Consumer medicine information

Indopril Combi 4/1.25 Tablets

Perindopril erbumine; Indapamide hemihydrate

BRAND INFORMATION

Brand name

Indopril Combi 4/1.25 Tablets

Active ingredient

Perindopril erbumine; Indapamide hemihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Indopril Combi 4/1.25 Tablets.

What is in this leaflet

This leaflet answers some common questions about Indopril Combi 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 Indopril Combi 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 INDOPRIL COMBI 4/1.25 mg tablets are

Indopril Combi 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 chlorosulphamoyl diuretics.

What INDOPRIL COMBI 4/1.25 mg tablets are used for

Indopril Combi 4/1.25 mg tablets are available only with a doctor's prescription.

There is no evidence that Indopril Combi 4/1.25 mg tablets are addictive.

Why Indopril Combi 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.

Indopril Combi 4/1.25 mg tablets help to lower your blood pressure.

Ask your doctor if you have any questions about why Indopril Combi 4/1.25 mg tablets has been prescribed for you.

Before You Take INDOPRIL COMBI 4/1.25 mg Tablets

Do not take Indopril Combi 4/1.25 mg tablets:

There are some people who should not take Indopril Combi 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 Indopril Combi 4/1.25 mg tablets if:

  • You are allergic to perindopril, indapamide, or any of the other ingredients of Indopril Combi 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 pregnant or trying to become pregnant.
  • You are breastfeeding or plan to breast-feed.
  • You undergo renal dialysis using polyacrylonitrile membranes
  • You have renal artery stenosis (a problem with the blood vessels to one or both kidneys).
  • 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 angio-oedema).
  • The packaging is torn or shows signs of tampering, or the tablets do not look quite right.
  • The expiry date (EXP) on the pack has passed.

Tell your doctor if:

  • You become pregnant while you are taking Indopril Combi 4/1.25 mg tablets.
  • You are undergoing desensitisation treatment, or have had an allergic reaction during previous desensitisation treatment (e.g. treatments using bee, wasp or ant venom)
  • You are undergoing, or have had an allergic reaction during previous, low-density lipoprotein (LDL) apheresis, a technique where LDL is 'filtered' out of a patient's blood, using dextran sulphate
  • You have any other health problems, including:
    - Kidney disease.
    - Liver disease
    - High or low levels of potassium, sodium, or other problems with salt balance
    - Diabetes.
    - Gout.
    - Heart disease
    - Systemic lupus erythematosus (a disease affecting the skin, joints and kidneys).

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 Indopril Combi 4/1.25 mg tablets may change the effect of some medicines, and some medicines may affect how well Indopril Combi 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 Indopril Combi 4/1.25 mg tablets include the following:

  • Some anaesthetic drugs
  • Some drugs used to treat gout (allopurinol)
  • Some steroid medicines.
  • Some drugs used to treat cancer or to suppress the immune system.
  • Diuretics (sometimes called "fluid" or "water" tablets)
  • Lithium medications (used to treat mood swings and some types of depression)
  • Sources of potassium, like potassium tablet and salt substitutes containing potassium
  • Some medications used to treat high blood pressure, a fast or irregular heartbeat, and other heart conditions
  • Medicines used to treat diabetes (tablets and insulin).

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Indopril Combi 4/1.25 mg tablets.

For older people or children

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

How to take INDOPRIL COMBI 4/1.25 mg tablets

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 Indopril Combi 4/1.25 mg tablets for you. The usual dose is one tablet once daily.

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

How long to take Indopril Combi 4/1.25 mg tablets for

Indopril Combi 4/1.25 mg tablets can help to control your blood pressure, but cannot cure this condition. Indopril Combi 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 Indopril Combi 4/1.25 mg tablets

  • 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 Indopril Combi 4/1.25 mg tablets

Taking too much Indopril Combi 4/1.25 mg tablets (an overdose) may cause low blood pressure (also known as hypotension). Other effects like sickness, cramps, sleepiness, confusion, kidney problems, salt and water disturbances are possible. You may require urgent medical attention.

If you think that you or anyone else may have taken too much Indopril Combi 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 INDOPRIL COMBI 4/1.25 mg tablets

Things you must do

Take Indopril Combi 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 Indopril Combi 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 Indopril Combi 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 Indopril Combi 4/1.25 mg tablets to treat any other complaints unless your doctor tells you to.

Do not stop taking Indopril Combi 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 Indopril Combi 4/1.25 mg tablets affects you.

You may feel light-headed or dizzy when you begin to take Indopril Combi 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

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 Indopril Combi 4/1.25 mg tablets then tell your doctor or pharmacist as soon as possible.

All medicines can have side effects. Most of the time they are not serious but sometimes they can be.

Indopril Combi 4/1.25 mg tablets help most people with high blood pressure, but it may sometimes have unwanted side effects. These can include:

  • A dry cough
  • Headache
  • Feeling tired or as if you have less energy.
  • Feeling faint, light-headed, or dizzy
  • Feeling sick or having stomach pain
  • Muscle pain.
  • An increased risk of becoming dehydrated (in elderly patients and in patients with heart failure).
  • Low potassium levels. Symptoms of low potassium can include a number of those listed above, and very occasionally this may be severe.

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. However, if you do - or if you notice anything else that is making you feel unwell - you should consult your doctor or pharmacist.

If any of the signs below occur then tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital:

  • Swelling of your lips, face, mouth, tongue or throat
  • 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)
  • A fast and irregular heart beat.
  • Severe blisters, skin rash, itching or other allergic reactions.

These side effects are extremely rare but can become serious.

After taking INDOPRIL COMBI 4/1.25 mg tablets

Storage

Keep Indopril Combi 4/1.25 mg tablets where children cannot reach them.

Keep tablets in the pack until it is time to take them. Indopril Combi 4/1.25 mg tablets 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 degrees 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 Indopril Combi 4/1.25 mg tablets, or the tablets have passed their expiry date, return any leftover tablets to your pharmacist for disposal.

Product description

Australian Register Numbers:

Indopril Combi 4/1.25 mg tablets 4/1.25 mg .
AUST R 147151

What Indopril Combi 4/1.25 mg tablets looks like

Perindopril erbumine and Indapamide hemihydrate tablets 4mg/1.25mg 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 eq. to Indapamide hemihydrate 1.25mg.

Indopril Combi 4/1.25 mg tablets come in a blister strip. Each box contains 30 tablets.

Ingredients

Active ingredient
Each tablet of Indopril Combi 4/1.25 mg tablets contains 4mg of perindopril erbumine and 1.25mg of indapamide hemihydrate as active ingredients.

The inactive ingredients
in Indopril Combi 4/1.25 mg tablets include cellulose - microcrystalline, lactose, magnesium stearate, and silica dimethyl salicylate.

Distributor

INDOPRIL COMBI 4/1.25 mg TABLETS are distributed in Australia by:
Aspen Pharma Pty Ltd
34 -36 Chandos Street
St. Leonards, 2065, NSW
Australia

This document was updated in October 2011

BRAND INFORMATION

Brand name

Indopril Combi 4/1.25 Tablets

Active ingredient

Perindopril erbumine; Indapamide hemihydrate

Schedule

S4

 

Name of the medicine

Perindopril erbumine 4 mg, indapamide hemihydrate 1.25 mg.

Excipients.

Lactose, microcrystalline cellulose, hydrophobic anhydrous colloidal silica, magnesium stearate.

Description

Perindopril erbumine.

Chemical name: tert-butylammonium (2S, 3aS, 7aS)-1- (N-[(S)-1-ethoxycarbonyl butyl]- L-alanyl) perhydroindole-2-carboxylate. Molecular formula: C19H32N2O5, C4H11N. MW: 441.6. CAS: 107133-36-8. 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.

Chemical name: 4-chloro-N-(2-methyl-1-indolinyl)- 3-sulphamoyl benzamide hemihydrate. Molecular formula: C16H16ClN3O3S, ½H2O. MW: 385.84. CAS: 26807-65-8. 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.

Pharmacology

Mechanism of action.

Indopril Combi 4/1.25 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 up to two times lower than the usual dose 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.
Indopril Combi 4/1.25 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.
Indopril Combi 4/1.25 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 humans have demonstrated an improvement in the viscoelastic properties of large vessels and in compliance. Studies in animals and humans suggest that specific and competitive suppression of the renin angiotensin aldosterone system 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 duration of these effects is 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 agent. 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 to functionally anephric patients lends support to the 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 kaliuresis 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 Indopril Combi 4/1.25 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.

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, perindopril and indapamide together have greater toxicity than that of each individual component. Renal manifestations of the effects of perindopril in the rat are increased when the drug is given in combination with indapamide (about 3-fold relative to 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 drugs individually.

Pharmacokinetics.

Pharmacokinetics of perindopril and indapamide.

The coadministration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
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. Bioequivalence was established based on AUC and Cmax. Only the Tmax of indapamide was shorter after administration of the combination. (See Table 1.)

Pharmacokinetics of perindopril.

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%. Peak plasma concentrations of perindoprilat occur 3 to 4 hours after oral administration of perindopril and peak pharmacological activity occurs after 4 to 6 hours. Protein binding of perindoprilat is below 30%. 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. When perindopril is administered chronically, steady-state perindoprilat concentration is reached within 4 days, and perindoprilat does not accumulate. Food intake may reduce hepatic biotransformation to perindoprilat. The elimination of perindoprilat is reduced in elderly patients and in patients with cardiac and renal failure (see Dosage and Administration). 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.

Pharmacokinetics of indapamide.

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.
Indapamide is widely distributed throughout the body, with extensive binding to some 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, the drug 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.
Plasma elimination half-life of unchanged indapamide is biphasic with half-lives between 14 and 25 hours. Both single and multiple dose data indicate that indapamide's kinetics are linear. Steady-state plasma levels are reached within three to four days after starting treatment and the drug 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 drugs that alter the activity of these enzymes (see also Interactions with Other Medicines). 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 drug; 20 to 23% of total radioactivity is eliminated into the faeces. Renal clearance of indapamide (as unchanged drug) is approximately 5 mL/minute, representing less than 10% of systemic clearance. The high lipid solubility of the indoline moiety confers to indapamide it's highly localised binding to structures in the cardiovascular system.

Indications

Treatment of hypertension: treatment should not be initiated with this combination.

Contraindications

History of previous hypersensitivity to either of the active ingredients, perindopril or indapamide, or excipient ingredients present in Indopril Combi 4/1.25 tablets.
During pregnancy and for lactating women (see Precautions, Use in pregnancy; Use in lactation).
Patients with severe renal insufficiency (creatinine clearance below 30 mL/minute).
Patients with severe untreated decompensated heart failure.

Related to perindopril component.

Bilateral or unilateral renal artery stenosis.
Previous history of hereditary and/or idiopathic angioedema or angioedema associated with previous treatment with an ACE inhibitor (see Precautions, Related to perindopril component).
Hypersensitivity to any other ACE inhibitor.

Haemodialysis.

Patients haemodialysed using high flux polyacrylonitrile (AN69) membranes are highly likely to experience anaphylactoid reactions if they are treated with ACE inhibitors. This combination should therefore be avoided, either by use of alternative antihypertensive drugs or alternative membranes (e.g. cuprophane or polysulfone PSF) for haemodialysis.

Related to indapamide component.

History of hypersensitivity to sulfonamides.
Anuria, progressive and severe oliguria, hepatic encephalopathy, severe hepatic impairment, hypokalaemia and concomitant administration with nonantiarrhythmic agents causing torsades de pointes.

Precautions

Related to Indopril Combi 4/1.25 tablets.

There are no special warnings specifically related to the use of Indopril Combi 4/1.25 tablets other than those described hereafter for the separate components of the combination.
Specific precautions relating to the use of Indopril Combi 4/1.25 tablets are the same as those which apply to the separate components of the combination. Consequently, caution should be observed when the drug is administered in patients with impaired renal function and the risk of hypotension and electrolyte imbalance should be borne in mind (see Contraindications; Dosage and Administration; and precautions specific to perindopril and indapamide under Precautions). The combination of perindopril and indapamide does not exclude the possibility of the onset of lowered potassium levels, in particular in patients with renal impairment. As with any antihypertensive agent containing a diuretic, regular monitoring of plasma levels of potassium should be carried out.

Elderly patients.

Renal impairment is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril containing products 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 Dosage and Administration).
In a study of 91 elderly patients with a mean age of 71.9 years, a 6% increase in serum potassium occurred in the first month of treatment and subsequently remained stable. There was no change in the group in blood urea, creatinine or creatinine clearance.
Particular care should be taken in elderly patients with congestive heart failure who have renal and/or hepatic insufficiency.

Fluid and electrolyte imbalance.

Patients should be monitored for signs and symptoms of fluid or electrolyte imbalance; namely hyponatraemia, hypochloraemia, hyperuricaemia, hyperkalaemia (see Precautions below) and hypokalaemia (see Precautions below). Plasma urea and uric acid levels should also be monitored during therapy.
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.
Rarely gout has been reported.

Potassium levels.

The combination of perindopril and indapamide does not prevent the onset of hypokalaemia particularly in diabetic patients 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.

Related to perindopril component.

Hyperkalaemia.

Diabetics and particularly the elderly may be at increased risk of hyperkalaemia. However, hyperkalaemia (> 5.5 mmol/L) is more likely in patients with some degree of renal impairment or those treated with potassium sparing diuretics or with potassium supplements and/or consuming potassium containing salt substitutes. In some patients, hyponatraemia may coexist with hyperkalaemia.

Angioedema.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. Severe 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 nonimmunogenic and may be related to accentuated bradykinin activity. Usually the angioedema is nonpitting oedema of the skin mucous membrane and subcutaneous tissue.
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients with ACE inhibitors and has been reported on rare occasions with perindopril. 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 therapy (e.g. adrenaline and oxygen) should be given promptly. Treatment of progressive angioedema should be aggressive and failing a rapid response to medical therapy, 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.
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Angioedema may occur with or without urticaria.
Rarely, patients receiving 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 therapy prior to each apheresis.
Patients receiving ACE inhibitors during desensitisation treatment (e.g. Hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Hypotension.

Hypotension has been reported in patients commencing treatment with ACE inhibitors. Excessive hypotension is rarely seen in uncomplicated hypertension but is a potential consequence of perindopril use in severely salt/ volume depleted patients with impaired renal function, those treated vigorously with diuretics, after severe diarrhoea or patients on dialysis (see Precautions and Adverse Effects).
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed following administration of perindopril and may therefore occur. 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, therapy 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 dosage 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.
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.

Impaired renal function.

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 clinical studies where hypertensive patients with unilateral or bilateral renal artery stenosis were treated with perindopril and indapamide tablets 4/1.25, increases in blood urea, nitrogen and serum creatinine were observed in 20% of patients. These increases are usually reversible upon discontinuation of treatment.
ACE inhibitors should be avoided in patients with known or suspected renal artery stenosis. When an ACE inhibitor is given to a patient with stenosis of the artery supplying a solitary kidney or bilateral renal artery stenosis, acute renal insufficiency may occur.
ACE inhibition may also cause a decrease in renal function 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. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors.
Some hypertensive patients with no apparent pre-existing renovascular disease have developed increases in blood urea, nitrogen and serum creatinine which are usually minor and transient. This is more likely to occur in patients with pre-existing renal impairment.
Evaluation of the hypertensive patient should always include an assessment of renal function (see Dosage and Administration). If a deterioration in renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by another and in these patients usage 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.
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.

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.

Impaired hepatic function.

Biotransformation of perindopril to perindoprilat mainly occurs in the liver. Studies in patients with impaired hepatic function 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 Pharmacokinetics of perindopril). The administration of perindopril leads to the formation of a glucuronoconjugate derivative of perindoprilat by a hepatic first pass effect. The kinetic parameters of perindoprilat glucuronide are not modified by hepatic failure. The small changes in the kinetics of perindoprilat do not justify the need to change the usual dosage in most patients with hepatic 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; the ACE inhibitor should be added to the beta-blocker.

Insulin dependent diabetes mellitus.

Patients with insulin dependent diabetes mellitus (spontaneous tendency to increased levels of potassium) should be monitored closely during the initial stages of treatment. Treatment should be initiated with a reduced dose.

Cough.

A persistent dry (nonproductive) 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 therapy with the incidence of cough varying depending upon the drug, dosage and duration of use.
The cough is often worse at 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 nonsmokers 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 drugs may be required in severe cases.

Proteinuria.

Perindopril monotherapy has occasionally been associated with mild or transient proteinuria (< 1 g per 24 hours). However in the majority of patients with pre-existing proteinuria treated with perindopril, proteinuria disappeared or remained stable.

Neutropenia/ agranulocytosis/ thrombocvtopenia/ anaemia.

Neutropenia/ agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Indopril Combi 4/1.25 tablets should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Indopril Combi 4/1.25 tablets are 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 maculopapular 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). A causal relationship is difficult to assess. Patients who develop a cutaneous reaction with one ACE inhibitor might not when switched to another drug of the same class, but there are reports of crossreactivity.

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 in this respect 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. Any dysgeusia occurs usually in the first weeks of treatment and may disappear in most cases within 1-3 months.

Agents causing renin release.

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

Surgery and anesthesia.

In patients undergoing major surgery or who require anaesthesia, hypotension due to anaesthetic agents may be greater in patients receiving ACE inhibitors because of interference with compensatory mechanisms associated with the renin angiotensin system. If perioperative hypotension occurs, volume expansion would be required.

Valvular stenosis.

There has been some concern on theoretical grounds that patients with aortic stenosis 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.

Related to indapamide component.

Lithium.

In general, diuretics should not be given with lithium because they reduce its renal clearance and add a high risk of lithium toxicity.

Hypokalaemia.

Hypokalaemia is a particular hazard in digitalised patients since dangerous or fatal arrhythmias may be precipitated by it.

Impaired hepatic function.

When liver function is impaired, thiazide and thiazide related diuretics may cause hepatic encephalopathy.

Orthostatic hypotension.

Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, narcotics or concurrent therapy with other antihypertensives.
When indapamide is given with other nondiuretic antihypertensive agents, the effects on blood pressure are additive.

Lupus erythematosus.

Sulphonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus. These possibilities should be kept in mind with the use of indapamide although no case has been reported to date.

Photosensitivity.

Very rare cases of photosensitivity reactions have been reported. 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 to protect exposed areas to the sun or to artificial UVA.

Impaired renal function.

Although indapamide can safely be administered to hypertensive patients with impaired renal function, the treatment should be discontinued if increasing increase 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 drug accumulation, despite the fact that indapamide is not dialysable.

Use in pregnancy.

(Category D)
As this combination contains an ACE inhibitor, Indopril Combi 4/1.25 tablets should not be used during pregnancy.

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 drug is given separately.

Related to perindopril component.

As with all ACE inhibitors, Indopril Combi 4/1.25 tablets should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with Indopril Combi 4/1.25 tablets and avoided during the treatment. 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. Postmarketing 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.
A historical cohort study in over 29,000 infants born to nondiabetic 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 hypotension, renal failure, skull hypoplasia 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. If such complications arise, appropriate medical treatment should be initiated to support blood pressure and renal perfusion.

Related to indapamide component.

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 thrombocytopenia 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.
There is no information on the use of indapamide in pregnancy. Whilst animal studies have not suggested any teratogenic effect, indapamide is not recommended for administration to pregnant women unless the expected benefit outweighs the potential risk.
In animals treated with oral doses of indapamide, a reduction in the number of implantation sites was seen at 25 mg/kg/day and 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).

Use in lactation.

Animal studies have shown that perindopril and its metabolites are excreted in milk during lactation, but there are no human data. Indapamide is excreted in human milk during lactation. Other antihypertensive diuretics closely related to indapamide have been associated during breastfeeding, with decrease or even suppression of milk lactation. Serious adverse reactions might occur in nursing infants such as hypersensitivity to sulfonamide derived drugs, hypokalaemia and nuclear icterus. Indopril Combi 4/1.25 tablets should not be used in lactating women (see Contraindications).

Paediatric use.

Use of Indopril Combi 4/1.25 tablets in children is not recommended as no data establishing safety or effectiveness in children are available.

Carcinogenicity, genotoxicity, impairment of fertility.

No carcinogenicity or genotoxicity studies of perindopril in combination with indapamide have been conducted, and the effect of the combination on fertility has not been investigated.
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). Indapamide was negative in mutagenicity tests in bacteria and in a bone marrow micronucleus test in mice.
In studies of the component drugs, 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 was administered via the drinking water at levels up to 7.5 mg/kg/day.
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.
Studies in rats showed no impairment of male or female fertility at oral perindopril doses up to 10 mg/kg/day, or at oral indapamide doses up to 25 mg/kg/day.

Effects on the ability to drive or operate machinery.

Neither of the two active substances nor Indopril Combi 4/1.25 tablets 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.

Interactions

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

Shared by perindopril and indapamide.

Combinations which are not recommended.

Lithium.

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

Combinations which require special care.

Baclofen.

Potentiation of antihypertensive effect. Monitoring of blood pressure and renal function, and dose adaptation of the antihypertensive if necessary.

NSAID (systemic route), high dose salicylates.

Acute renal insufficiency in dehydrated patients (reduction in glomerular filtration). The patient should be well hydrated; renal function should be monitored at the start of treatment.

Combinations which require some care.

Neuroleptics, imipramine-like antidepressants (tricyclics).

Increased antihypertensive effect and risk of orthostatic hypotension due to additive effect.

Corticosteroids, tetracosactide.

Reduction in antihypertensive effect (salt and water retention due to corticosteroids).

Agents affecting sympathetic activity.

As the sympathetic nervous system plays an important part in physiological blood pressure regulation, caution should be exercised with concomitant administration of a drug with sympathetic activity.

Related to perindopril component.

Combinations which are not recommended.

Agents affecting serum potassium.

The ACE inhibitor class can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. The concomitant therapy of an ACE inhibitor with a potassium sparing diuretic (e.g. spironolactone, triamterene, or amiloride), potassium supplement, or potassium containing salt substitute can increase the risk of hyperkalaemia, therefore if coadministration is indicated they should be used with caution and the patient's serum potassium should be monitored frequently.

Antidiabetic agents (insulin, hypoglycaemic sulphonylureas).

Reported with captopril and enalapril.
The use of ACE inhibitors may increase the hypoglycaemic effect in diabetics receiving treatment with insulin or with hypoglycaemic sulphonylureas. The onset of hypoglycaemic episodes is very rare (improvement in glucose tolerance with a resulting reduction in insulin requirements).

Anaesthetic drugs.

The ACE inhibitor class may enhance the hypotensive effects of certain anaesthetic drugs.

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

Concomitant administration with ACE inhibitors may lead to an increased risk for leucopenia.

Antihypertensive agents.

The concomitant administration of antihypertensive agents may increase the hypotensive effect of ACE inhibitors.

Combinations which require special care.

Diuretics.

When a diuretic is added to the therapy of a patient receiving an ACE inhibitor, the antihypertensive effect is usually additive. Patients receiving diuretics, especially those in whom diuretic therapy was recently instituted or in those with intravascular volume depletion, may sometimes experience an excessive reduction of blood pressure after initiation of therapy with an ACE inhibitor.
The possibility of excessive hypotensive effects may be minimised by ensuring adequate hydration and salt intake prior to commencing Indopril Combi 4/1.25 therapy. The patient should be closely observed for several hours following the initial dose and until the blood pressure has stabilised.

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

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

Gold.

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

Related to indapamide component.

No interactions have been reported between indapamide and oral hypoglycaemic agents, anticoagulants and uricosurics. It is recommended that the drug not be used in combination with a diuretic agent since the combination may produce hypokalaemia and hyperuricaemia.

Combinations which require special care.

Torsades de pointes inducing drugs.

Due to the risk of hypokalemia, indapamide should be administered with caution when associated with medicinal products that induced torsades de pointes such as class IA antiantiythmic agents (disopyrarnide); class III antiarrhythmic agents (amiodarone, sotalol); some neuroleptics (chlorpromazine, thioridazine, trifluoperazine), benzamides (amisulpride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide); other substances such as diphemanil, IV erythromycin, moxifloxacin, pentamidine and methadone. Prevention of low potassium levels and correction if necessary: monitoring of the QT interval.

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

Increased risk of low potassium levels (additive effects). Monitoring of potassium levels, and correction if necessary; particular consideration required in cases of treatment with cardiac glycosides. Nonstimulant laxatives should be used.

Cardiac glycosides.

Low potassium levels favour the toxic effects of cardiac glycosides. Potassium levels and ECG should be monitored and treatment reconsidered if necessary.

Combinations which require some care.

Potassium sparing diuretics (amiloride, spironolactone, triamterene).

The rationale combination, which is useful for some patients, does not exclude the onset of low potassium levels or, particularly in patients with renal insufficiency, raised potassium levels. Potassium levels and ECG should be monitored and treatment reconsidered if necessary.

Metformin.

Lactic acidosis due to metformin caused by possible functional renal insufficiency linked to diuretics and in particular to loop diuretics. Do not use metformin when plasma creatinine levels exceed 15 mg/L (135 micromol/L) in men and 12 mg/L (110 micromol/L) in women.

Iodinated contrast media.

In cases of dehydration caused by diuretics, there is an increased risk of acute renal insufficiency, particularly when high doses of iodinated contrast media are used. Rehydration should be carried out before the iodinated compound is administered.

Calcium (salts).

Risk of increased levels of calcium due to reduced elimination of calcium in the urine.

Cyclosporin.

Risk of increased creatinine levels with no change in circulating levels of cyclosporin, even when there is no salt and water depletion.

Effects on laboratory tests.

Potassium depletion with particularly serious reduction in levels of potassium in some at risk populations (see Precautions).
Reduced sodium levels with hypovolaemia causing dehydration and orthostatic hypotension.
Increase in uric acid levels and blood glucose levels during treatment.
Altered high potassium levels, usually transitory, have been noted.
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.
Rarely, raised plasma calcium levels have been noted.
Elevation of liver enzymes and serum bilirubin have been reported rarely.

Adverse Effects

Reported with perindopril and indapamide tablets 4/1.25 mg.

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 perindopril and indapamide tablets 4/1.25 mg for 12 weeks. After 12 weeks of treatment, the mean reduction in potassium levels was 0.20 mmol/L.
Adverse experiences have generally been mild and transient and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in only 2.1% of patients treated with both the combination or placebo.
The most frequent treatment emergent adverse reactions (incidence > 1%) reported in 3 month controlled clinical trials including a total of 1898 patients treated with the combination (both perindopril 2 mg/ indapamide 0.625 mg and perindopril 4 mg/ indapamide 1.25 mg) and 717 patients treated with placebo were presented in Table 2.
The following undesirable effects could be observed during treatment 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).

Psychiatric and nervous system disorders.

Common: headache, dizziness, drowsiness, vertigo, paresthaesia. Uncommon: mood or sleep disturbances (insomnia, dream abnormality), lethargy, anxiety. Very rare: depression, confusion, hallucinations.

Ear/ labyrinth and eye disorders.

Common: tinnitus, vision disturbance.

Cardiovascular disorders.

Common: hypotension whether orthostatic or not (see Precautions). Uncommon: palpitations, flushing, chest pain, impaired peripheral circulation; ECG changes (including nonspecific ST-T, changes, U waves, left ventricular strain). Very rare: arrhythmia including bradycardia, ventricular tachycardia, atrial fibrillation, angina pectoris, myocardial infarction and stroke possibly secondary to excessive hypotension in high risk patients (see Precautions), vasculitis.

Respiratory, thoracic and mediastinal disorders.

Common: cough, dyspnoea, epistaxis, discomfort on exertion. Uncommon: bronchospasm, bronchitis, upper respiratory acute infection. Very rare: eosinophilic pneumonia, rhinitis.

Gastrointestinal disorders.

Common: constipation, dry mouth, nausea, vomiting, abdominal pain, epigastric pain, anorexia, dysgeusia, dyspepsia, diarrhoea. Uncommon: noninfective gastroenteritis and colitis. Very rare: pancreatitis.

Hepatobiliary disorders.

Very rare: hepatitis either cytolytic or cholestatic (see Precautions), abnormal hepatic function. Not known: in case of hepatic insufficiency, there is a possibility of onset of hepatic encephalopathy (see Precautions).

Skin and subcutaneous tissue disorders.

Common: rash, pruritus, maculopapular eruptions. Uncommon: angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria (see Precautions), hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions, purpura, possible aggravation of pre-existing acute disseminated lupus erythematosus. Very rare: erythema multiforme, toxic epidermic necrolysis, Stevens-Johnson syndrome, cases of photosensitivity reactions have been reported (see Precautions).

Musculoskeletal connective tissue and bone disorders.

Common: muscle cramps, weakness of legs. Uncommon: lumbago, joint pain.

Renal and urinary disorders.

Uncommon: renal insufficiency, cystitis, polyuria. Very rare: acute renal failure.

Reproductive system and breast disorders.

Uncommon: impotence, modification of libido.

General disorders.

Common: asthenia. Uncommon: sweating, atypical chest pain.

Blood and the lymphatic system disorders.

Very rare: decreases in haemoglobin and haematocrit, thrombocytopenia, leucopenia/ neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia. Anaemia (see Precautions) has been reported with angiotensin converting enzyme inhibitors in specific circumstances (patients who have had kidney transplants, patients undergoing haemodialysis) and in patients with congenital G-6PDH deficiency.

Dosage and Administration

Note that Indopril Combi 4/1.25 tablets are not available in a 2 mg/0.625 mg strength. Other brands are available if this dose strength is required.
One tablet per day as a single dose, preferably to be taken in the morning.

Use in the elderly.

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril containing products 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.

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 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.

Overdosage

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.
The first measures to be taken consist of restoring fluid and electrolyte balance in a specialised centre until they return to normal.
If marked hypotension is produced, this can be treated by placing the patient in a supine position with the head lowered. If necessary an IV infusion of isotonic saline may be given, or any other method of volaemic expansion may be used.
Perindoprilat, the active form of perindopril, can be dialysed (see Pharmacokinetics of perindopril).
In the event of overdose, further information on management should be obtained from the Poisons Information Centre 131 126.

Presentation

Tablets, perindopril 4 mg/ indapamide 1.25 mg (white to off white, capsule shaped, uncoated, plain on both sides): 30's (blister).

Storage

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

Poison Schedule

S4.