usually reversible upon discontinuation of treatment. 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 has been combined 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 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 4.8 Adverse Effects (Undesirable Effects)). 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).
Anaemia has been observed in patients who have had a kidney transplant or have been undergoing dialysis. The reduction in haemoglobin levels is more apparent as initial values were high. This effect does not seem to be dose-dependent but may be linked to the mechanism of action of angiotensin converting enzyme inhibitors. This reduction in haemoglobin is slight, occurs within 1 to 6 months, and then remains stable. It is reversible when treatment is stopped. Treatment can be continued with regular haematological testing.
Perindopril is dialysable with a clearance of 70 mL/min.

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 contributing 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 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 receiving 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)).

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). 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.

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.

Cardiac failure/severe cardiac insufficiency (grade IV).

Patients with severe cardiac insufficiency (grade IV) should be monitored closely during the initial stages of treatment. Treatment should be initiated with a reduced dose.
Treatment with beta-blockers in hypertensive patients with coronary insufficiency should not be stopped. When initiating, the ACE inhibitor should be added to the beta-blocker.

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 depending upon the ACE inhibitor, dosage 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 2/3 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 an 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 monotherapy 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, 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 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 renal impairment. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic treatment. If perindopril 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 high (up to 12.5%) with high doses of one ACE inhibitor. The actual incidence of taste disturbance is probably low (< 0.5%) but data is 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 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 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 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 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 vasodilation. 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 and indapamide 4/1.25 mg tablet is not recommended.

Related to indapamide component.

Water and electrolyte balance.

Hypovolaemia, resulting from the loss of water and sodium caused by the diuretic at the start of treatment, causes a reduction in glomerular filtration. It may result in an increase in urea and creatinine levels. This transitory functional renal insufficiency is of no adverse consequence in patients with normal renal function but may however worsen pre-existing renal impairment.

Plasma sodium.

This must be measured before starting treatment and then subsequently at regular intervals as treatment with any diuretic may cause hyponatraemia, sometimes with very serious consequences. The decrease in plasma sodium may initially be asymptomatic. Regular monitoring is therefore essential, and should be more frequent in the elderly and in patients with cirrhosis (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose). Hyponatraemia with hypovolaemia may be responsible for dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis.

Plasma potassium.

Potassium depletion with hypokalaemia is the major risk of thiazide and related diuretics. Hypokalaemia may cause muscle disorders. Cases of Rhabdomyolysis have been reported, mainly in the context of severe hypokalaemia. The risk of onset of hypokalaemia (< 3.4 mmol/L) must be prevented in certain high risk populations, i.e. the elderly, malnourished and/or polymedicated, cirrhotic patients with oedema and ascites, and patients with coronary artery disease and/or heart failure. In these patients, hypokalaemia increases the cardiac toxicity of digitalis preparations and increases the risk of arrhythmias. Hypokalaemia will be more common when combined with a steroid or adrenocorticoptropic (ACTH) treatment and when electrolyte intake is inadequate. Individuals with a long QT interval, whether the origin is congenital or iatrogenic, are also at increased risk as hypokalaemia and bradycardia, are predisposing factors to the onset of severe arrhythmias, in particular, potentially fatal Torsades de pointes. Plasma potassium should be measured in the first week of treatment. More frequent monitoring of plasma potassium is required in all the situations indicated above. Hypokalaemia, if detected, should be corrected.

Plasma calcium.

Diuretic treatment should be withdrawn before the investigation of parathyroid function. Thiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in calcium. Frank hypercalcaemia may be due to previously unrecognised hyperparathyroidism.

Impaired hepatic function/hepatic encephalopathy.

When liver function is impaired, thiazide and thiazide-related diuretics may cause, particularly in case of electrolyte imbalance, hepatic encephalopathy which can progress to hepatic coma. Caution should be used in treating patients with severe hepatic disease to avoid metabolic alkalosis in cases of potassium depletion, which may precipitate episodes of hepatic encephalopathy. Treatment with the diuretic must be stopped immediately if this occurs.

Orthostatic hypotension.

Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, narcotics or concurrent treatment with other antihypertensives. When indapamide is combined with other non-diuretic antihypertensive agents, the effects on blood pressure are additive.

Lupus erythematosus.

Sulphonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus. Serious allergic skin reactions (such as Stevens-Johnson syndrome) have also occasionally been reported associated with sulphonamides. This should be considered when using indapamide.

Photosensitivity.

Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a readministration of the diuretic is deemed necessary, it is recommended that areas exposed to the sun or to artificial UVA are protected.

Use in renal impairment.

Although indapamide can safely be administered to hypertensive patients with renal impairment, treatment should be discontinued if increases in blood nitrogen and oliguria occur. Studies in functionally anephric patients on indapamide monotherapy for one month undergoing chronic haemodialysis have not shown evidence of accumulation, despite the fact that indapamide is not dialysable. Thiazide diuretics and thiazide-related diuretics are only fully effective when renal function is normal or only slightly impaired (creatinine levels lower than approximately 25 mg/L, i.e. 220 micromol/L for an adult).

Blood glucose.

Monitoring of blood glucose is important in patients with diabetes, in particular in the presence of hypokalaemia.

Athletes.

Perindopril and indapamide 4/1.25 mg tablets contain indapamide which may give a positive result in doping tests.

Choroidal effusion, acute myopia and secondary angle-closure glaucoma.

Sulfonamide, or sulphonamide derivatives such as indapamide can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma.
Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide and penicillin allergy.

Use in the elderly.

Renal impairment is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril-containing medicines to elderly hypertensive patients. The initial dose in the elderly should always be one tablet of the perindopril 2 mg/ indapamide 0.625 mg fixed dose combination product daily, and patients should be monitored closely during the initial stages of treatment (see Section 4.2 Dose and Method of Administration).
In the elderly the value of plasma creatinine levels should be adjusted to take account of the age, weight and sex of the patient.
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 and indapamide 4/1.25 mg tablets in children is not recommended as no data establishing safety or effectiveness in children are available.

Effects on laboratory tests.

Potassium depletion with particularly serious reduction in levels of potassium in some at risk populations.
Reduced sodium levels with hypovolaemia causing dehydration and orthostatic hypotension.
Increase in uric acid levels and in blood glucose levels during treatment.
Slight increase in urea and in plasma creatinine levels, reversible when treatment is stopped. This increase is more frequent in cases of renal artery stenosis, arterial hypertension treated with diuretics, renal insufficiency.
Increased levels of potassium, usually transitory.
Elevation of liver enzymes and serum bilirubin have been reported rarely.
Rarely, raised plasma calcium levels have been noted.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The combined use of perindopril and indapamide in perindopril and indapamide tablets 4/1.25 mg is not associated with additional interactions with concomitant medicines other than those known for each of these components.

Shared by perindopril and indapamide.

Combined use which is not recommended.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during combined administration 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 combined with indapamide 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).

Combined use which requires special care.

Baclofen.

Increased antihypertensive effect. It is recommended that hydration and renal function be monitored at the start of treatment. Monitoring of blood pressure, renal function and adequate hydration is recommended with dose adaptation of the antihypertensive to occur if necessary.

Non-steroidal anti-inflammatory medicines (NSAIDs) including aspirin ≥ 3 g/day.

Medicines with prostaglandin synthetase inhibitor properties (e.g. indomethacin) 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 and indapamide 4/1.25 mg tablets or indomethacin or other NSAIDS. Treatment with an NSAID 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. Due to the risk of acute renal failure in patients with dehydration as a result of decreased glomerular filtration, it is recommended that hydration and renal function be monitored at the start of treatment, and periodically thereafter.

Combined use which requires some care.

Tricyclic antidepressants/ antipsychotics/ anaesthetics.

Combined use of certain anaesthetic medicines, 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).

Other antihypertensive agents.

Combined use of other antihypertensive agents may increase hypotensive effects.

Related to perindopril component.

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 heart 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).

Medicines inducing hyperkalaemia.

The ACE inhibitor class can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with an ACE inhibitor. The combined use of an ACE inhibitor with a potassium-sparing diuretic (e.g. spironolactone, triamterene, amiloride), immunosuppressant (e.g. cyclosporin), trimethoprim, angiotensin receptor blocker, NSAID, heparin, potassium supplement, or potassium-containing salt substitute can increase the risk of hyperkalaemia. The combination of perindopril with the above mentioned medicines is not recommended (see Section 4.4 Special Warnings and Precautions for Use). If combined use is indicated they should be used with caution and the patient's serum potassium should be monitored frequently.

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, worsening of renal function (including acute renal failure) and cardiovascular morbidity and mortality increase (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

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 sulphate 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 polysulphone PSF) or a different class of antihypertensive agent.

Sacubitril/valsartan.

The combination of perindopril and indapamide 4/1.25 mg tablets 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 and indapamide 4/1.25 mg tablets. Perindopril and indapamide 4/1.25 mg therapy 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 which is 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 4.4 Special Warnings and Precautions for Use).

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 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.

Potassium sparing diuretics (amiloride, spironolactone, triamterene).

The combined use of perindopril and indapamide 4/1.25 mg tablets 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 'Related to perindopril component, Combined use which requires special care'.

Allopurinol, cytostatic or immunosuppressant agents, corticosteroids (main route) or procainamide.

Combination with ACE inhibitors may lead to an increased risk for leucopaenia.

Co-trimoxazole (trimethoprim/sulfamethoxazole).

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

Combined use which requires special care.

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

Concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic medicines) may cause an increased blood-glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment.

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 and indapamide tablets. 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. The ACE inhibitor must be commenced at a low dose and progressively increased prior to a non-potassium-sparing diuretic being commenced. 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 generally 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.

Combined 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).

Combined use which requires some care.

Antihypertensive agents 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.

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

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).

Medicines affecting sympathetic activity.

As the sympathetic nervous system plays an important part in physiological blood pressure regulation, caution should be exercised when combined administration of a medicine with sympathetic activity and perindopril and indapamide 4/1.25 mg tablets. Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Gold.

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

Aspirin, thrombolytics, beta-blockers, nitrates.

Perindopril may be combined with thrombolytics, aspirin (when used as a thrombolytic), beta-blockers and/or nitrates.

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.

Related to indapamide component.

No interactions have been reported between indapamide, anticoagulants and uricosurics however it is recommended that these products not be used in combination with a diuretic agent since the combination may produce hypokalaemia and hyperuricaemia.

Combined use which requires special care.

Torsades de pointes inducing medicines.

The combined use of indapamide and Torsades de pointes-inducing medicines, is not recommended due to the increased risk of ventricular arrhythmias and hypokalaemia. Medicines which can induce Torsades de pointes include (but are not limited to):
class Ia antiarrhythmic agents (e.g. disopyramide) and class Ic antiarrhythmic agents (e.g. flecainide);
class III antiarrhythmic agents (e.g. amiodarone, sotalol);
some antipsychotics: phenothiazines (e.g. chlorpromazine, trifluoperazine), benzamides (e.g. amisulpride, sulpiride), butyrophenones (e.g. droperidol, haloperidol) and other antipsychotics;
psychoanaleptic (eg. donepezil);
some antidepressants (e.g. citalopram, escitalopram);
antimicrobial agents: fluoroquinolones (e.g. moxifloxacin, ciprofloxacin), macrolides (e.g. erythromycin IV, clarithromycin), azole antifungals (e.g. fluconazole);
antiparasitics (e.g. chloroquine, pentamidine);
antihistamines;
antiemetics (e.g. ondansetron, domperidone);
antineoplastic and immunomodulating agents (e.g. vandetanib, oxaliplatin, anagrelide);
anaesthetics (e.g. propofol, sevoflurane);
others, diphemanil, methadone, papaverine, cilostazol.
This list is indicative and not exhaustive. While not recommended, if combination of indapamide and a Torsades de pointes-inducing medicine is deemed necessary, hypokalaemia should be monitored (using plasma electrolytes and ECG) and corrected if required, before using indapamide and a Torsades de pointes-inducing medicine in combination.

Potassium-lowering medicines: amphotericin B (IV route), glucocorticoids and mineralocorticoids (systemic route), tetracosactide, stimulant laxatives.

Due to the increased risk of hypokalaemia (additive effect): monitoring, and correction if required, of plasma potassium (especially during treatment with digoxin) is recommended; the use of non-stimulant laxatives is recommended.

Digoxin.

Monitoring of plasma potassium and ECG is recommended due to the increased risk of hypokalaemia following co-administration of indapamide and digoxin.

Allopurinol.

Combined use with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.

Combined use which requires some care.

Potassium sparing diuretics (amiloride, spironolactone, triamterene).

Due to the increased risk of either hyperkalaemia or hypokalaemia, particularly in patients with renal failure or diabetes, care should be taken when co-administering potassium-sparing diuretics. Potassium levels and ECG should be monitored and, if necessary, treatment reviewed.

Metformin.

Do not combine with metformin when plasma creatinine exceeds 15 mg/L (135 micromol/L) in men and 12 mg/L (110 micromol/L) in women due to the increased risk of metformin-induced lactic acidosis as a result of the possibility of functional renal failure associated with diuretics, particularly loop diuretics.

Iodinated contrast media.

Adequate hydration before administration of the iodinated compound is recommended due to an increased risk of acute renal failure resulting from dehydration, particularly when large doses of iodinated contrast media are used.

Calcium (salts).

Caution is recommended with these combination due to the risk of hypercalcaemia resulting from decreased urinary elimination of calcium.

Immunosuppressants (cyclosporin, tacrolimus).

Caution is recommended with this combination due to the risk of increased plasma creatinine without any change in circulating cyclosporin levels, even in the absence of water/ sodium depletion.

Corticosteroids (systemic route), tetracosactide.

Caution is recommended with this combination due to the risk of reduced antihypertensive effect (water/sodium retention due to corticosteroids).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of the combination on fertility has not been investigated.

Related to perindopril component.

Studies in rats showed no impairment of male or female fertility at oral perindopril doses up to 10 mg/kg/day.

Related to indapamide component.

A reproductive toxicity study in rats showed no impairment of male or female fertility at oral indapamide doses up to 25 mg/kg/day, however, the number of implantation sites was reduced at the highest dose. In animals treated with oral doses of indapamide, a reduction in the number of implantation sites was seen at 25 mg/kg/day.
(Category D)
As this combination contains an ACE inhibitor, perindopril and indapamide 4/1.25 mg tablets is contraindicated during pregnancy (see Section 4.3 Contraindications).

Related to perindopril/indapamide.

Reproductive toxicity studies in rats and rabbits showed evidence of increased maternal toxicity and increased embryotoxicity (including delayed foetal development and embryonic deaths) when perindopril and indapamide are given in combination than when each of the medicines is given separately.

Related to perindopril component.

The use of ACE-inhibitors is contra-indicated during pregnancy (see Section 4.3 Contraindications).
As with all ACE inhibitors, perindopril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with perindopril 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 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 intrauterine 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.

Related to indapamide component.

Indapamide should be avoided in pregnant women and should not be used to treat oedema in pregnancy.
There are limited data with the use of indapamide in pregnant women. Prolonged exposure to thiazides during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause foetal-placental ischaemia and growth retardation.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
Indapamide or its metabolites have been shown to cross the placenta and distribute in the foetus in pregnant animals. Thiazides, related diuretics and loop diuretics enter the foetal circulation and may cause electrolyte disturbances. Neonatal thrombocytopaenia has been reported with thiazides and related diuretics. Loop diuretics like frusemide and bumetanide are probably also associated with this risk. During the latter part of pregnancy products of this type should only be given on sound indications, and then in the lowest effective dose.
Thiazides, related diuretics and loop diuretics enter the foetal circulation and may cause electrolyte disturbances. Neonatal thrombocytopaenia has been reported with thiazides and related diuretics. Loop diuretics like frusemide and bumetanide are probably also associated with this risk. During the latter part of pregnancy medicines of this type should be used with caution and at the lowest effective dose.
 Perindopril and indapamide 4/1.25 mg tablets are contraindicated during lactation. A decision, taking into account the importance of this treatment for the mother, should therefore be made whether to discontinue nursing or to discontinue perindopril and indapamide 4/1.25 mg tablets.

Related to perindopril component.

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 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.

Related to indapamide component.

Indapamide should not be used during breastfeeding (see Section 4.3 Contraindications). Indapamide is excreted in human breast milk and the possible effect on the newborn is unknown and cannot be excluded. Indapamide is closely related to thiazide diuretics which have been associated with decrease in, or even suppression of, lactation. Serious adverse reactions might occur in nursing infants such as hypersensitivity to sulphonamide-derived medicines, hypokalaemia and nuclear icterus.

4.7 Effects on Ability to Drive and Use Machines

Neither of the two active substances nor the combination affect alertness but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication. As a result the ability to drive or operate machinery may be impaired.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects have generally been mild and transient and have not required discontinuation of treatment. In controlled clinical trials, discontinuation of treatment due to clinical adverse effects was required in only 2.1% of patients treated with both the combination or placebo. The administration of perindopril inhibits the renin-angiotensin-aldosterone axis and tends to reduce the potassium loss caused by indapamide. During clinical trials a reduction in potassium levels to less than 3.4 mmol/L was observed in 4% of patients taking an equivalent dose to perindopril and indapamide 4/1.25 mg tablets for 12 weeks. After 12 weeks of treatment, the mean reduction in potassium levels was 0.20 mmol/L. In a long term study involving 165 patients treated with a dose of perindopril and indapamide equivalent to perindopril and indapamide 4/1.25 mg tablets for up to one year, the nature and frequency of adverse effects were similar to those listed below.
The most frequent treatment-emergent adverse effects (incidence > 1%) reported in 3-month controlled clinical trials including a total of 1,898 patients treated with a dose of perindopril and indapamide equivalent to either perindopril and indapamide 4/1.25 mg tablets or perindopril 2 mg/ indapamide 0.625 mg and 717 patients treated with placebo were as follows (see Table 1).

Tabulated list of adverse effects observed during clinical trials and/or post-marketing use.

The following adverse effects (see Table 2) have been observed during clinical trials and/or post-marketing use and ranked under the following frequency:
Very common (> 10%); common (> 1%, < 10%); uncommon (> 0.1%, < 1%); rare (> 0.01%, < 0.1%), very rare (> 0.001%, < 0.01%), not known (cannot be estimated from the available data).

Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases of SIADH have been reported with other ACE inhibitors. SIADH can be considered as a very rare but possible complication associated with ACE inhibitor therapy including perindopril and indapamide 4/1.25.

Reporting suspected adverse effects.

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

4.9 Overdose

The most likely adverse event in cases of overdose is hypotension, with the possibility of nausea, vomiting, cramps, dizziness, sleepiness, mental confusion, polyuria or oliguria which may progress to anuria (due to hypovolaemia). Salt and water disturbances (low sodium levels, low potassium levels) may occur. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. If hypotension occurs, the patient should be placed in the shock position. The recommended treatment of overdosage is intravenous infusion of normal saline solution. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously. Perindoprilat, the active form of perindopril may be removed from the general circulation by haemodialysis (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
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 and indapamide 4/1.25 mg tablets are a combination of perindopril erbumine, an angiotensin converting enzyme (ACE) inhibitor, and indapamide, a chlorosulphamoyl diuretic, in which the doses of the ACE inhibitor and diuretic components are lower than the usual doses used for monotherapy. Its pharmacological properties are derived from each of its components, in addition to those due to the synergistic action of the two products when combined on vascular endothelium and the target-organs of hypertension, with:
an increase in vasorelaxation and a reduction in vasoconstriction, which are endothelium-dependent;
a regression in renal effects (glomerulosclerosis, proteinuria), myocardial effects (left ventricular hypertrophy) and a reduction in capillary density.
Perindopril and indapamide 4/1.25 mg tablets exert a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure whilst supine or standing in hypertensive patients regardless of age. This antihypertensive effect lasts for 24 hours. The reduction in blood pressure is obtained in less than one month without tachyphylaxis; stopping treatment has no associated effects. During clinical trials, the concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergistic nature when compared with each of the products administered alone.
The combination of perindopril with indapamide is justified in the treatment of hypertension due to its action on several pathophysiological mechanisms, and due to the lessening of counter-regulatory mechanisms by one or other of the two components:
indapamide reduces the vascular response to angiotensin II by depleting the cell of sodium and of calcium, whilst perindopril opposes the stimulation of the renin-angiotensin system (RAS) and the sympathetic nervous system induced by indapamide;
the stimulation of the RAS caused by indapamide is blocked by perindopril;
the potassium depletion linked to indapamide is compensated by the potassium-sparing effect of perindopril.
Perindopril and indapamide 4/1.25 mg tablets do not adversely affect lipid metabolism (total cholesterol, HDL and LDL cholesterol, triglycerides) or carbohydrate metabolism, even in hypertensive patients with diabetes.

Pharmacology of perindopril.

Perindopril (prodrug) following hydrolysis to perindoprilat, inhibits 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 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 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 may also inhibit the degradation of the potent vasodepressor peptide, bradykinin, and this action may contribute to its antihypertensive action. Perindopril appears to reduce peripheral resistance and may influence arterial compliance.
Studies carried out in animal models of hypertension have shown that perindopril is a specific competitive angiotensin I-converting enzyme inhibitor. The administration of perindopril 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 has not been associated with a rebound rise in blood pressure. Single dose studies have demonstrated that peak initiation of ACE activity and peak reduction in blood pressure occurs 4-6 hours after administration of perindopril. 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 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 is administered together with a thiazide-type diuretic, the antihypertensive activity of perindopril may be potentiated in some patients, and this effect is evident after four weeks of treatment. Perindopril like other ACE inhibitors may compensate thiazide induced hypokalaemia.

Pharmacology of indapamide.

Indapamide is an oral antihypertensive medicine. The mechanism whereby indapamide exerts its antihypertensive action has not been completely elucidated; both vascular and renal actions have been implicated.
The renal effects of indapamide are minimal and the antihypertensive effect of indapamide has been attributed to a reduction in vascular reactivity to pressor amines. The finding that indapamide retains its antihypertensive activity in those who are functionally anephric lends support to this hypothesis.
The renal site of action of indapamide is the proximal segment of the distal tubule. Indapamide appears to have natriuretic properties (sodium and chloride being excreted in equivalent amounts) with less effect on potassium or uric acid excretion. Only at doses greater than 2.5 mg/day, i.e. at doses of indapamide two times greater than the amount present in one perindopril and indapamide 4/1.25 mg tablet, is an appreciable increase in urinary volume observed in man. No significant changes in plasma sodium levels have been observed in clinical studies.
Indapamide does not adversely affect serum triglycerides, LDL cholesterol, the LDL-HDL cholesterol ratio, or glucose tolerance.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Pharmacokinetics of perindopril and indapamide.

The co-administration of perindopril and indapamide does not change the pharmacokinetic properties of the components administered separately.
In a bioequivalence study comparing perindopril 4 mg and indapamide 1.25 mg (as single component capsules) with the fixed dose formulation the pharmacokinetics of each active ingredient were shown to be predominantly unchanged (see Table 3). Bioequivalence was established based on AUC and Cmax. Only the Tmax of indapamide was shorter after administration of the combination.

Pharmacokinetics of perindopril.

Absorption.

Following oral administration, perindopril is rapidly absorbed and is 61-85% bioavailable. Elimination is rapid, occurring predominantly via the urine. Plasma half-life is approximately 1 hour. Biotransformation of perindopril to the active metabolite perindoprilat is approximately 20%.

Distribution.

Peak plasma concentrations of perindoprilat occur 3 to 4 hours after oral administration of perindopril. Protein binding of perindoprilat is below 30%. When perindopril 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 and hence its bioavailability.

Excretion.

Perindoprilat binds to plasma and tissue ACE, and free perindoprilat is eliminated through the urine. The elimination half-life of the free fraction is between 3 and 5 hours. The terminal half-life which corresponds to the dissociation of perindoprilat from ACE, is approximately 25 to 30 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).

Pharmacokinetics of indapamide.

Absorption.

Possibly related to its high lipid solubility, absorption of indapamide from the gastrointestinal tract is rapid (within 0.5 to 1 hour after an oral dose) and complete.

Distribution and metabolism.

Indapamide is widely distributed throughout the body, with extensive binding to specific sites. In blood, it is highly bound to red blood cells (80%) and, more specifically, to carbonic acid anhydrase (98%) without having any inhibiting activity on this enzyme. In plasma, it is relatively highly bound to plasma proteins (79%). It is also taken up to a significant degree in the vascular compartment, indapamide has a relatively low apparent volume of distribution (approximately 60 L) and 40% of the dose is located in the blood one hour after administration. The decrease in plasma concentrations of unchanged indapamide is biphasic terminal with half-lives between 14 and 25 hours. Both single and multiple dose data indicate that the kinetics of indapamide are linear. Steady state plasma levels are reached within three to four days after starting treatment and indapamide does not accumulate in hypertensive patients with various degrees of renal insufficiency. Indapamide is extensively metabolised in the liver, mainly by CYP2C9 and CYP3A4 isozymes and by cytosolic hydrolysis enzymes. Care should be taken when administering indapamide in combination with medicines that alter the activity of these enzymes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

Following radioactivity studies using carbon-14, the main route of elimination is the urine, but only 5% to 7% of the dose is excreted into the urine as unchanged indapamide; 20% to 23% of total radioactivity is eliminated into the faeces. Renal clearance of unchanged indapamide is approximately 5 mL/minute, representing less than 10% of systemic clearance. The high lipid solubility of the indoline moiety confers to indapamide its highly localised binding to structures in the cardiovascular system.

5.3 Preclinical Safety Data

Perindopril displays the typical effects of ACE inhibitors. In the rat, the target organ is the kidney; perindopril causes anatomical modifications in arteries which result in intrarenal haemodynamic changes and an increase in blood urea and creatinine levels. The highest doses of indapamide administered by the oral route in different animal species manifested as an exacerbation of the diuretic properties of indapamide. The main symptoms in acute toxicity studies with indapamide administered by the intravenous or intraperitoneal routes are related to the pharmacological action of indapamide, i.e. bradypnoea and peripheral vasodilatation.
In animal models, the combination of perindopril and indapamide has greater toxicity than that of each individual component. Renal manifestations of the effects of perindopril in the rat are increased when it is given in combination with indapamide (about three times the effects of perindopril alone). Renal impairment, resulting from loss of functional nephrons and irreversible renal fibrosis, is observed when perindopril is given in combination with indapamide in the rat. The combination of perindopril and indapamide produced gastrointestinal toxicity (haemorrhage, erosion and necrosis) in dogs, but similar effects were not observed in dogs with much higher doses of the individual components. The mechanism underlying perindopril/indapamide-induced gastrointestinal toxicity in dogs is unknown and the clinical relevance of this finding is questionable. In addition, the toxic effects of perindopril/indapamide in pregnant rats and rabbits are increased when compared to the effects of the individual components.

Genotoxicity.

No genotoxicity studies of perindopril in combination with indapamide have been conducted.

Related to perindopril component.

Results from a broad set of assays for gene mutation and chromosomal damage with perindopril arginine suggest no genotoxic potential at clinical doses. Perindopril showed no evidence of genotoxicity potential in assays for gene mutation (Ames reverse mutation test, mouse lymphoma thymidine kinase assay), chromosomal damage (mouse micronucleus test, Chinese hamster bone marrow cells in vivo, human lymphocytes in vitro) and other genotoxic effects (gene conversion assay in Saccharomyces cerevisiae, unscheduled DNA synthesis in rat hepatic cells).

Related to indapamide component.

Indapamide was negative in mutagenicity tests in bacteria, and bone marrow micronucleus tests in mice. In animals treated with oral doses of indapamide, decreases were seen in weight gain of the F1 generation from rats treated at doses ≥ 2.5 mg/kg/day. Galactopoiesis was reduced in the F1 generation from rats treated orally at 0.5 mg/kg/day and this led to increased mortality of the F2 generation during the first 48 hours of life. No embryotoxicity or teratogenic potential was seen in rats (up to 150 mg/kg/day) or rabbits (up to 180 mg/kg/day).

Carcinogenicity.

No carcinogenicity studies of perindopril in combination with indapamide have been conducted. In studies of perindopril erbumine and indapamide hemihydrate, no evidence of carcinogenic activity was observed in mice and rats when indapamide was administered via the diet at levels up to 100 mg/kg/day, or when perindopril erbumine was administered via drinking water at levels up to 7.5 mg/kg/day for two years.

Related to perindopril component.

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 it does occur, it is considered as benign.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet contains the following excipients: lactose monohydrate, microcrystalline cellulose, hydrophobic colloidal anhydrous silica, magnesium stearate.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Keep out of the reach of children.

6.5 Nature and Contents of Container

The tablets are supplied in an Aclar (PVC/PCTFE)/aluminium foil blister pack of 30 tablets.

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 erbumine is a white powder, readily soluble in purified water, ethanol and chloroform. Perindopril erbumine has five asymmetric centres. The drug is synthesised stereoselectively so that it is a single enantiomer (all S stereochemistry).
Indapamide hemihydrate is white crystalline lipophilic powder, soluble in methanol, ethanol, acetic acid and ethyl acetate, very slightly soluble in ether, chloroform and benzene and practically insoluble in water.

Perindopril erbumine.


Chemical structure.


Chemical Name: tert-butylammonium (2S, 3aS, 7aS)-1-(N-[(S)-1-ethoxycarbonyl butyl]-L-alanyl) perhydroindole-2-carboxylate.
Molecular Formula: C19H32N2O5, C4H11N.
Molecular Weight: 441.6.

CAS number.

107133-36-8.

Indapamide hemihydrate.


Chemical structure.


Chemical Name: 4-chloro-N-(2 methyl-1-indolinyl)-3-sulphamoyl benzamide hemihydrate.
Molecular Formula: C16H16ClN3O3S, ½ H2O.
Molecular Weight: 365. 84.

CAS number.

26807-65-8.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription-Only Medicine.

Summary Table of Changes