Consumer medicine information

Indopril Tablets

Perindopril erbumine

BRAND INFORMATION

Brand name

Indopril Tablets

Active ingredient

Perindopril erbumine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Indopril Tablets.

What is in this leaflet

This leaflet answers some common questions about INDOPRIL. It does not contain all the available information. It 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 taking INDOPRIL against the benefits they expect it will have 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 is used for

INDOPRIL is available only with a doctor's prescription.

INDOPRIL lowers high blood pressure, a condition which doctors call hypertension.

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

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

You may be prescribed INDOPRIL for heart failure. Heart failure means that the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops working. Some people develop heart failure after having had a heart attack. However there are also other causes of heart failure.

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

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

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

Before you take INDOPRIL

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

WHEN YOU MUST NOT TAKE INDOPRIL

Do not take INDOPRIL if:

  • 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 swelling of the face, tongue, lips or throat either spontaneously or in response to another medicine in the past. (This rare condition is known as angio-oedema)
  • you are allergic to it or any of the ingredients listed at the end of this leaflet
  • the packaging is torn or shows sign of tampering
  • the expiry date (EXP) on the pack has passed

Tell your doctor straight away if:

  • You become pregnant while you are taking INDOPRIL
  • 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.
  • If you are to undergo anaesthesia and/or surgery
  • if you have recently suffered from diarrhoea or vomiting,
  • You have any other health problems, including:
    - Kidney disease
    - Liver disease
    - High or low levels of potassium, or other problems with salt balance
    - Diabetes
    - Heart disease

INDOPRIL can generally be used safely by elderly people. However reduced kidney function is often found in elderly people and in this case, the starting dose should always be 2 mg. INDOPRIL is not recommended for children.

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

Taking other medicines

Taking INDOPRIL may change the effect of some medicines, and some medicines may affect how well INDOPRIL works. You may need different amounts of your medication or to take different medicines.

The medicines that may interact with INDOPRIL include the following:

  • Some antibiotic drugs
  • Some antiinflammatory drugs
  • Lithium medications (used to treat mood swings and some types of depression)
  • Potassium-sparing diuretics, sources of potassium, like potassium tablet and salt substitutes containing potassium.
  • Some medications used to treat high blood pressure (including diuretics sometimes called ‘fluid’ or ‘water’ tablets because they increase the amount of urine passed each day), a fast or irregular heartbeat, and other heart conditions
  • Medicines used to treat diabetes (tablets and insulin).

It is a good idea to remind your doctor of all other medicines you take. Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking INDOPRIL.

How to Take INDOPRIL

The dose of INDOPRIL you may need each day will be decided and adjusted by your doctor. This will normally be 2 mg, 4 mg or 8 mg once daily for high blood pressure and for people with coronary artery disease, and 2 mg to 4 mg once daily for heart failure.

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

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking it as you would normally.

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

How long to take it

INDOPRIL helps control your blood pressure or your heart failure, but does not cure it. Continue taking the tablets for as long as your doctor tells you.

If you take too much

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26) if you think you or anyone else may have taken too much INDOPRIL. Do this even if there are no signs of discomfort or poisoning.

While you are taking INDOPRIL

Things you must not do

Do not give INDOPRIL to anyone else, even if they have the same condition as you.

Do not use INDOPRIL to treat other complaints unless your doctor tells you to.

Do not stop taking INDOPRIL or change the dosage, without checking with your doctor.

Do not stop taking your tablets because you are feeling better, unless advised by your doctor.

Side effects

INDOPRIL helps most people with high blood pressure, heart failure or coronary artery disease, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not.

With INDOPRIL, the side effects can include:

  • cough, often described as dry and irritating
  • headache, dizziness, vertigo, paraesthesia
  • tinnitus, vision disturbances
  • hypotension
  • feeling tired or lethargic
  • nausea or stomach pain
  • muscle cramps
  • rash, pruritus

These side effects when they occur are usually mild.

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

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

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.
  • A fast and irregular heart beat
  • Difficulty in breathing
  • Severe blisters, skin rash, itching or other allergic reactions

These side effects are extremely rare but can become serious.

After taking INDOPRIL

Storage

Heat and dampness can destroy some medicines.

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

Keep them in a cool, dry place where it stays below 30 degrees Celcius.

Do not store medicines in a bathroom or near a sink. Do not leave them in a car or on a windowsill

Keep them where children cannot reach them.

Disposal

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

Product description

Australian Register Numbers:
INDOPRIL 2 mg tablets: AUST R 125451
INDOPRIL 4 mg tablets: AUST R 125452I
NDOPRIL 8 mg tablets: AUST R 125453

What INDOPRIL looks like

  • INDOPRIL TABLETS 2 mg are white, round, biconvex uncoated tablets, plain on both sides and contain 2 mg of perindopril erbumine.
  • INDOPRIL TABLETS 4 mg are white, capsule shaped uncoated tablets, with a breakline on both sides and contain 4 mg of perindopril erbumine.
  • INDOPRIL TABLETS 8 mg are white, round-shaped uncoated tablets, plain on both sides and contain 8 mg of perindopril erbumine .

INDOPRIL 2 mg, INDOPRIL 4 mg and INDOPRIL 8 mg are contained in a blister strip that is itself enclosed in an aluminium foil envelope containing a desiccant sachet. Each carton contains 30 tablets. A desiccant is a substance that absorbs moisture and helps to protect the tablets, especially when it is very humid.

Ingredients

Each Indopril tablet contains perindopril erbumine as the active ingredient as well as the inactive microcrystalline cellulose, lactose, magnesium stearate and silica dimethyl silylate.

Distributor

INDOPRIL is sponsored in Australia by:
Aspen Pharma Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia

This document was last revised in October 2011

BRAND INFORMATION

Brand name

Indopril Tablets

Active ingredient

Perindopril erbumine

Schedule

S4

 

Name of the medicine

Perindopril erbumine.

Excipients

Lactose, microcrystalline cellulose, magnesium stearate and silica dimethyl silylate.

Description

Chemical name: tert-butylammonium (2S,3aS,7aS)-1-N- [(S)-1-ethoxycarbonylbutyl]- L-alanyl)perhydroindole- 2-carboxylate. Molecular formula: C19H32N2O5.C4H11N. 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, 95% ethanol and chloroform. Perindopril erbumine has five asymmetric centres. The drug is synthesised stereoselectively so that it is a single enantiomer (all S stereochemistry).

Pharmacology

Mechanism of action.

Perindopril (prodrug), following hydrolysis to perindoprilat, inhibits angiotensin converting enzyme (ACE) both in vitro and in vivo. It is thought that ACE inhibitors reduce blood pressure by inhibiting the enzyme which catalyses the conversion of angiotensin I to angiotensin II. Decreased plasma angiotensin II leads to increased plasma renin activity and a decrease in aldosterone. In addition to its effects on circulating ACE, perindopril 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 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.

Pharmacokinetics and metabolism.

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 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.

Pharmacodynamics.

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 inhibition of ACE activity and peak reduction in blood pressure occurs 4-6 hours after administration. The durations of these effects are dose related and at the recommended dose range, both effects have been shown to be maintained over a 24 hour period.
In haemodynamic studies carried out in animal models of hypertension, blood pressure reduction after perindopril 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 for thiazide induced hypokalaemia.
In one study of 48 patients where low dose perindopril (2 mg), was compared with correspondingly low doses of enalapril (2.5 mg) or captopril (6.25 mg) in patients with congestive heart failure, significantly different blood pressure responses were noted. Blood pressure fell significantly with captopril and enalapril following the first dose. However, whilst perindopril inhibited plasma ACE comparably with enalapril, the blood pressure changes were insignificant and similar to placebo for up to 10 hours of regular observation. The possibility of late hypotensive response cannot be ruled out with perindopril.

Clinical Trials

Patients with stable coronary artery disease.

The effects of perindopril were compared to placebo in patients with stable coronary artery disease with no clinical signs of heart failure. The EUROPA (European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease) study was a multicentre, international, randomised, double blind, placebo controlled clinical trial lasting 4 years. 12218 patients aged over 18 were randomised: 6110 patients to high dose perindopril (8 mg) and 6108 patients to placebo.
The primary endpoint was the composite of cardiovascular mortality, nonfatal myocardial infarction, and/or cardiac arrest with successful resuscitation.
The trial population had evidence of coronary artery disease documented by previous myocardial infarction at least 3 months before screening, coronary revascularisation at least 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain.
Study medication was added to conventional therapy, including medication used for the management of hyperlipidaemia, hypertension and diabetes mellitus. Patients randomised to perindopril were initiated on doses of perindopril 2 mg or perindopril 4 mg for 2 weeks, and then titrated up to a dose of perindopril 8 mg during the 2 following weeks. A dose of perindopril 8 mg was then maintained for the whole duration of the study. If this dose was not well tolerated, it could be reduced to a dose of perindopril 4 mg once daily.
Most of the patients also received platelet inhibitors, lipid lowering agents and β-blockers. At the end of the study, the proportions of patients on these concomitant medications were 91%, 69% and 63% respectively.
The results of the EUROPA study, specifically the primary endpoint and its components (cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest) for the intention to treat (lTT) population are presented in Table 1.
The reduction in the primary composite endpoint was mainly due to a reduction in the number of nonfatal myocardial infarctions. There was no significant reduction in the rate of cardiovascular mortality or total mortality in patients taking perindopril compared to those taking placebo. After a mean follow-up of 4.2 years, treatment with a dose of perindopril 8 mg once daily resulted in a significant relative risk reduction of 20% (95%CI: 9-29) in the primary combined endpoint: 488 patients (8.0%) reported events in the perindopril group compared to 603 patients (9.9%) in the placebo group (p = 0.0003). Improvements in the primary composite endpoint achieved statistical significance after 3 years of continuous treatment on perindopril.

Indications

Indopril tablets are indicated for the following.
The treatment of hypertension.
The treatment of heart failure. In such patients it is recommended that Indopril tablets be given with a diuretic and/or digoxin under close medical supervision. (The safety and efficacy of perindopril tablets have not been demonstrated for New York Heart Association Category IV patients).
Patients with established coronary artery disease (see Clinical Trials) who are stable on concomitant therapy and have no heart failure, to reduce the risk of nonfatal myocardial infarction or cardiac arrest.

Contraindications

Indopril tablets are contraindicated in the following.
In patients with a history of previous hypersensitivity to the active ingredient perindopril or any of the excipient ingredients present in Indopril tablets.
During pregnancy and for lactating women.
In patients with bilateral or unilateral renal artery stenosis.
In patients with a history of hereditary and/or idiopathic angioedema or angioedema associated with previous ACE inhibitor treatment.
In patients haemodialysed using high flux polyacrylonitrile (“AN69") membranes who 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 polysulphone PSF).

Precautions

Hyperkalaemia.

Since ACE inhibitors reduce angiotensin II formation resulting in decreased production of aldosterone, an increase in serum potassium may be observed. 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. Diabetics and elderly patients may be at increased risk. It is recommended that serum electrolytes (including sodium potassium and urea) should be measured from time to time when ACE inhibitors are given, especially when diuretics are also prescribed.

Angioedema.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
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 treated with ACE inhibitors and has been reported on rare occasions with perindopril. In such cases perindopril 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 either 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.
Angioedema may occur with or without urticaria.
Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
There are reports when changing a patient to another ACE inhibitor was followed by recurrence of angioedema and others where it was not. Because of the potential severity of this rare event, another ACE inhibitor should not be used in patients with a history of angioedema to a drug of this class (see Contraindications).
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 use of perindopril 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). Administration of a dose of perindopril 2 mg to patients with mild to moderate heart failure was not associated with any significant reduction in blood pressure.
In patients with severe congestive heart failure, with or without associated renal impairment, excessive hypotension has been observed. 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, or diuretic therapy is commenced or increased.
Patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident should be closely followed for the first two weeks of treatment and whenever the dose of perindopril and/or diuretic is increased. In all high risk patients it is advisable to initiate treatment with one Indopril 2 mg tablet.
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 in hypertensive patients, with unilateral or bilateral renal artery stenosis, increases in blood urea, nitrogen and serum creatinine were observed in 20% of patients. These increases are usually reversible upon discontinuation of ACE inhibitor 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 renal 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 or in those on diuretics. Dosage reduction of the ACE inhibitor and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include assessment of renal function (see Dosage and Administration). If 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.
Some ACE inhibitors have been associated with the occurrence of proteinuria (up to 0.7%) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium sparing diuretics or high doses of other diuretics, limited cardiac reserve, or treatment with a nonsteroidal anti-inflammatory drug.
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 perindoprll 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 Pharmacology, Pharmacokinetics).The administration of perindopril leads to the formation of a glucuronoconjugate derivative of perindoprilat by 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.

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 between 2-15% depending upon the drug, 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 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 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.

Treatment with perindopril tablets has occasionally been associated with mild or transient proteinuria (< 1 gram/24 hours). However in the majority of patients with pre-existing proteinuria treated with perindopril tablets, proteinuria disappeared or remained stable. ACE inhibitors have a real potential to delay the progression of nephropathy in diabetic as well as hypertensive patients.

Neutropenia/ agranulocytosis/ thrombocytopenia/ 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. Perindopril 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 perindopril 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 has 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 cross reactivity.

Taste disturbances (dysgeusia).

Taste disturbances were reported to be common (prevalence up to 12.5%) with high doses of one ACE inhibitor. The actual incidence of taste disturbance is probably low (< 0.5%) but data are scarce and difficult to interpret.
Taste disturbances with ACE inhibitors have been described as suppression of taste or a metallic sensation in the mouth. Any dysgeusia usually occurs 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 anaesthesia.

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 vasodilatation. The true clinical importance of this concern is uncertain.

Use in pregnancy.

(Category D)
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. 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. ACE inhibitors have 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.

Use in lactation.

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.

Paediatric use.

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

Use in elderly patients.

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril to elderly patients. The initial dose in the elderly should always be one 2 mg tablet 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.

Carcinogenicity, mutagenesis, impairment of fertility.

At least one ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential of the ACE inhibitor class to cause this effect in man is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when this occurs, it is considered as benign.

Effects on ability to drive or operate machinery.

When driving or operating machines it should be taken into account that occasionally dizziness or weariness related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication.

Interactions

Lithium.

Reversible increases in serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. If a diuretic is also used, the risk of lithium toxicity may be increased. Use of perindopril with lithium is not recommended, but if the combination is necessary, frequent monitoring of serum lithium levels is recommended.

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 hypotensive effects may be minimised by ensuring adequate hydration and salt intake prior to commencing ACE inhibitor therapy. The starting dose of the ACE inhibitor should be reduced and the patient closely observed for several hours following the initial dose of the ACE inhibitor 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.

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 use of an ACE inhibitor with a potassium sparing diuretic (e.g. spironolactone, triamterene, or amiloride), potassium supplements, 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 monitored frequently.

Antidiabetic agents (e.g. 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).

Nonsteroidal anti-inflammatory drugs.

Drugs with prostaglandin synthetase inhibitor properties (e.g. indomethacin) may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors. However, clinical studies have not demonstrated any interaction between perindopril or indomethacin or other nonsteroidal anti-inflammatory drugs.

Tetracycline and other drugs 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 coprescribing an ACE inhibitor and tetracycline or other drugs that interact with magnesium.

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 and perindopril.

Effects on laboratory tests.

A small reduction in haemoglobin and haematocrit has been reported (this has been noted with other ACE inhibitors). An unexplained change in prothrombin ratio was reported in one patient.
Rare cases of hyperkalaemia have been noted. Increases in urea and in plasma creatinine levels, reversible when treatment is stopped, have been noted. These increases are more frequent in cases of renal artery stenosis, arterial hypertension treated with diuretics, renal insufficiency, renovascular hypertension and severe heart failure. Elevation of liver enzymes and serum bilirubin have been reported rarely.

Adverse Effects

Adverse events that have been observed during treatment with perindopril are listed below ranked under the following frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000 and including isolated reports).
The most frequent adverse reactions noted in clinical studies were as follows (incidence 2% - 5.3%).
Headache (5.3%) usually at the beginning of treatment and resulting in withdrawal of treatment in 7 of 1275 patients (0.5%).
Asthenia (4.9%) leading to withdrawal in 0.4% of cases.
Dizziness (4.2%) and nausea or epigastric pain (2.4%) leading to withdrawal in 0.5% of patients.
Cough (3.1%). ACE inhibitor induced cough is generally a nocturnal, dry, irritating laryngeal cough occurring at the beginning of treatment. Using these criteria perindopril induced cough was reported in 18 cases (1.4%). Treatment was discontinued in 6 cases.
Other adverse reactions reported were as follows.

General disorders.

Uncommon: sweating, atypical chest pain.

Cardiovascular system.

Common: hypotension and effects related to hypotension, palpitations, flushing, impaired peripheral circulation.
Very rare: arrhythmia, angina pectoris, myocardial infarction and stroke, possibly secondary to excessive hypotension in high risk patients, vasculitis.

Musculoskeletal.

Common: muscle cramps.

GI system.

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

Metabolic disorder.

oedema.

Nervous system.

Common: drowsiness, vertigo, paraesthesia.
Uncommon: mood or sleep disturbance (insomnia, dream abnormality).
Very rare: depression, confusion, hallucinations.

Respiratory system.

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

Skin and appendages.

Common: rash, pruritus.
Uncommon: urticaria, angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx.
Very rare: erythema multiforme.

Special senses.

Common: visual disturbances, tinnitus.

Urogenital.

Uncommon: impotence.

Hepatobiliary disorders.

Very rare: hepatitis, either cytolytic or cholestatic.

Renal and urinary disorders.

Uncommon: renal insufficiency.
Very rare: acute renal failure.

Blood and the lymphatic system disorders.

Very rare: decreases in haemoglobin and haematocrit, thrombocytopenia, leucopenia/ neutropenia, agranulocytosis or pancytopenia. An unexplained change in prothrombin ratio was reported in one patient. Haemolytic anaemia has been reported in patients with congenital G-6PDH deficiency.

Withdrawals.

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

Dosage and Administration

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

Renal impairment.

In patients with renal failure, treatment should begin with one 2 mg tablet daily. Dosage should be adjusted as indicated below according to creatinine clearance. Creatinine and potassium levels should be closely monitored.
If the creatinine clearance is between 30 and 60 mL/minute, dosage should be one 2 mg tablet daily. If the creatinine clearance is between 15 and 30 mL/minute, dosage should be one 2 mg tablet every two days. If the creatinine clearance is below 15 mL/minute, dosage should be one 2 mg tablet on the day of dialysis (perindopril is dialysable (70 mL/minute)).

Hypertension.

The usual starting dose is one 4 mg tablet once daily, taken in the morning. Optimum control of blood pressure is achieved by increasing the dose, titrating it against the blood pressure to a maximum of one 8 mg tablet once daily.
A starting dose of one 2 mg tablet per day is recommended in the following patients who may be at risk of ACE inhibitor induced hypotension.

Combination with a diuretic.

The administration of perindopril to patients under current diuretic therapy may induce hypotension and sometimes, but more rarely, acute renal failure, at the beginning of the treatment. It is recommended to monitor plasma creatinine during the first month of treatment.

Elderly hypertensives.

Elderly hypertensive patients should start treatment with one 2 mg tablet daily, with titration to one 4 mg tablet if necessary. It is recommended that renal function be assessed before starting treatment.

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

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

Congestive heart failure.

Treatment of congestive heart failure with perindopril should be initiated under close medical supervision.
The usual starting dose of perindopril one 2 mg tablet once daily, which should be given with a diuretic and/or digitalis. This is increased to one 4 mg tablet once daily for maintenance.
Patients with severe hepatic or renal impairment and/or severe salt/ volume depletion are particularly sensitive to ACE inhibitors. Doses in these patients should be carefully titrated as no pharmacokinetic and dose titration studies have been conducted.

Reduction of risk of cardiovascular events.

In patients with stable coronary artery disease, perindopril should be introduced at a dose of one 4 mg tablet once daily for two weeks, and then increased to one 8 mg tablet once daily, depending on tolerance and renal function.
Elderly patients should receive one 2 mg tablet once daily for one week, then one 4 mg tablet once daily the next week, before increasing the dose up to one 8 mg tablet once daily depending on tolerance and renal function.

Overdosage

Limited data are available for overdosage in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. The recommended treatment of overdosage is intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in the shock position. Perindopril may be removed from the general circulation by haemodialysis (see Precautions section). Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
Advice on overdose management can be obtained from the national Poisons Information Centre by telephoning 131 126.

Presentation

Tablets (white, uncoated), 2 mg (round, biconvex, plain on both sides); 4 mg (capsule shaped, scored on both sides); 8 mg (round, plain on both sides): 30's (blister pack in aluminium pouch containing dessicant).

Storage

Store in a dry place below 30°C.

Poison Schedule

S4.