APO-PERINDOPRIL ARGININE perindopril arginine 5 mg tablet blister pack

Main information

  • Trade name:
  • APO-PERINDOPRIL ARGININE perindopril arginine 5 mg tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • APO-PERINDOPRIL ARGININE perindopril arginine 5 mg tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 184814
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

184814

APO-PERINDOPRIL ARGININE perindopril arginine 5 mg tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Apotex Pty Ltd

Postal Address

PO Box 280,NORTH RYDE BC, NSW, 1670

Australia

ARTG Start Date

26/04/2012

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. APO-PERINDOPRIL ARGININE perindopril arginine 5 mg tablet blister pack

Product Type

Single Medicine Product

Effective date

3/03/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Treatment of hypertension and the treatment of heart failure. In such patients it is recommended that perindopril arginine be given with a diuretic and/or

digoxin under close medical supervision. (The safety and efficacy of perindopril arginine has not been demonstrated for New York Heart Association

Category IV patients); and patients with established coronary artery disease (See Clinical Trials) who are stable on concomitant therapy and have no

heart failure, to reduce the risk of non-fatal myocardial infarction or cardiac arrest.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

Al/Al

24 Months

Store below 25

degrees Celsius

Not recorded

Protect from Moisture

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. APO-PERINDOPRIL ARGININE perindopril arginine 5 mg tablet blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

Light green coloured, capsule-shaped, biconvex, film coated tablets, with

notch and engraved APO on one side and P 5 on the other side

Active Ingredients

perindopril arginine

5 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 04:14:15 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Product Information – Australia

APO- Perindopril Arginine tablets

Page 1

APO-

PERINDOPRIL ARGININE TABLET

NAME OF THE MEDICINE

Perindopril Arginine.

Chemical Name:

L-arginine (2S,3aS,7aS)-1-N-[(S)-1-ethoxycarbonyl butyl]-L-alanyl)

perhydroindole-2-carboxylate

Structural Formula:

Molecular Formula:

Molecular Weight:

542.669

CAS Registry Number:

612548-45-5

DESCRIPTION

Perindopril is a dipeptide monoacid monoester with a perhydroindole group and no sulphydryl radical.

Perindopril arginine is a white powder, readily soluble in purified water, slightly soluble in 95% ethanol

and practically insoluble in chloroform. Perindopril has five asymmetric centres and is synthesised

stereoselectively so that it is a single enantiomer (all S stereochemistry).

Each tablet contains the active ingredient perindopril arginine and following inactive ingredients:

isomalt, colloidal anhydrous silica, magnesium stearate, hypromellose, hyprolose, macrogol 8000 and

titanium dioxide.

5 mg and 10mg tablets contain brilliant blue FCF aluminium lake and yellow iron oxide.

PHARMACOLOGY

Pharmacological 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

perindopril

arginine

unknown.

Animal

studies

have

demonstrated

reversal

vascular

hypertrophy and an improvement in the ratio of elastin to collagen in the vessel wall. Studies in man

have demonstrated an improvement in the visco-elastic properties of large vessels and in compliance.

Studies in animals and humans suggest that specific and competitive suppression of the renin-

angiotensin-aldosterone system (RAAS) is the main mechanism by which blood pressure is reduced.

However,

antihypertensive

activity

also

been

observed

patients

with

renin

activity.

Perindopril arginine may also inhibit the degradation of the potent vasodepressor peptide, bradykinin,

and this action may contribute to its antihypertensive action. Perindopril arginine appears to reduce

peripheral resistance and may influence arterial compliance.

Product Information – Australia

APO- Perindopril Arginine tablets

Page 2

Studies carried out in animal models of hypertension have shown that perindopril arginine is a specific

competitive angiotensin I converting enzyme inhibitor. The administration of perindopril arginine to

patients with essential hypertension results in a reduction in supine and standing blood pressure

without any significant effect on heart rate. Abrupt withdrawal of perindopril arginine has not been

associated with a rebound rise in blood pressure. Single dose studies have demonstrated that peak

inhibition of ACE activity and peak reduction in blood pressure occurs 4-6 hours after administration.

The durations of these effects are dose related and at the recommended dose range, both effects

have been shown to be maintained over a 24-hour period.

In haemodynamic studies carried out in animal models of hypertension, blood pressure reduction after

perindopril arginine administration was accompanied by a reduction in peripheral arterial resistance

and improved arterial wall compliance. In studies carried out in patients with essential hypertension

the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no

change, or a small increase in renal blood flow and no change in glomerular filtration rate. An

increase in the compliance of large arteries was also observed. When perindopril arginine is

administered together with a thiazide-type diuretic, the antihypertensive activity of perindopril arginine

may be potentiated in some patients, and this effect is evident after four weeks of treatment.

Perindopril arginine, like other ACE inhibitors, may compensate for thiazide-induced hypokalaemia.

In one study of 48 patients where low-dose perindopril, equivalent to perindopril arginine 2.5 mg, was

compared with correspondingly low doses of enalapril (2.5 mg) or captopril (6.25 mg) in patients with

congestive heart failure, significantly different blood pressure responses were noted. Blood pressure

fell significantly with captopril and enalapril following the first dose. However, whilst perindopril

inhibited plasma ACE comparably with enalapril, the blood pressure changes were insignificant and

similar to placebo for up to 10 hours of regular observation. The possibility of a late hypotensive

response are not available for perindopril.

Pharmacokinetics

Absorption

Following oral administration, perindopril arginine is rapidly absorbed with bioavailability of 24%.

Elimination is rapid, occurring predominantly via the urine. Plasma half-life is approximately 1 hour.

Bioavailability of the active metabolite perindoprilat is approximately 27%.

Distribution

Peak plasma concentrations of perindoprilat occur 3 to 4 hours after oral administration of perindopril

arginine. Protein binding of perindoprilat is 20%, principally to angiotensin converting enzyme. When

perindopril arginine is administered chronically, steady state of perindoprilat is reached within 4 days,

and perindoprilat does not accumulate.

Metabolism

Apart from perindoprilat, the administration of perindopril leads to the formation of 5 other metabolites,

all of which are inactive and exist in very low quantities. One of these is the glucuronoconjugate of

perindoprilat, which is formed by a hepatic first-pass effect. This effect does not appear to have any

influence on the kinetics of perindoprilat. Food intake may reduce hepatic biotransformation to

perindoprilat.

Elimination

Perindoprilat binds to plasma and tissue ACE, and free perindoprilat is eliminated through the urine.

The terminal half-life of the unbound fraction is approximately 17 hours.

The elimination of perindoprilat is reduced in elderly patients and in patients with cardiac and renal

failure (see DOSAGE AND ADMINISTRATION).

In a study comparing this product with the reference product, the two products were shown to be

bioequivalent. The 90% confidence intervals for the ratio of AUC

and C

were found to be

between 0.98-1.06 and 0.93-1.15 respectively for perindopril; 0.96-1.02 (AUC

) and 0.91-1.04 per

perindoprilat.

CLINICAL TRIALS

Patients with stable coronary artery disease:

Product Information – Australia

APO- Perindopril Arginine tablets

Page 3

The effects of perindopril were compared to placebo in patients with stable coronary artery disease

with no clinical signs of heart failure. The EUROPA (European trial on Reduction Of cardiac events

with Perindopril in stable coronary Artery disease) study was a multicentre, international, randomised,

double blind, placebo-controlled clinical trial lasting 4 years. 12,218 patients aged over 18 were

randomised: 6110 patients to high dose perindopril, equivalent to perindopril arginine 10 mg and 6108

patients to placebo.

The primary endpoint was the composite of cardiovascular mortality, non-fatal myocardial infarction,

and/or cardiac arrest with successful resuscitation.

The trial population had evidence of coronary artery disease documented by previous myocardial

infarction at least 3 months before screening, coronary revascularisation at least 6 months before

screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary

arteries), or positive stress test in men with a history of chest pain.

Study

medication

added

conventional

treatment,

including

medication

used

management

hyperlipidaemia,

hypertension

diabetes

mellitus.

Patients

randomised

perindopril

were

initiated

doses

perindopril

equivalent

perindopril

arginine

perindopril arginine 5 mg for 2 weeks, and then titrated up to a dose of perindopril equivalent to

perindopril arginine 10 mg during the 2 following weeks. A dose of perindopril equivalent to perindopril

arginine 10 mg was then maintained for the whole duration of the study. If this dose was not well

tolerated, it could be reduced to a dose of perindopril equivalent to perindopril arginine 5 mg once

daily.

Most of the patients also received platelet inhibitors, lipid-lowering agents and beta-blockers. At the

end of the study, the proportions of patients treated with a combination of these medications were

91%, 69% and 63% respectively.

results

EUROPA

study,

specifically

primary

endpoint

components

(cardiovascular

mortality,

non-fatal

myocardial

infarction

resuscitated

cardiac

arrest)

intention-to-treat (ITT) population are presented in the following table.

EUROPA Study Results (ITT population)

Note 1

Perindopril

(n=6110)

Placebo

(n=6108)

Absolute

Risk

Reduction

[95% CI]

NMT

Note 2

over 4.2 yr

trial period

(per year)

Relative

Risk

Reduction

[95% CI]

p

(log-rank)

Cardiovascular events

(Primary composite

endpoint)

488 (8.0%)

603 (9.9%)

1.9%

[0.87; 2.90]

(227)

[9; 29]

0.0003

Primary Endpoint

Component :

– Cardiovascular

mortality

215 (3.5%)

249 (4.1%)

non-

significant

[-3; 28]

0.107

– Non-fatal MI

Note 3

295 (4.8%)

378 (6.2%)

1.4%

[0.55; 2.17]

(311)

[10; 33]

0.001

– Cardiac arrest with

successful

resuscitation

6 (0.1%)

11 (0.2%)

non-

significant

[-47; 80]

0.223

Secondary Endpoints:

Total mortality

375 (6.1%)

420 (6.9%)

non-

significant

[-2; 23]

0.101

Non-fatal and fatal MI

320 (5.2%)

418 (6.8%)

1.6%

[0.76; 2.44]

(265)

23.9%

[12, 34]

<0.001

Notes:

The EUROPA study was designed to have adequate statistical power to detect a treatment effect on the

composite primary endpoint, and not for the individual components.

NNT = Number of patients needed to be treated to prevent one event.

MI = Myocardial Infarction.

Product Information – Australia

APO- Perindopril Arginine tablets

Page 4

The reduction in the primary composite endpoint was mainly due to a reduction in the number of non-

fatal myocardial infarctions. There was no significant reduction in the rate of cardiovascular mortality

or total mortality in patients taking perindopril compared to those taking placebo.

After a mean follow-up of 4.2 years, treatment with a dose of perindopril equivalent to perindopril

arginine 10 mg once daily resulted in a significant relative risk reduction of 20% (95%CI: 9-29) in the

primary combined endpoint: 488 patients (8.0%) reported events in the perindopril group compared to

603 patients (9.9%) in the placebo group (p = 0.0003). Improvements in the primary composite

endpoint achieved statistical significance after 3 years of continuous treatment on perindopril.

INDICATIONS

The treatment of hypertension;

The treatment of heart failure. In such patients it is recommended that perindopril arginine be

given with a diuretic and/or digoxin under close medical supervision. (The safety and efficacy of

perindopril arginine has not been demonstrated for New York Heart Association Category IV

patients); and

Patients

with

established

coronary

artery

disease

(See

Clinical

Trials)

stable

concomitant therapy and have no heart failure, to reduce the risk of non-fatal myocardial infarction

or cardiac arrest.

CONTRAINDICATIONS

Perindopril arginine tablets are contraindicated

in patients with a history of previous hypersensitivity to the active ingredient perindopril or any of

the excipient ingredients present in this product;

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

experience

anaphylactoid

reactions

they

treated

with

inhibitors.

This

combination should therefore be avoided, either by use of alternative antihypertensive drugs or

alternative membranes (e.g. cuprophane or polysulphone PSF);

combined use with aliskiren-containing products in patients with diabetes or renal impairment

(GFR

<

mL/min/1.73

(see

INTERACTIONS

WITH

OTHER

MEDICINES

PRECAUTIONS).

PRECAUTIONS

Hyperkalaemia

Since ACE inhibitors reduce angiotensin II formation resulting in decreased production of aldosterone,

increases in serum potassium have been observed in some patients treated with ACE inhibitors

including perindopril. Serum electrolytes (including sodium potassium and urea) should be measured

from time to time when ACE inhibitors are given and especially in combination with diuretics.

Hyperkalaemia can cause serious, sometimes fatal, arrhythmias. Risk factors for the development of

hyperkalaemia include those with renal insufficiency, worsening of renal function, age (> 70 years),

diabetes, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic

acidosis

combined

potassium-sparing

diuretics

(e.g.

spironolactone,

eplerenone,

triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or those

patients

taking

other

medicines

associated

with

increases

serum

potassium

(e.g.

heparin).

Combined use of the above-mentioned medicines should be used with caution in combination with

ACE inhibitors. Frequent monitoring of serum potassium is needed (see INTERACTIONS WITH

OTHER MEDICINES). In some patients hyponatraemia may co-exist with hyperkalaemia.

Diabetes

Product Information – Australia

APO- Perindopril Arginine tablets

Page 5

Glycaemic control should be closely monitored during the first month of treatment with an ACE

inhibitor in patients with diabetes treated with oral medicines or insulin (see INTERACTIONS WITH

OTHER MEDICINES).

Angioedema

Patients with a history of angioedema unrelated to ACE inhibitor treatment may be at increased risk of

angioedema while treated with an ACE inhibitor.

Life-threatening angioedema has been reported with most ACE inhibitors. The overall incidence is

approximately 0.1-0.2%. The aetiology is thought to be non-immunogenic and may be related to

accentuated bradykinin activity. Usually the angioedema is non-pitting oedema of the skin mucous

membrane and subcutaneous tissue.

Angioedema of the face, extremities, lips, tongue, mucous membranes, glottis and/or larynx has been

reported in patients treated with ACE inhibitors and has been reported uncommonly with perindopril

arginine (see ADVERSE EFFECTS). This may occur at any time during treatment. In such cases

perindopril arginine should be promptly discontinued and the patient carefully observed until the

swelling disappears.

Where such cases have been described with other ACE inhibitors and swelling has been confined to

the face and lips, the condition has generally resolved without treatment although antihistamines have

been useful in relieving symptoms. Angioedema associated with laryngeal oedema may be fatal or

near fatal. In most cases symptoms occurred during the first week of treatment and the incidence

appears to be similar in both sexes or those with heart failure or hypertension.

Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction,

appropriate

treatment

(e.g.

adrenaline

oxygen)

should

given

promptly.

Treatment

progressive angioedema should be aggressive and failing a rapid response to medical treatment,

mechanical methods to secure an airway should be undertaken before massive oedema complicates

oral or nasal intubation.

Patients who respond to medical treatment should be observed carefully for a possible rebound

phenomenon.

The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months.

Patients may have multiple episodes of angioedema with long symptom-free intervals.

Angioedema may occur with or without urticaria.

Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients

presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior

facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by

procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after

stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of

patients on ACE inhibitors presenting with abdominal pain.

ACE inhibitors should not be reintroduced in patients who have a history of angioedema due to rare

reports of recurrence.

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

Rarely, patients treated with ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran

sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by

temporarily withholding ACE inhibitor therapy prior to each apheresis.

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes, who are

treated with an ACE inhibitor. In these patients consider using a different type of dialysis membrane or

a different class of antihypertensive medicines (see CONTRAINDICATIONS).

Anaphylactic reactions during desensitisation

Product Information – Australia

APO- Perindopril Arginine tablets

Page 6

Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have

experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when

the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Hypotension

Hypotension has been reported in patients commencing treatment with ACE inhibitors. Symptomatic

hypotension is rarely seen in uncomplicated hypertension but is a potential consequence of perindopril

arginine use in salt/volume-depletion, for example, in patients vigorously treated with diuretics, in

patients on dialysis, with impaired renal function, following severe diarrhoea or vomiting, in patients on

dietary restrictions or those with severe renin-dependent hypertension (see PRECAUTIONS and

ADVERSE EFFECTS).

Administration of a dose of perindopril equivalent to perindopril arginine 2.5 mg to patients with mild-

moderate heart failure was not associated with any significant reduction in blood pressure. In patients

with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension

has been observed. This is more likely to occur in those patients with severe heart failure, as reflected

by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. This may be

associated with syncope, neurological deficits, oliguria and/or progressive increase in blood nitrogen,

and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in

these patients, treatment should be started at low doses under very close supervision. Such patients

should be followed closely for the first two weeks of treatment and whenever the dose is increased, or

the diuretic treatment is commenced or increased.

Patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure

could result in myocardial infarction or cerebrovascular accident should be closely followed for the first

two weeks of treatment and whenever the dose of perindopril arginine and/or diuretic is increased. In

all high-risk patients it is advisable to initiate treatment with one perindopril arginine 2.5 mg tablet once

daily.

In some patients with congestive heart failure who have normal or low blood pressure, additional

lowering of systemic blood pressure may occur with perindopril. This is anticipated and is usually not

a reason to discontinue treatment. If symptomatic hypotension occurs, a reduction of dose or

discontinuation of perindopril may be necessary.

If hypotension occurs the patient should be placed in a supine position and if necessary infused with

normal saline. A transient hypotensive response is not a contraindication to further doses, which can

usually be given without difficulty when blood pressure has increased following volume expansion.

Renal Impairment

As a consequence of inhibiting the RAAS, changes in renal function may be anticipated in susceptible

individuals. In patients with severe congestive heart failure whose renal function may depend on

RAAS activity, treatment with ACE inhibitors may be associated with oliguria and/or progressive

increase in blood nitrogen, and rarely with acute renal failure and/or death.

In patients with symptomatic heart failure, hypotension following the initiation of treatment with ACE

inhibitors may lead to further impairment in renal function. Acute renal failure, usually reversible, has

been reported in this situation.

ACE inhibitors should be avoided in patients with known or suspected renal artery stenosis (see

CONTRAINDICATIONS section).

In clinical studies in patients with hypertension and unilateral or bilateral renal artery stenosis,

increases in blood urea, nitrogen and serum creatinine were observed in 20% of patients. These

increases are usually reversible upon discontinuation. 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 Renal function may also be reduced in patients with stenosis

of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces the

pressure

afferent

glomerular

arteriole,

transglomerular

hydrostatic

pressure

then

maintained by angiotensin II-induced constriction of the efferent arteriole. When an ACE inhibitor is

given, the efferent arteriole relaxes, glomerular filtration pressure falls, and renal failure may result.

ACE inhibitors can lead to the thrombotic occlusion of a stenosed renal artery.

Product Information – Australia

APO- Perindopril Arginine tablets

Page 7

If renovascular hypertension is also present, treatment should be started under close medical

supervision

with

doses

careful

dose

titration.

There

increased

risk

severe

hypotension and renal insufficiency. Since treatment with diuretics may be a contributory factor to the

above, they should be discontinued and renal function should be monitored during the first weeks of

perindopril treatment.

Some patients with hypertension and no apparent pre-existing renovascular disease have developed

increases in blood urea, nitrogen and serum creatinine, which are usually minor and transient,

particularly when perindopril has been given in combination with a diuretic. However, increases in

blood urea, nitrogen and serum creatinine are more likely to occur in patients with pre-existing renal

impairment or in those on diuretics. Dose reduction of the ACE inhibitor and/or discontinuation of the

diuretic may be required.

Renal function should always be assessed (see DOSAGE AND ADMINISTRATION). In the case of

renal impairment, the initial perindopril dose should be adjusted according to the patient’s creatinine

clearance (see DOSAGE AND ADMINISTRATION). Routine monitoring of potassium and creatinine

are part of normal medical practice for these patients (see ADVERSE EFFECTS). If a deterioration in

renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by

another and in these patients use of another class of antihypertensive agent would be preferable.

Patients with unilateral renal artery disease present a special problem as deterioration of function may

not be apparent from measurement of blood urea and serum creatinine.

Some ACE inhibitors have been associated with the occurrence of proteinuria (up to 0.7%) and/or

decline in renal function in patients with one or more of the following characteristics: old age, pre-

existing renal disease, concomitant treatment with potassium-sparing diuretics or high doses of other

diuretics, limited cardiac reserve, or treatment with a non-steroidal anti-inflammatory drug (NSAID).

Perindopril is dialysable with a clearance of 70 mL/min.

Kidney transplantation

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

transplantation.

Hepatic failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and

progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is

not understood. Patients treated with ACE inhibitors who develop jaundice or marked

elevations of

hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up (see

ADVERSE EFFECTS).

Hepatic Impairment

Biotransformation of perindopril to perindoprilat mainly occurs in the liver. Studies in patients with

hepatic impairment have shown that kinetic parameters of perindopril were not modified by hepatic

failure. With the exception of bioavailability, which was increased, kinetic parameters of perindoprilat

(including T

) were also unchanged. The increase in bioavailability could be due to inhibition of the

formation

perindopril

metabolites

other

than

perindoprilat

(see

PHARMACOLOGY,

Pharmacokinetics). The administration of perindopril leads to the formation of a glucuronoconjugate

derivative of perindoprilat by a hepatic first-pass effect. The kinetic parameters of perindoprilat

glucuronide are not modified by hepatic failure. The small changes in the kinetics of perindoprilat do

not justify the need to change the usual dose in most patients with hepatic failure.

Ethnicity

ACE inhibitors cause a higher rate of angioedema in patients of indigenous African origin than in

patients of other racial origin. As with other ACE inhibitors, perindopril may be less effective in

lowering blood pressure in people of indigenous African origin than in people of other racial origin,

possibly because of a higher prevalence of low-renin states in this population. It is unknown if the

same observations have been made in patients of indigenous Australian origin.

Cough

A persistent dry (non-productive) irritating cough has been reported with most of the ACE inhibitors.

The frequency of reports has been increasing since cough was first recognised as a class-effect of

Product Information – Australia

APO- Perindopril Arginine tablets

Page 8

ACE inhibitor treatment with the incidence of cough varying between 2-15% depending upon the drug,

dose and duration of use.

The cough is often worse when lying down or at night, and has been reported more frequently in

women (who account for two-thirds of the reported cases). Patients who cough may have increased

bronchial reactivity compared with those who do not. The observed higher frequency of this side-

effect in non-smokers may be due to a higher level of tolerance of smokers to cough.

The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or

prostaglandins,

which

accumulate

because

inhibition.

Once

patient

developed

intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor; the reaction

may recur but this is not invariably the case. A change to another class of drugs may be required in

severe cases.

Proteinuria

Perindopril arginine treatment has occasionally been associated with mild or transient proteinuria

(< 1 gram/per 24 hours). However in the majority of patients with pre-existing proteinuria treated with

perindopril arginine, proteinuria disappeared or remained stable. ACE inhibitors have potential to

delay the progression of nephropathy in patients with diabetes, or hypertension.

Neutropaenia/Agranulocytosis/Thrombocytopenia/Anaemia

Neutropaenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients treated

with ACE inhibitors. In patients with normal renal function and no other complicating factors,

neutropaenia occurs rarely. Perindopril arginine should be used with extreme caution in patients with

collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or

a combination of these complicating factors, especially if there is pre-existing impaired renal function.

Some of these patients developed serious infections, which in a few instances did not respond to

intensive antibiotic treatment. If perindopril arginine is used in such patients, periodic monitoring of

white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g.

sore throat, fever).

Dermatological Reactions

Dermatological

reactions

characterised

maculo-papular

pruritic

rashes

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. 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.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

As a consequence of inhibiting the RAAS, hypotension, syncope, stroke, hyperkalaemia, and changes

in renal function (including acute renal failure) have been reported in susceptible individuals, especially

if combining medicines that affect this system. Dual blockade of the RAAS through the combined use

of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see

CONTRAINDICATIONS and INTERACTIONS WITH OTHER MEDICINES). If dual blockade therapy

is considered absolutely necessary, this should be limited to individually defined cases under specialist

supervision with frequent close monitoring of renal function, electrolytes and blood pressure.

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APO- Perindopril Arginine tablets

Page 9

The combination of perindopril with aliskiren is contraindicated in patients with diabetes or renal

impairment (GFR < 60 mL/min/1.73 m

) (see CONTRAINDICATIONS and INTERACTIONS WITH

OTHER MEDICINES).

ACE inhibitors and angiotensin receptor blockers should not be used in combination in patients with

diabetic nephropathy.

Surgery and Anaesthesia

Perindopril may block angiotensin II formation secondary to compensatory renin release in patients

undergoing major surgery during anaesthesia with agents that produce hypotension, and cause further

reduction in blood pressure. Treatment should be discontinued one day prior to the surgery.

Perioperative hypotension can be corrected with volume expansion.

Aortic or Mitral Valve Stenosis / Hypertrophic Cardiomyopathy

There has been some concern on theoretical grounds that patients with mitral valve stenosis and

obstruction

outflow

left

ventricle

such

aortic

stenosis

with

hypertrophic

cardiomyopathy might be at particular risk of decreased coronary perfusion when treated with

vasodilators, including ACE inhibitors. Vasodilators may tend to drop diastolic pressure, and hence

coronary perfusion pressure, without producing the concomitant reduction in myocardial oxygen

demand that normally accompanies vasodilatation. The true clinical importance of this concern is

uncertain.

Stable Coronary Artery Disease

If an episode of unstable angina pectoris, regardless of severity, occurs during the first month of

perindopril treatment, a careful appraisal of the benefits/risks of continuing treatment should be

performed.

Effects on Fertility

The effects of perindopril arginine on fertility have not been investigated. Studies in rats showed no

impairment of male or female fertility at oral perindopril erbumine doses up to 10mg/kg/day.

Use in Pregnancy (Category D)

The use of ACE inhibitors is contraindicated during pregnancy (see CONTRAINDICATIONS).

As with all ACE inhibitors, perindopril arginine should not be taken during pregnancy. Pregnancy

should be excluded before starting treatment

with perindopril arginine

and avoided during the

treatment. Unless continued treatment with an ACE inhibitor is considered essential, patients planning

pregnancy should be changed to alternative anti-hypertensive treatments which have an established

safety profile for use in pregnancy. If a patient intends to become pregnant, treatment with ACE

inhibitors must be discontinued and replaced by another form of treatment. If a patient becomes

pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in

medication and further management.'

Perindopril or its metabolites have been shown to cross the placenta and distribute to the foetus in

pregnant animals. There are no adequate and well-controlled studies of ACE inhibitors in pregnant

women, but foetotoxicity is well documented in animal models. Data, however, show that ACE

inhibitors cross the human placenta. Post marketing experience with all ACE inhibitors suggests that

exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus.

ACE inhibitors have also been associated with foetal death in utero.

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors

during the first trimester of pregnancy has not been conclusive; however a small increase in risk

cannot be excluded.

A historical cohort study in over 29,000 infants born to non-diabetic mothers has shown 2.7 times

higher risk for congenital malformations in infants exposed to ACE inhibitors during the first trimester

compared

exposure.

risk

ratios

cardiovascular

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.

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APO- Perindopril Arginine tablets

Page 10

When ACE inhibitors have been used during the second and third trimesters of pregnancy, there have

been

reports

foetal

neonatal

toxicity,

hypotension,

hyperkalaemia,

renal

failure,

skull

hypoplasia, oligohydramnios and death.

Oligohydramnios has been reported, presumably resulting from decreased foetal renal function;

oligohydramnios

been

associated

with

foetal

limb

contractures,

craniofacial

deformities,

hypoplastic lung development and intra-uterine growth retardation. Prematurity and patent ductus

arteriosus have been reported, however it is not clear whether these events were due to ACE inhibitor

exposure or to the mother's underlying disease.

Infants exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria, and

hyperkalaemia. Should exposure to ACE inhibitors have occurred from the second trimester of

pregnancy, ultrasound check of renal function and skull is recommended. If such complications arise,

appropriate medical treatment should be initiated to support blood pressure and renal perfusion.

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 arginine should not be

given to lactating women as the possible effect on the newborn is unknown. Alternative treatments

with better established safety profiles during breastfeeding are preferable, especially while nursing a

newborn or preterm infant.

Paediatric Use

Use of perindopril arginine in children is not recommended as no data establishing safety or

effectiveness in children are available.

Use in the Elderly

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when

prescribing perindopril arginine to elderly patients. The initial dose in the elderly should always be one

perindopril arginine 2.5 mg tablet once daily and patients should be monitored closely during the initial

stages of treatment (see 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.

Genotoxicity

Results from a broad set of assays for gene mutation and chromosomal damage with perindopril

arginine suggest no genotoxic potential at clinical doses.

Carcinogenicity

Carcinogenicity studies have not been conducted with perindopril arginine.

No evidence of carcinogenic activity was observed in mice and rats when perindopril erbumine was

administered via drinking water at levels up to 7.5mg/kg/day for 2 years. At least one ACE inhibitor

has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The

potential of ACE inhibitors to cause this effect in man is unknown. Moreover, the progression of

oxyphilic cells to oncocytomas is rare in humans and when it does occur, it is considered to be benign.

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.

Effects on Laboratory Tests

Increases in blood urea and plasma creatinine, hyperkalaemia reversible on discontinuation may

occur,

especially

presence

renal

insufficiency,

severe

heart

failure

renovascular

hypertension. Elevation of liver enzymes and serum bilirubin have been reported rarely.

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APO- Perindopril Arginine tablets

Page 11

INTERACTIONS WITH OTHER MEDICINES

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS)

through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated

with higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal

function (including acute heart failure) compared to the use of a single RAAS-acting agent (see

CONTRAINDICATIONS, PRECAUTIONS and CLINICAL TRIALS).

Medicines Inducing Hyperkalaemia:

ACE inhibitors can attenuate potassium loss caused by thiazide diuretics and increase serum

potassium when used alone. Although serum potassium usually remains within normal limits,

hyperkalaemia may occur in some patients treated with an ACE inhibitor. The combined use of an

ACE inhibitor

with

potassium-sparing

diuretic (e.g.

spironolactone, triamterene,

amiloride),

immunosuppressant (e.g. cyclosporin), angiotensin receptor blocker, NSAID, heparin, potassium

supplement, or potassium-containing salt substitute can increase the risk of hyperkalaemia. The

combination of perindopril arginine with the above mentioned medicines is not recommended (see

PRECAUTIONS). If combined use is indicated they should be used with caution and the patient’s

serum potassium monitored frequently.

Combined use which is contraindicated (see CONTRAINDICATIONS and PRECAUTIONS):

Aliskiren

Patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m

), may be at risk of hypotension,

syncope, stroke, hyperkalaemia and changes in renal function (including acute renal failure).

Combined use not recommended (see PRECAUTIONS section):

Aliskiren

Patients other than those with diabetes or renal impairment may be at risk of hyperkalaemia,

worsening

renal

function

cardiovascular

morbidity,

increase

mortality

(see

CONTRAINDICATIONS).

Combined use with ACE inhibitor and angiotensin-receptor blocker

It is reported in the literature that in patients with established atherosclerosis, heart failure, or diabetes

with end organ damage, combined use with an ACE inhibitor and an angiotensin-receptor blocker is

associated with a higher frequency of hypotension, syncope, hyperkalaemia, and worsening renal

function (including acute renal failure) as compared to use of a single RAAS agent. Dual blockade

(e.g., by combining an ACE-inhibitor with an angiotensin receptor blocker) should be limited to

individually defined cases with close monitoring of renal

function, serum potassium, and blood

pressure.

Lithium

Reversible

increases

serum

lithium

concentrations

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.

Potassium Sparing Diuretics (e.g. triamterene, amiloride, potassium salts)

The combined use of perindopril arginine and potassium sparing diuretics may result in potentially

lethal hyperkalaemia especially in patients with renal impairment (additive hyperkalaemic effects). The

combination

perindopril

with

above-mentioned

medicines

recommended

(see

PRECAUTIONS). If the combination is required, it should be used with caution and with frequent

monitoring of serum potassium. For use of spironolactone and eplerenone in heart failure, see

paragraph under ‘combined medicines which require special care’.

Combined use which requires special care:

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

ACE inhibitors may add to the glucose lowering effect, with risk of hypoglycaemia, in patients with

diabetes who are treated with insulin or with oral hypoglycaemic medicines. Hypoglycaemia is very

Product Information – Australia

APO- Perindopril Arginine tablets

Page 12

rare and appears to be more likely to occur during the first weeks of combined treatment, and in

patients with renal impairment.

Baclofen

Baclofen may increase the antihypertensive effect of perindopril arginine. Monitor blood pressure and

adjust the dose of perindopril arginine if necessary.

Non-potassium-sparing Diuretics

Patients treated with diuretics, especially those who are volume and/or salt depleted, may experience

excessive reduction in blood pressure after initiation of treatment with an ACE inhibitor. The possibility

of hypotensive effects can be reduced by discontinuation of the diuretic or by increasing volume or salt

intake prior to commencing treatment with low and progressive doses of perindopril arginine. If it is

not possible to discontinue the diuretic, the starting dose of the ACE inhibitor should be reduced. The

patient should be closely observed for several hours following the initial dose of the ACE inhibitor and

until the blood pressure has stabilised. In arterial hypertension, when prior diuretic treatment has

caused salt/volume depletion, the diuretic must be discontinued before commencing treatment with the

ACE inhibitor. A non-potassium-sparing diuretic can then be reintroduced, or the ACE inhibitor can be

commenced at a low dose and progressively increased. In diuretic-treated congestive heart failure,

the ACE inhibitor should be initiated at a very low dose, possibly after reducing the dose of the

associated non-potassium-sparing diuretic.

In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE

inhibitor treatment.

Potassium-sparing diuretics (eplerenone, spironolactone)

combination

perindopril

potassium

sparing

medicines

(e.g

eplerenone

spironolactone),

potassium

supplements

potassium-containing

salt

substitutes

general

recommended:

Ensure patients do not have hyperkalaemia or renal impairment before commencing treatment with

this combination.

There is a risk of potentially lethal hyperkalaemia with this combination in patients treated for NYHA

Class II-IV heart failure with a reduced ejection fraction, who have been previously treated with

ACE inhibitors and loop diuretics. This risk is particularly high when recommendations for use of

this combination have not been followed.

Weekly monitoring of serum potassium and creatinine levels is recommended in the first month of

the treatment and, monthly thereafter.

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including aspirin > 3 g/day

Medicines with prostaglandin synthetase inhibitor properties (e.g. indomethacin) or an NSAID (i.e.

acetylsalicylic acid at anti-inflammatory dose regimens, non-selective NSAIDs or COX-2 inhibitors)

may diminish the antihypertensive efficacy of concomitantly administered ACE inhibitors. However,

clinical studies have not demonstrated any interaction between perindopril arginine and indomethacin

or other NSAIDs. Combination use of ACE inhibitors and NSAIDs may lead to an increased risk of

worsening

renal

function,

including

possible

acute

renal

failure,

increase

serum

potassium, especially in patients with poor pre-existing renal function. The combination should be

administered with caution, especially in the elderly. Patients should be adequately hydrated and

consideration should be given to monitoring renal function after commencing treatment with the

combination, and periodically thereafter.

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

The combined 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. The combination of

drugs from these three classes should be used with caution particularly in elderly patients or those

with pre-existing renal impairment. Combined use of these medications should be accompanied by

increased monitoring of serum creatinine, particularly at initiation.

Combined use which requires some care:

Gold

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APO- Perindopril Arginine tablets

Page 13

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been

reported rarely in patients treated with injectable gold (sodium aurothiomalate) and concomitant ACE

inhibitor therapy including perindopril.

Antihypertensive agents and vasodilators

Concomitant use of these agents may increase the hypotensive effects of perindopril. Concomitant

use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

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

When an ACE inhibitor and a gliptin are used in combination, there is an increased risk of angioedema

due to the decreased activity of the dipeptidyl peptidase IV (DPP-IV).

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 co-prescribing 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 arginine. Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Tricyclic antidepressants/Antipsychotics/Anaesthetics

Combined use of certain anaesthetics, tricyclic antidepressants and antipsychotics with ACE inhibitors

may result in further reduction of blood pressure (see PRECAUTIONS section).

ADVERSE EFFECTS

The safety profile of perindopril is consistent with the safety profile of ACE inhibitors. The most

frequent adverse events reported in clinical trials and observed with perindopril are: dizziness,

headache,

paraesthesia,

vertigo,

visual

disturbances,

tinnitus,

hypotension,

cough,

dyspnoea,

abdominal

pain,

constipation,

diarrhoea,

dysgeusia,

dyspepsia,

nausea,

vomiting,

pruritis,

rash,

muscle cramps, and asthenia.

Adverse events that have been observed during clinical trials and/or post-marketing use of perindopril

ranked

under

following

frequency:

Very

common

(>1/10);

common

(>1/100,

<1/10);

uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000); very rare (<1/10000 and including isolated

reports).

Blood and the lymphatic system disorders

Uncommon:

Eosinophilia

Very rare:

Decreases

haemoglobin

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 (see PRECAUTIONS)

Metabolism and nutrition disorders

Uncommon:

Hypoglycaemia

(see

PRECAUTIONS

INTERACTIONS

WITH

OTHER

MEDICINES), hyperkalaemia

, reversible on discontinuation (see PRECAUTIONS),

hyponatraemia

Psychiatric Disorders

Uncommon:

Mood or sleep disturbances (insomnia, dream abnormality), somnolence

Very rare:

Depression, confusion, hallucinations

Nervous system disorders

Common:

Headache, dizziness, drowsiness, vertigo, paresthaesia

Uncommon:

Syncope

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APO- Perindopril Arginine tablets

Page 14

Eye disorders

Common:

Vision disturbance

Ear disorders

Common:

Tinnitus

Cardiac disorders

Common:

Palpitations

Uncommon:

Tachycardia

Very rare:

Arrhythmia, angina pectoris, myocardial infarction - possibly secondary to excessive

hypotension in high-risk patients (see PRECAUTIONS)

Vascular disorders

Common:

Hypotension

(and

effects

related

hypotension),

vasculitis,

flushing,

impaired

peripheral circulation

Very rare:

Stroke - possibly secondary to excessive hypotension in high risk patients (see

PRECAUTIONS)

Respiratory, thoracic and mediastinal disorders

Common:

Cough, dyspnoea, epistaxis, discomfort on exertion

Uncommon:

Bronchospasm

Very rare:

Eosinophilic pneumonia, rhinitis

Gastrointestinal disorders

Common:

Nausea, vomiting, abdominal pain, dysgeusia, diarrhoea, dyspepsia, constipation

Uncommon:

Dry mouth

Very rare:

Pancreatitis

Hepatobiliary disorders

Very rare:

Hepatitis, either cytolytic or cholestatic (see PRECAUTIONS)

Skin and subcutaneous tissue disorders

Common:

Rash, pruritus

Uncommon:

Urticaria

(see

PRECAUTIONS),

angioedema

face,

extremities,

lips,

mucous

membranes,

tongue,

glottis

and/or

larynx

(see

PRECAUTIONS),

hyperhidrosis,

photosensitivity reactions

, pemphigoid

, eczema

Very rare:

Erythema multiforme

Musculoskeletal, connective tissue and bone disorders

Common:

Muscle cramps

Uncommon:

Arthralgia

, myalgia

Renal and urinary disorders

Uncommon:

Renal insufficiency

Very rare:

Acute renal failure

Reproductive system and breast disorders

Uncommon:

Erectile dysfunction

General disorders

Common:

Asthenia

Uncommon:

Sweating, chest pain

, atypical chest pain, malaise

, oedema peripheral

, pyrexia

Investigations

Uncommon:

Blood urea increased

, blood creatinine increased

Rare:

Blood bilirubin elevation, hepatic enzyme increases

Injury, poisoning and procedural complications

Uncommon:

Fall

Product Information – Australia

APO- Perindopril Arginine tablets

Page 15

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

Withdrawals

In total, 56 of 1275 patients studied (4.4%) stopped treatment because of adverse reactions. In a

specific study of 632 patients, in which 36 patients (5.7%) withdrew because of adverse events, a

plausible or probable relationship with perindopril treatment was considered to exist in 19 cases (3%).

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 perindopril arginine should be taken

before meals.

Renal Impairment

In patients with renal failure, treatment should begin with one perindopril arginine 2.5 mg tablet daily.

Dosage should be adjusted as indicated below according to creatinine clearance. Creatinine and

potassium levels should be closely monitored.

CREATININE CLEARANCE

(mL/min)

DOSAGE

Between 30 and 60

One 2.5 mg tablet daily

Between 15 and 30

One 2.5 mg tablet every 2 days

Below 15

One 2.5 mg tablet on day of dialysis

[Perindopril is dialysable (70 mL/min)].

Hypertension

The usual starting dose is one perindopril arginine

5 mg tablet once daily, taken in the morning.

Optimum control of blood pressure is achieved by increasing the dose, titrating it against the blood

pressure to a maximum of one perindopril arginine

10 mg tablet once daily.

A starting dose of one perindopril arginine

2.5 mg tablet per day is recommended in the following

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

Combination with a Diuretic

The administration of perindopril arginine to patients currently treated with a diuretic may induce

hypotension and sometimes, but more rarely, acute renal failure, at the beginning of the treatment.

Monitoring of plasma creatinine is recommended during the first month of treatment.

Elderly Patients

Elderly

patients

with

hypertension

should

start

treatment

with

perindopril

arginine

tablet

daily,

with

titration

perindopril

arginine

tablet

necessary.

recommended that renal function be assessed before starting treatment.

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

Patients with renovascular hypertension, salt and/or volume depletion, or cardiac decompensation

may have a strongly activated RAAS. These patients may experience an excessive drop in blood

pressure following the first dose of an ACE inhibitor.

Congestive Heart Failure

Treatment of congestive heart failure with perindopril arginine

should be initiated under close medical

supervision.

The usual starting dose of perindopril arginine

is one perindopril arginine

2.5 mg tablet once daily,

which should be given with a diuretic and/or digitalis. This is increased to one perindopril arginine

mg tablet once daily for maintenance.

Product Information – Australia

APO- Perindopril Arginine tablets

Page 16

Patients with severe hepatic or renal impairment and/or severe salt/volume depletion are particularly

sensitive to ACE inhibitors. Doses in these patients should be carefully titrated as no pharmacokinetic

and dose titration studies have been conducted.

Reduction of risk of cardiovascular events

For stable coronary artery disease, perindopril arginine

should be introduced at a dose of one

perindopril arginine

5 mg tablet once daily for two weeks, and then increased to one perindopril

arginine

10 mg tablet once daily, depending on tolerance and renal function.

Elderly patients should receive one perindopril arginine

2.5 mg tablet once daily for one week, then

one perindopril arginine

5 mg tablet once daily the next week, before increasing the dose up to one

perindopril arginine 10 mg tablet once daily depending on tolerance and renal function (see table

under DOSAGE AND ADMINISTRATION, Renal Impairment

OVERDOSAGE

Limited data are available for overdose in humans. Symptoms associated with overdose of ACE

inhibitors

include

hypotension,

circulatory

shock,

electrolyte

disturbances,

renal

failure,

hyperventilation,

tachycardia,

palpitations,

bradycardia,

dizziness,

anxiety,

cough.

recommended treatment of overdose is intravenous infusion of normal saline solution. If hypotension

occurs, the patient should be placed in the shock position. If available, treatment with intravenous

catecholamines may also be considered. Perindopril may be removed from the general circulation by

haemodialysis (see PRECAUTIONS). Vital signs, serum electrolytes and creatinine concentrations

should be monitored continuously.

For information on the management of overdose, contact the Poisons Information Centre on

13 11 26 (Australia).

PRESENTATION AND STORAGE CONDITIONS

APO-Perindopril Arginine tablets are intended for oral administration.

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

2.5 mg tablets:

White coloured, round shaped, biconvex, film coated tablets, with engraved “APO” on one side and

“2.5” on the other side.

Blister packs (Aluminium/Aluminium silver foil) of 10, 30 and 100 tablets (AUST R 184819).

Bottles (white, round HDPE bottle with child-resistant cap and desiccant) of 30 and 100 tablets (AUST

R 184808).

5 mg tablets:

Light green coloured, capsule-shaped, biconvex, film coated tablets, with notch and engraved “APO”

on one side and “P 5” on the other side.

Blister packs (Aluminium/Aluminium silver foil) of 10, 30 and 100 tablets (AUST R 184814).

Bottle (white, round HDPE bottle with child-resistant cap and desiccant) of 30 and 100 tablets (AUST

R 184806).

10 mg tablets:

Green coloured, round shaped, biconvex, film coated tablets, with engraved “APO” on one side and

“P 10” on the other side.

Blister packs (Aluminium/Aluminium silver foil) of 10, 30 and 100 tablets (AUST R 184809).

Bottles (white, round HDPE bottle with child-resistant cap and desiccant) of 30 and 100 tablets (AUST

R 184812).

Not all strengths, pack types and/or pack sizes may be available.

Product Information – Australia

APO- Perindopril Arginine tablets

Page 17

Storage

Store below 25°C. Protect from moisture.

NAME AND ADDRESS OF THE SPONSOR

Apotex Pty Ltd

16 Giffnock Avenue

Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

POISON SCHEDULE OF THE MEDICINE

S4 – Prescription Only Medicine.

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE

ARTG):

26 April 2012

DATE OF MOST RECENT AMENDMENT:

23 February 2017