Aprovel

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 75 mg tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 75 mg of irbesartan. 
 
Excipient with known effect: 15.37 mg of lactose monohydrate per tablet. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2771 
engraved on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Aprovel is indicated in adults for the treatment of essential hypertension. 
 
It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 
diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 
and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. 
Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 
75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed 
patients and in the elderly over 75 years. 
 
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 
300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In 
particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive 
effect with Aprovel (see section 4.5). 
 
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily 
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. 
 
The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on 
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach 
target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special Populations 
 
Renal impairment 
 



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No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose 
(75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). 
 
Hepatic impairment 
 
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no 
clinical experience in patients with severe hepatic impairment. 
 
Older people 
 
Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of 
age, dosage adjustment is not usually necessary for older people. 
 
Paediatric population 
 
The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently 
available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be 
made. 
 
Method of Administration 
 
For oral use. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Second and third trimesters of pregnancy (see sections 4.4 and 4.6). 
 
The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with 
diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see 
sections 4.5 and 5.1). 
 
4.4 Special warnings and precautions for use 
 
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in 
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, 
diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. 
 
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency 
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney 
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is 
not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor 
antagonists. 
 
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal 
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no 
experience regarding the administration of Aprovel in patients with a recent kidney transplantation. 
 
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and 
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study 
with patients with advanced renal disease. In particular, they appeared less favourable in women and 
non-white subjects (see section 5.1). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 



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aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, 
hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal 
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of 
serum potassium in patients at risk is recommended (see section 4.5). 
 
Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Aprovel is not recommended. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or 
ischaemic cardiovascular disease could result in a myocardial infarction or stroke. 
 
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin 
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, 
possibly because of higher prevalence of low-renin states in the black hypertensive population (see 
section 5.1). 
 
Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but 
the current data are insufficient to support an extension of the use in children until further data become 
available (see sections 4.8, 5.1 and 5.2). 
 
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Diuretics and other antihypertensive agents: other antihypertensive agents may increase the 
hypotensive effects of irbesartan; however Aprovel has been safely administered with other 
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide 
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of 
hypotension when initiating therapy with Aprovel (see section 4.4). 
 
Aliskiren-containing products or ACE-inhibitors: clinical trial data has shown that dual blockade of 
the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, 



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angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events 
such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) 
compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 
 
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other 
medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing 
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products 
that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and 
is, therefore, not recommended (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended 
(see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is 
recommended. 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of 
irbesartan. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 



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Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Breast-feeding 
 
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not 
recommended and alternative treatments with better established safety profiles during breast-feeding 
are preferable, especially while nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
 
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 
Fertility 
 
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing 
the first signs of parental toxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use 
machines. When driving vehicles or operating machines, it should be taken into account that dizziness 
or weariness may occur during treatment. 
 
4.8 Undesirable effects 
 
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did 
not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any 
clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for 
placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the 
recommended dose range), gender, age, race, or duration of treatment. 
 
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic 
dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in 
excess of placebo. 
 
The following table presents the adverse drug reactions that were reported in placebo-controlled trials 
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the 
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with 
chronic renal insufficiency and overt proteinuria and in excess of placebo. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Adverse reactions additionally reported from post-marketing experience are also listed. These adverse 
reactions are derived from spontaneous reports. 
 



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Blood and lymphatic system disorders 
 
Not known:  thrombocytopenia 
 
Immune system disorders 
 
Not known:  hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, 

anaphylactic shock 
 
Metabolism and nutrition disorders 
 
Not known:  hyperkalaemia 
 
Nervous system disorders 
 
Common: dizziness, orthostatic dizziness* 
Not known: vertigo, headache 
 
Ear and labyrinth disorder 
Not known: tinnitus 
 
Cardiac disorders 
 
Uncommon: tachycardia 
 
Vascular disorders 
 
Common: orthostatic hypotension* 
Uncommon: flushing 
 
Respiratory, thoracic and mediastinal disorders 
 
Uncommon: cough 
 
Gastrointestinal disorders 
 
Common: nausea/vomiting 
Uncommon: diarrhoea, dyspepsia/heartburn 
Not known: dysgeusia 
 
Hepatobiliary disorders 
 
Uncommon: jaundice 
Not known: hepatitis, abnormal liver function 
 
Skin and subcutaneous tissue disorders 
 
Not known: leukocytoclastic vasculitis 
 
Musculoskeletal and connective tissue disorders 
 
Common: musculoskeletal pain* 
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase 

levels), muscle cramps 
 



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Renal and urinary disorders 
 
Not known:  impaired renal function including cases of renal failure in patients at risk (see 

section 4.4) 
 
Reproductive system and breast disorders 
 
Uncommon: sexual dysfunction 
 
General disorders and administration site conditions 
 
Common: fatigue 
Uncommon: chest pain 
 
Investigations 
 
Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than 

with placebo. In diabetic hypertensive patients with microalbuminuria and normal 
renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the 
irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic 
hypertensive patients with chronic renal insufficiency and overt proteinuria, 
hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group 
and 26.3% of the patients in the placebo group. 

Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in 
irbesartan treated subjects. None of these increases were associated with identifiable 
clinical musculoskeletal events. 
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with 
irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been 
observed. 

 
Paediatric population  
 
In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following 
adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), 
dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent 
laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of 
child recipients. 
 
Reporting of suspected adverse reactions  
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.  
 
4.9 Overdose 
 
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most 
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might 
also occur from overdose. No specific information is available on the treatment of overdose with 
Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and 
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal 
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 
 
 



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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Angiotensin-II antagonists, plain. 
 
ATC code: C09C A04. 
 
Mechanism of action  
 
Irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It is 
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source 
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors 
results in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasma 
aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at 
the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates 
angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require 
metabolic activation for its activity. 
 
Clinical efficacy 
 
Hypertension 
 
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is 
dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 
150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by 
an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. 
 
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood 
pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood 
pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended 
doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice 
daily dosing on the same total dose. 
 
The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect 
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long 
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound 
hypertension has not been observed. 
 
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients 
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide 
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at 
trough of 7-10/3-6 mm Hg (systolic/diastolic). 
 
The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal 
products that affect the renin-angiotensin system, black hypertensive patients have notably less 
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose 
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches 
that of white patients. 
 
There is no clinically important effect on serum uric acid or urinary uric acid secretion. 
 
Paediatric population 
 
Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target 
titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of 
hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the 



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three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic 
blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high 
dose). No significant difference was apparent between these doses. Adjusted mean change of trough 
seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium 
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized 
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg 
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of 
irbesartan (see section 4.2). 
 
Hypertension and type 2 diabetes with renal disease 
 
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression 
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double 
blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 
1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine 
ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of 
renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a 
maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. 
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., 
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg 
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of 
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% 
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk 
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal 
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative 
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine 
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all 
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant 
reduction in doubling of serum creatinine were observed. 
 
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum 
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black 
subgroups which represented 32% and 26% of the overall study population respectively, a renal 
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary 
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups 
in the overall population, although an increased incidence of non-fatal MI was seen for women and a 
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the 
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart 
failure was reduced in the overall population. However, no proper explanation for these findings in 
women has been identified. 
 
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in 
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function 
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term 
effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin 
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The 
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding 
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added 
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all 
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or 
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% 
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying 
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of 



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treatment. The slowing in the progression to clinical proteinuria was evident as early as three months 
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more 
frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group than in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of 
approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of 
irbesartan.  
 
Distribution 
 
Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. 
The volume of distribution is 53-93 litres.  
 
Biotransformation 
 
Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 
 
Linearity/non-linearity 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal 
recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations 
are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157-



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176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. 
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 
regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 
dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female 
hypertensive patients. However, there was no difference in the half-life and accumulation of 
irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values 
were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18-40 years). 
However the terminal half-life was not significantly altered. No dosage adjustment is necessary in 
older people. 
 
Elimination 
 
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
 
Paediatric population 
 
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration 
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for 
four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults 
(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC 
and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan 
daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily 
dosing. 
 
Renal impairment 
 
In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters 
of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. 
 
Hepatic impairment 
 
In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not 
significantly altered. 
 
Studies have not been performed in patients with severe hepatic impairment. 
 
5.3 Preclinical safety data 
 
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In 
non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in 
macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). 
At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial 
nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and 
creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the 
hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, 
irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in 
macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the 
pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ 
hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
 
Fertility and reproductive performance were not affected in studies of male and female rats even at 
oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including 
mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live 



 13 

foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
Irbesartan is excreted in the milk of lactating rats. 
 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption were noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
Colloidal hydrated silica 
Pregelatinised maize starch 
Poloxamer 188 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 tablet in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 



 14 

8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/97/046/001-003 
EU/1/97/046/010 
EU/1/97/046/013 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 August 1997 
Date of latest renewal: 27 August 2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 



 15 

1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 150 mg tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 150 mg of irbesartan. 
 
Excipient with known effect: 30.75 mg of lactose monohydrate per tablet. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2772 
engraved on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Aprovel is indicated in adults for the treatment of essential hypertension. 
 
It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 
diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 
and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. 
Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 
75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed 
patients and in the elderly over 75 years. 
 
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 
300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In 
particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive 
effect with Aprovel (see section 4.5). 
 
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily 
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. 
 
The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on 
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach 
target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special Populations 
 
Renal impairment 
 



 16 

No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose 
(75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). 
 
Hepatic impairment 
 
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no 
clinical experience in patients with severe hepatic impairment. 
 
Older people 
 
Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of 
age, dosage adjustment is not usually necessary for older people. 
 
Paediatric population 
 
The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently 
available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be 
made. 
 
Method of Administration 
 
For oral use. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Second and third trimesters of pregnancy (see sections 4.4 and 4.6). 
 
The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with 
diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see 
sections 4.5 and 5.1). 
 
4.4 Special warnings and precautions for use 
 
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in 
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, 
diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. 
 
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency 
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney 
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is 
not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor 
antagonists. 
 
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal 
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no 
experience regarding the administration of Aprovel in patients with a recent kidney transplantation. 
 
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and 
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study 
with patients with advanced renal disease. In particular, they appeared less favourable in women and 
non-white subjects (see section 5.1). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 



 17 

blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, 
hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal 
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of 
serum potassium in patients at risk is recommended (see section 4.5). 
 
Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Aprovel is not recommended. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or 
ischaemic cardiovascular disease could result in a myocardial infarction or stroke. 
 
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin 
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, 
possibly because of higher prevalence of low-renin states in the black hypertensive population (see 
section 5.1). 
 
Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but 
the current data are insufficient to support an extension of the use in children until further data become 
available (see sections 4.8, 5.1 and 5.2). 
 
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Diuretics and other antihypertensive agents: other antihypertensive agents may increase the 
hypotensive effects of irbesartan; however Aprovel has been safely administered with other 
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide 
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of 
hypotension when initiating therapy with Aprovel (see section 4.4). 
 



 18 

Aliskiren-containing products or ACE-inhibitors: 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 a higher frequency of adverse events 
such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) 
compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 
 
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other 
medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing 
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products 
that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and 
is, therefore, not recommended (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended 
(see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is 
recommended. 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of 
irbesartan. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 



 19 

Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Breast-feeding 
 
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not 
recommended and alternative treatments with better established safety profiles during breast-feeding 
are preferable, especially while nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
 
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 
Fertility 
 
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing 
the first signs of parental toxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use 
machines. When driving vehicles or operating machines, it should be taken into account that dizziness 
or weariness may occur during treatment. 
 
4.8 Undesirable effects 
 
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did 
not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any 
clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for 
placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the 
recommended dose range), gender, age, race, or duration of treatment. 
 
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic 
dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in 
excess of placebo. 
 
The following table presents the adverse drug reactions that were reported in placebo-controlled trials 
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the 
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with 
chronic renal insufficiency and overt proteinuria and in excess of placebo. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Adverse reactions additionally reported from post-marketing experience are also listed. These adverse 
reactions are derived from spontaneous reports. 
 



 20 

Blood and lymphatic system disorders 
 
Not known:  thrombocytopenia 
 
Immune system disorders 
 
Not known:  hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, 

anaphylactic shock 
 
Metabolism and nutrition disorders 
 
Not known:  hyperkalaemia 
 
Nervous system disorders 
 
Common: dizziness, orthostatic dizziness* 
Not known: vertigo, headache 
 
Ear and labyrinth disorder 
 
Not known: tinnitus 
 
Cardiac disorders 
 
Uncommon: tachycardia 
 
Vascular disorders 
 
Common: orthostatic hypotension* 
Uncommon: flushing 
 
Respiratory, thoracic and mediastinal disorders 
 
Uncommon: cough 
 
Gastrointestinal disorders 
 
Common: nausea/vomiting 
Uncommon: diarrhoea, dyspepsia/heartburn 
Not known: dysgeusia 
 
Hepatobiliary disorders 
 
Uncommon: jaundice 
Not known: hepatitis, abnormal liver function 
 
Skin and subcutaneous tissue disorders 
 
Not known: leukocytoclastic vasculitis 
 
Musculoskeletal and connective tissue disorders 
 
Common: musculoskeletal pain* 
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase 

levels), muscle cramps 
 



 21 

Renal and urinary disorders 
 
Not known:  impaired renal function including cases of renal failure in patients at risk (see 

section 4.4) 
 
Reproductive system and breast disorders 
 
Uncommon: sexual dysfunction 
 
General disorders and administration site conditions 
 
Common: fatigue 
Uncommon: chest pain 
 
Investigations 
 
Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than 

with placebo. In diabetic hypertensive patients with microalbuminuria and normal 
renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the 
irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic 
hypertensive patients with chronic renal insufficiency and overt proteinuria, 
hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group 
and 26.3% of the patients in the placebo group. 

Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in 
irbesartan treated subjects. None of these increases were associated with identifiable 
clinical musculoskeletal events. 
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with 
irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been 
observed. 

 
Paediatric population 
 
In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following 
adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), 
dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent 
laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of 
child recipients. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.  
 
4.9 Overdose 
 
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most 
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might 
also occur from overdose. No specific information is available on the treatment of overdose with 
Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and 
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal 
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 
 
 



 22 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Angiotensin-II antagonists, plain. 
 
ATC code: C09C A04. 
 
Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) 
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, 
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the 
angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and 
a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected 
by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an 
enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. 
Irbesartan does not require metabolic activation for its activity. 
 
Clinical efficacy 
 
Hypertension 
 
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is 
dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 
150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by 
an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. 
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood 
pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood 
pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended 
doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice 
daily dosing on the same total dose. 
 
The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect 
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long 
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound 
hypertension has not been observed. 
 
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients 
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide 
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at 
trough of 7-10/3-6 mm Hg (systolic/diastolic). 
 
The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal 
products that affect the renin-angiotensin system, black hypertensive patients have notably less 
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose 
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches 
that of white patients. 
 
There is no clinically important effect on serum uric acid or urinary uric acid secretion. 
 
Paediatric population 
 
Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target 
titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of 
hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the 
three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic 
blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high 
dose). No significant difference was apparent between these doses. Adjusted mean change of trough 



 23 

seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium 
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized 
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg 
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of 
irbesartan (see section 4.2). 
 
Hypertension and type 2 diabetes with renal disease 
 
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression 
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double 
blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 
1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine 
ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of 
renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a 
maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. 
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., 
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg 
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of 
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% 
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk 
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal 
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative 
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine 
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all 
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant 
reduction in doubling of serum creatinine were observed. 
 
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum 
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black 
subgroups which represented 32% and 26% of the overall study population respectively, a renal 
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary 
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups 
in the overall population, although an increased incidence of non-fatal MI was seen for women and a 
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the 
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart 
failure was reduced in the overall population. However, no proper explanation for these findings in 
women has been identified. 
 
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in 
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function 
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term 
effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin 
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The 
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding 
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added 
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all 
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or 
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% 
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying 
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of 
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months 
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more 
frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 



 24 

 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group than in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of 
approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of 
irbesartan.  
 
Distribution 
 
Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. 
The volume of distribution is 53-93 litres.  
 
Biotransformation 
 
Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 
 
Linearity/non-linearity 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal 
recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations 
are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157-
176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. 
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 
regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 



 25 

dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female 
hypertensive patients. However, there was no difference in the half-life and accumulation of 
irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values 
were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18-40 years). 
However the terminal half-life was not significantly altered. No dosage adjustment is necessary in 
older people. 
 
Elimination 
 
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
 
Paediatric population 
 
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration 
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for 
four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults 
(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC 
and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan 
daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily 
dosing. 
 
Renal impairment 
 
In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters 
of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. 
 
Hepatic impairment 
 
In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not 
significantly altered. 
 
Studies have not been performed in patients with severe hepatic impairment. 
 
5.3 Preclinical safety data 
 
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In 
non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in 
macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). 
At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial 
nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and 
creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the 
hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, 
irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in 
macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the 
pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ 
hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
 
Fertility and reproductive performance were not affected in studies of male and female rats even at 
oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including 
mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
Irbesartan is excreted in the milk of lactating rats. 



 26 

 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption were noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
Colloidal hydrated silica 
Pregelatinised maize starch 
Poloxamer 188 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 tablet in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 



 27 

8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/97/046/004-006 
EU/1/97/046/011 
EU/1/97/046/014 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 August 1997 
Date of latest renewal: 27 August 2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 



 28 

1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 300 mg tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 300 mg of irbesartan. 
 
Excipient with known effect: 61.50 mg of lactose monohydrate per tablet. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2773 
engraved on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Aprovel is indicated in adults for the treatment of essential hypertension. 
 
It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 
diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 
and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. 
Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 
75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed 
patients and in the elderly over 75 years. 
 
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 
300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In 
particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive 
effect with Aprovel (see section 4.5). 
 
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily 
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. 
 
The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on 
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach 
target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special Populations 
 
Renal impairment 
 



 29 

No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose 
(75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). 
 
Hepatic impairment 
 
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no 
clinical experience in patients with severe hepatic impairment. 
 
Older people 
 
Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of 
age, dosage adjustment is not usually necessary for older people. 
 
Paediatric population 
The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently 
available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be 
made. 
 
Method of Administration 
 
For oral use. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Second and third trimesters of pregnancy (see sections 4.4 and 4.6). 
 
The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with 
diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see 
sections 4.5 and 5.1). 
 
4.4 Special warnings and precautions for use 
 
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in 
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, 
diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. 
 
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency 
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney 
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is 
not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor 
antagonists. 
 
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal 
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no 
experience regarding the administration of Aprovel in patients with a recent kidney transplantation. 
 
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and 
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study 
with patients with advanced renal disease. In particular, they appeared less favourable in women and 
non-white subjects (see section 5.1). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 



 30 

considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, 
hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal 
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of 
serum potassium in patients at risk is recommended (see section 4.5). 
 
Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Aprovel is not recommended. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or 
ischaemic cardiovascular disease could result in a myocardial infarction or stroke. 
 
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin 
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, 
possibly because of higher prevalence of low-renin states in the black hypertensive population (see 
section 5.1). 
 
Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but 
the current data are insufficient to support an extension of the use in children until further data become 
available (see sections 4.8, 5.1 and 5.2). 
 
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Diuretics and other antihypertensive agents: other antihypertensive agents may increase the 
hypotensive effects of irbesartan; however Aprovel has been safely administered with other 
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide 
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of 
hypotension when initiating therapy with Aprovel (see section 4.4). 
 
Aliskiren-containing products or ACE-inhibitors: 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 a higher frequency of adverse events 



 31 

such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) 
compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 
 
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other 
medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing 
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products 
that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and 
is, therefore, not recommended (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended 
(see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is 
recommended. 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of 
irbesartan. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
 



 32 

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Breast-feeding 
 
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not 
recommended and alternative treatments with better established safety profiles during breast-feeding 
are preferable, especially while nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
 
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 
Fertility 
 
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing 
the first signs of parental toxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use 
machines. When driving vehicles or operating machines, it should be taken into account that dizziness 
or weariness may occur during treatment. 
 
4.8 Undesirable effects 
 
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did 
not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any 
clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for 
placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the 
recommended dose range), gender, age, race, or duration of treatment. 
 
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic 
dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in 
excess of placebo. 
 
The following table presents the adverse drug reactions that were reported in placebo-controlled trials 
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the 
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with 
chronic renal insufficiency and overt proteinuria and in excess of placebo. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Adverse reactions additionally reported from post-marketing experience are also listed. These adverse 
reactions are derived from spontaneous reports. 
 



 33 

Blood and lymphatic system disorders 
 
Not known:  thrombocytopenia 
 
Immune system disorders 
 
Not known:  hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, 

anaphylactic shock 
 
Metabolism and nutrition disorders 
 
Not known:  hyperkalaemia 
 
Nervous system disorders 
 
Common: dizziness, orthostatic dizziness* 
Not known: vertigo, headache 
 
Ear and labyrinth disorder 
 
Not known: tinnitus 
 
Cardiac disorders 
 
Uncommon: tachycardia 
 
Vascular disorders 
 
Common: orthostatic hypotension* 
Uncommon: flushing 
 
Respiratory, thoracic and mediastinal disorders 
 
Uncommon: cough 
 
Gastrointestinal disorders 
 
Common: nausea/vomiting 
Uncommon: diarrhoea, dyspepsia/heartburn 
Not known: dysgeusia 
 
Hepatobiliary disorders: 
 
Uncommon: jaundice 
Not known: hepatitis, abnormal liver function 
 
Skin and subcutaneous tissue disorders 
 
Not known: leukocytoclastic vasculitis 
 
Musculoskeletal and connective tissue disorders 
 
Common: musculoskeletal pain* 
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase 

levels), muscle cramps 
 



 34 

Renal and urinary disorders 
 
Not known: impaired renal function including cases of renal failure in patients at risk (see 

section 4.4) 
 
Reproductive system and breast disorders 
 
Uncommon: sexual dysfunction 
 
General disorders and administration site conditions 
 
Common: fatigue 
Uncommon: chest pain 
 
Investigations 
 
Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than 

with placebo. In diabetic hypertensive patients with microalbuminuria and normal 
renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the 
irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic 
hypertensive patients with chronic renal insufficiency and overt proteinuria, 
hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group 
and 26.3% of the patients in the placebo group. 

Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in 
irbesartan treated subjects. None of these increases were associated with identifiable 
clinical musculoskeletal events. 
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with 
irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been 
observed. 

 
Paediatric population 
 
In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following 
adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), 
dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent 
laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of 
child recipients. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.  
 
4.9 Overdose 
 
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most 
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might 
also occur from overdose. No specific information is available on the treatment of overdose with 
Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and 
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal 
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 
 
 



 35 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Angiotensin-II antagonists, plain. 
ATC code: C09C A04. 
 
Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) 
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, 
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the 
angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and 
a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected 
by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an 
enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. 
Irbesartan does not require metabolic activation for its activity. 
 
Clinical efficacy 
 
Hypertension 
 
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is 
dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 
150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by 
an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. 
 
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood 
pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood 
pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended 
doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice 
daily dosing on the same total dose. 
 
The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect 
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long 
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound 
hypertension has not been observed. 
 
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients 
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide 
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at 
trough of 7-10/3-6 mm Hg (systolic/diastolic). 
 
The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal 
products that affect the renin-angiotensin system, black hypertensive patients have notably less 
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose 
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches 
that of white patients. 
 
There is no clinically important effect on serum uric acid or urinary uric acid secretion. 
 
Paediatric population 
 
Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target 
titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of 
hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the 
three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic 
blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high 
dose). No significant difference was apparent between these doses. Adjusted mean change of trough 



 36 

seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium 
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized 
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg 
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of 
irbesartan (see section 4.2). 
 
Hypertension and type 2 diabetes with renal disease 
 
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression 
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double 
blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 
1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine 
ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of 
renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a 
maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. 
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., 
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg 
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of 
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% 
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk 
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal 
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative 
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine 
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all 
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant 
reduction in doubling of serum creatinine were observed. 
 
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum 
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black 
subgroups which represented 32% and 26% of the overall study population respectively, a renal 
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary 
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups 
in the overall population, although an increased incidence of non-fatal MI was seen for women and a 
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the 
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart 
failure was reduced in the overall population. However, no proper explanation for these findings in 
women has been identified. 
 
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in 
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function 
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term 
effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin 
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The 
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding 
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added 
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all 
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or 
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% 
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying 
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of 
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months 
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more 
frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 



 37 

 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group than in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of 
approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of 
irbesartan.  
 
Distribution 
 
Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. 
The volume of distribution is 53-93 litres.  
 
Biotransformation 
 
Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 
 
Linearity/non-linearity 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal 
recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations 
are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157-
176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. 



 38 

Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 
regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 
dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female 
hypertensive patients. However, there was no difference in the half-life and accumulation of 
irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values 
were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18-40 years). 
However the terminal half-life was not significantly altered. No dosage adjustment is necessary in 
older people. 
 
Elimination 
 
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
 
Paediatric population 
 
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration 
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for 
four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults 
(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC 
and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan 
daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily 
dosing. 
 
Renal impairment  
 
In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters 
of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. 
 
Hepatic impairment  
 
In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not 
significantly altered. 
 
Studies have not been performed in patients with severe hepatic impairment. 
 
5.3 Preclinical safety data 
 
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In 
non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in 
macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). 
At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial 
nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and 
creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the 
hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, 
irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in 
macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the 
pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ 
hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
 
Fertility and reproductive performance were not affected in studies of male and female rats even at 
oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including 
mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 



 39 

Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
Irbesartan is excreted in the milk of lactating rats. 
 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption were noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Magnesium stearate 
Colloidal hydrated silica 
Pregelatinised maize starch 
Poloxamer 188 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
Cartons of 14 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 tablet in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 



 40 

8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/97/046/007-009 
EU/1/97/046/012 
EU/1/97/046/015 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 August 1997 
Date of latest renewal: 27 August 2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 



 41 

1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 75 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 75 mg of irbesartan. 
 
Excipient with known effect: 25.50 mg of lactose monohydrate per film-coated tablet. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2871 
engraved on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Aprovel is indicated in adults for the treatment of essential hypertension. 
 
It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 
diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 
and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. 
Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 
75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed 
patients and in the elderly over 75 years. 
 
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 
300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In 
particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive 
effect with Aprovel (see section 4.5). 
 
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily 
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. 
 
The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on 
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach 
target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special Populations 
 
Renal impairment 
 



 42 

No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose 
(75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). 
 
Hepatic impairment 
 
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no 
clinical experience in patients with severe hepatic impairment. 
 
Older people  
Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of 
age, dosage adjustment is not usually necessary for older people. 
 
Paediatric population 
 
The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently 
available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be 
made. 
 
Method of Administration 
 
For oral use. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Second and third trimesters of pregnancy (see sections 4.4 and 4.6). 
 
The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with 
diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see 
sections 4.5 and 5.1). 
 
4.4 Special warnings and precautions for use 
 
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in 
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, 
diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. 
 
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency 
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney 
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is 
not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor 
antagonists. 
 
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal 
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no 
experience regarding the administration of Aprovel in patients with a recent kidney transplantation. 
 
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and 
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study 
with patients with advanced renal disease. In particular, they appeared less favourable in women and 
non-white subjects (see section 5.1). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 



 43 

aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, 
hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal 
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of 
serum potassium in patients at risk is recommended (see section 4.5). 
 
Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Aprovel is not recommended. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or 
ischaemic cardiovascular disease could result in a myocardial infarction or stroke. 
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin 
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, 
possibly because of higher prevalence of low-renin states in the black hypertensive population (see 
section 5.1). 
 
Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but 
the current data are insufficient to support an extension of the use in children until further data become 
available (see sections 4.8, 5.1 and 5.2). 
 
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Diuretics and other antihypertensive agents: other antihypertensive agents may increase the 
hypotensive effects of irbesartan; however Aprovel has been safely administered with other 
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide 
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of 
hypotension when initiating therapy with Aprovel (see section 4.4). 
 
Aliskiren-containing products and ACE-inhibitors: 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 a higher frequency of adverse events 



 44 

such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) 
compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 
 
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other 
medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing 
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products 
that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and 
is, therefore, not recommended (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended 
(see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is 
recommended. 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of 
irbesartan. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
 



 45 

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Breast-feeding 
 
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not 
recommended and alternative treatments with better established safety profiles during breast-feeding 
are preferable, especially while nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
 
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 
Fertility 
 
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing 
the first signs of parental toxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use 
machines. When driving vehicles or operating machines, it should be taken into account that dizziness 
or weariness may occur during treatment. 
 
4.8 Undesirable effects 
 
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did 
not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any 
clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for 
placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the 
recommended dose range), gender, age, race, or duration of treatment. 
 
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic 
dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in 
excess of placebo. 
 
The following table presents the adverse drug reactions that were reported in placebo-controlled trials 
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the 
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with 
chronic renal insufficiency and overt proteinuria and in excess of placebo. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Adverse reactions additionally reported from post-marketing experience are also listed. These adverse 
reactions are derived from spontaneous reports. 
 



 46 

Blood and lymphatic system disorders 
 
Not known:  thrombocytopenia 
 
Immune system disorders 
 
Not known:  hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, 

anaphylactic shock 
 
Metabolism and nutrition disorders 
 
Not known:  hyperkalaemia 
 
Nervous system disorders 
 
Common: dizziness, orthostatic dizziness* 
Not known: vertigo, headache 
 
Ear and labyrinth disorder 
 
Not known: tinnitus 
 
Cardiac disorders: 
 
Uncommon: tachycardia 
 
Vascular disorders 
 
Common: orthostatic hypotension* 
Uncommon: flushing 
 
Respiratory, thoracic and mediastinal disorders 
 
Uncommon: cough 
 
Gastrointestinal disorders 
 
Common: nausea/vomiting 
Uncommon: diarrhoea, dyspepsia/heartburn 
Not known: dysgeusia 
 
Hepatobiliary disorders 
 
Uncommon: jaundice 
Not known: hepatitis, abnormal liver function 
 
Skin and subcutaneous tissue disorders 
 
Not known: leukocytoclastic vasculitis 
 
Musculoskeletal and connective tissue disorders  
 
Common: musculoskeletal pain* 
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase 

levels), muscle cramps 
 



 47 

Renal and urinary disorders 
 
Not known: impaired renal function including cases of renal failure in patients at risk (see 

section 4.4) 
 
Reproductive system and breast disorders 
 
Uncommon: sexual dysfunction 
 
General disorders and administration site conditions 
 
Common: fatigue 
Uncommon: chest pain 
 
Investigations 
 
Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than 

with placebo. In diabetic hypertensive patients with microalbuminuria and normal 
renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the 
irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic 
hypertensive patients with chronic renal insufficiency and overt proteinuria, 
hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group 
and 26.3% of the patients in the placebo group. 

Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in 
irbesartan treated subjects. None of these increases were associated with identifiable 
clinical musculoskeletal events. 
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with 
irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been 
observed. 

 
Paediatric population 
 
In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following 
adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), 
dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent 
laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of 
child recipients. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.  
 
4.9 Overdose 
 
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most 
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might 
also occur from overdose. No specific information is available on the treatment of overdose with 
Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and 
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal 
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 
 
 



 48 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Angiotensin-II antagonists, plain. 
 
ATC code: C09C A04. 
 
Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) 
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, 
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the 
angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and 
a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected 
by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an 
enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. 
Irbesartan does not require metabolic activation for its activity. 
 
Clinical efficacy 
 
Hypertension 
 
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is 
dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 
150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by 
an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. 
 
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood 
pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood 
pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended 
doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice 
daily dosing on the same total dose. 
 
The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect 
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long 
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound 
hypertension has not been observed. 
 
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients 
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide 
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at 
trough of 7-10/3-6 mm Hg (systolic/diastolic). 
 
The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal 
products that affect the renin-angiotensin system, black hypertensive patients have notably less 
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose 
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches 
that of white patients. 
There is no clinically important effect on serum uric acid or urinary uric acid secretion. 
 
Paediatric population 
 
Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target 
titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of 
hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the 
three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic 
blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high 
dose). No significant difference was apparent between these doses. Adjusted mean change of trough 



 49 

seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium 
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized 
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg 
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of 
irbesartan (see section 4.2). 
 
Hypertension and type 2 diabetes with renal disease 
 
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression 
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double 
blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 
1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine 
ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of 
renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a 
maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. 
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., 
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg 
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of 
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% 
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk 
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal 
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative 
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine 
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all 
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant 
reduction in doubling of serum creatinine were observed. 
 
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum 
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black 
subgroups which represented 32% and 26% of the overall study population respectively, a renal 
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary 
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups 
in the overall population, although an increased incidence of non-fatal MI was seen for women and a 
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the 
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart 
failure was reduced in the overall population. However, no proper explanation for these findings in 
women has been identified. 
 
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in 
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function 
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term 
effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin 
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The 
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding 
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added 
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all 
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or 
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% 
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying 
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of 
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months 
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more 
frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 



 50 

 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group than in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of 
approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of 
irbesartan.  
 
Distribution 
 
Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. 
The volume of distribution is 53 - 93 litres.  
 
Biotransformatin 
 
Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 
 
Linearity/non-linearity 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal 
recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations 
are attained at 1.5 - 2 hours after oral administration. The total body and renal clearance are 157 -
 176 and 3 - 3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15 hours. 
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 



 51 

regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 
dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female 
hypertensive patients. However, there was no difference in the half-life and accumulation of 
irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values 
were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18 - 40 years). 
However the terminal half-life was not significantly altered. No dosage adjustment is necessary in 
older people. 
 
Elimination 
 
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
 
Paediatric population 
 
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration 
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for 
four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults 
(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC 
and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan 
daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily 
dosing. 
 
Renal impairment 
 
In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters 
of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. 
 
Hepatic impairment 
 
In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not 
significantly altered.  
 
Studies have not been performed in patients with severe hepatic impairment. 
 
5.3 Preclinical safety data 
 
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In 
non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in 
macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). 
At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial 
nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and 
creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the 
hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, 
irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in 
macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the 
pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ 
hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
 
Fertility and reproductive performance were not affected in studies of male and female rats even at 
oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including 
mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 



 52 

Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
Irbesartan is excreted in the milk of lactating rats. 
 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption were noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Hypromellose 
Silicon dioxide 
Magnesium stearate. 
 
Film-coating: 
Lactose monohydrate 
Hypromellose 
Titanium dioxide 
Macrogol 3000 
Carnauba wax. 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 film-coated tablet in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 



 53 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/97/046/016-020 
EU/1/97/046/031 
EU/1/97/046/034 
EU/1/97/046/037 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 August 1997 
Date of latest renewal: 27 August 2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



 54 

1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 150 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 150 mg of irbesartan. 
 
Excipient with known effect: 51.00 mg of lactose monohydrate per film-coated tablet. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2872 
engraved on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Aprovel is indicated in adults for the treatment of essential hypertension. 
 
It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 
diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 
and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. 
Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 
75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed 
patients and in the elderly over 75 years. 
 
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 
300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In 
particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive 
effect with Aprovel (see section 4.5). 
 
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily 
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. 
 
The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on 
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach 
target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special Populations 
 
Renal impairment 
 



 55 

No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose 
(75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). 
 
Hepatic impairment 
 
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no 
clinical experience in patients with severe hepatic impairment. 
 
Older people 
 
Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of 
age, dosage adjustment is not usually necessary for older people. 
 
Paediatric population 
 
The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently 
available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be 
made. 
 
Method of Administration 
 
For oral use. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Second and third trimesters of pregnancy (see sections 4.4 and 4.6). 
 
The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with 
diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see 
sections 4.5 and 5.1). 
 
4.4 Special warnings and precautions for use 
 
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in 
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, 
diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. 
 
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency 
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney 
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is 
not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor 
antagonists. 
 
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal 
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no 
experience regarding the administration of Aprovel in patients with a recent kidney transplantation. 
 
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and 
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study 
with patients with advanced renal disease. In particular, they appeared less favourable in women and 
non-white subjects (see section 5.1). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 



 56 

blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 
frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, 
hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal 
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of 
serum potassium in patients at risk is recommended (see section 4.5). 
 
Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Aprovel is not recommended. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive 
agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic 
cardiovascular disease could result in a myocardial infarction or stroke. 
 
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin 
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, 
possibly because of higher prevalence of low-renin states in the black hypertensive population (see 
section 5.1). 
 
Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but 
the current data are insufficient to support an extension of the use in children until further data become 
available (see sections 4.8, 5.1 and 5.2). 
 
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Diuretics and other antihypertensive agents: other antihypertensive agents may increase the 
hypotensive effects of irbesartan; however Aprovel has been safely administered with other 
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide 
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of 
hypotension when initiating therapy with Aprovel (see section 4.4). 
 



 57 

Aliskiren-containing products and ACE-inhibitors: 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 a higher frequency of adverse events 
such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) 
compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 
 
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other 
medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing 
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products 
that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and 
is, therefore, not recommended (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended 
(see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is 
recommended. 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of 
irbesartan. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 



 58 

Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Breast-feeding 
 
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not 
recommended and alternative treatments with better established safety profiles during breast-feeding 
are preferable, especially while nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 
Fertility 
 
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing 
the first signs of parental toxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use 
machines. When driving vehicles or operating machines, it should be taken into account that dizziness 
or weariness may occur during treatment. 
 
4.8 Undesirable effects 
 
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did 
not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any 
clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for 
placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the 
recommended dose range), gender, age, race, or duration of treatment. 
 
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic 
dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in 
excess of placebo. 
 
The following table presents the adverse drug reactions that were reported in placebo-controlled trials 
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the 
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with 
chronic renal insufficiency and overt proteinuria and in excess of placebo. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Adverse reactions additionally reported from post-marketing experience are also listed. These adverse 
reactions are derived from spontaneous reports. 
 



 59 

Blood and lymphatic system disorders 
 
Not known:  thrombocytopenia 
 
Immune system disorders 
 
Not known:  hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, 

anaphylactic shock 
 
Metabolism and nutrition disorders 
 
Not known:  hyperkalaemia 
 
Nervous system disorders 
 
Common: dizziness, orthostatic dizziness* 
Not known: vertigo, headache 
 
Ear and labyrinth disorder 
 
Not known: tinnitus 
 
Cardiac disorders 
 
Uncommon: tachycardia 
 
Vascular disorders 
 
Common: orthostatic hypotension* 
Uncommon: flushing 
 
Respiratory, thoracic and mediastinal disorders 
 
Uncommon: cough 
 
Gastrointestinal disorders 
 
Common: nausea/vomiting 
Uncommon: diarrhoea, dyspepsia/heartburn 
Not known: dysgeusia 
 
Hepatobiliary disorders 
 
Uncommon: jaundice 
Not known: hepatitis, abnormal liver function 
 
Skin and subcutaneous tissue disorders 
 
Not known: leukocytoclastic vasculitis 
 
Musculoskeletal and connective tissue disorders 
 
Common: musculoskeletal pain* 
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase 

levels), muscle cramps 
 



 60 

Renal and urinary disorders 
 
Not known: impaired renal function including cases of renal failure in patients at risk (see 

section 4.4) 
 
Reproductive system and breast disorders 
 
Uncommon: sexual dysfunction 
 
General disorders and administration site conditions 
 
Common: fatigue 
Uncommon: chest pain 
 
Investigations 
 
Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than 

with placebo. In diabetic hypertensive patients with microalbuminuria and normal 
renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the 
irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic 
hypertensive patients with chronic renal insufficiency and overt proteinuria, 
hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group 
and 26.3% of the patients in the placebo group. 

Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in 
irbesartan treated subjects. None of these increases were associated with identifiable 
clinical musculoskeletal events. 
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with 
irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been 
observed. 

 
Paediatric population 
 
In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following 
adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), 
dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent 
laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of 
child recipients. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.  
 
4.9 Overdose 
 
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most 
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might 
also occur from overdose. No specific information is available on the treatment of overdose with 
Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and 
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal 
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 
 
 



 61 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Angiotensin-II antagonists, plain. 
 
ATC code: C09C A04. 
 
Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) 
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, 
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the 
angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and 
a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected 
by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an 
enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. 
Irbesartan does not require metabolic activation for its activity. 
 
Clinical efficacy 
 
Hypertension 
 
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is 
dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 
150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by 
an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. 
 
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood 
pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood 
pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended 
doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice 
daily dosing on the same total dose. 
 
The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect 
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long 
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound 
hypertension has not been observed. 
 
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients 
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide 
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at 
trough of 7-10/3-6 mm Hg (systolic/diastolic). 
 
The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal 
products that affect the renin-angiotensin system, black hypertensive patients have notably less 
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose 
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches 
that of white patients. 
There is no clinically important effect on serum uric acid or urinary uric acid secretion. 
 
Paediatric population 
 
Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target 
titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of 
hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the 
three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic 
blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high 
dose). No significant difference was apparent between these doses. Adjusted mean change of trough 



 62 

seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium 
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized 
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg 
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of 
irbesartan (see section 4.2). 
 
Hypertension and type 2 diabetes with renal disease 
 
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression 
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double 
blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 
1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine 
ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of 
renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a 
maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. 
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., 
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg 
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of 
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% 
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk 
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal 
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative 
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine 
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all 
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant 
reduction in doubling of serum creatinine were observed. 
 
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum 
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black 
subgroups which represented 32% and 26% of the overall study population respectively, a renal 
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary 
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups 
in the overall population, although an increased incidence of non-fatal MI was seen for women and a 
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the 
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart 
failure was reduced in the overall population. However, no proper explanation for these findings in 
women has been identified. 
 
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in 
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function 
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term 
effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin 
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The 
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding 
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added 
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all 
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or 
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% 
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying 
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of 
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months 
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more 
frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 



 63 

 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group than in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values of 
approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of 
irbesartan.  
 
Distribution 
 
Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. 
The volume of distribution is 53 - 93 litres.  
 
Biotransformation 
 
Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 
 
Linearity/non-linearity 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal 
recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations 
are attained at 1.5 - 2 hours after oral administration. The total body and renal clearance are 157 -
 176 and 3 - 3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15 hours. 
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 
regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 



 64 

dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female 
hypertensive patients. However, there was no difference in the half-life and accumulation of 
irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values 
were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18 - 40 years). 
However the terminal half-life was not significantly altered. No dosage adjustment is necessary in 
older people. 
 
Elimination 
 
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
 
Paediatric population 
 
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration 
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for 
four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults 
(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC 
and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan 
daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily 
dosing. 
 
Renal impairment 
 
In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters 
of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. 
 
Hepatic impairment 
 
In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not 
significantly altered.  
 
Studies have not been performed in patients with severe hepatic impairment. 
 
5.3 Preclinical safety data 
 
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In 
non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in 
macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). 
At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial 
nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and 
creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the 
hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, 
irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in 
macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the 
pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ 
hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
 
Fertility and reproductive performance were not affected in studies of male and female rats even at 
oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including 
mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 
Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
Irbesartan is excreted in the milk of lactating rats. 



 65 

 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption were noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Hypromellose 
Silicon dioxide 
Magnesium stearate. 
 
Film-coating: 
Lactose monohydrate 
Hypromellose 
Titanium dioxide 
Macrogol 3000 
Carnauba wax. 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 film-coated tablet in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



 66 

7. MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/97/046/021-025 
EU/1/97/046/032 
EU/1/97/046/035 
EU/1/97/046/038 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 August 1997 
Date of latest renewal: 27 August 2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



 67 

1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 300 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 300 mg of irbesartan. 
 
Excipient with known effect: 102.00 mg of lactose monohydrate per film-coated tablet. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2873 
engraved on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Aprovel is indicated in adults for the treatment of essential hypertension. 
 
It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 
diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 
and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. 
Aprovel at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 
75 mg. However, initiation of therapy with 75 mg could be considered, particularly in haemodialysed 
patients and in the elderly over 75 years. 
 
In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 
300 mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In 
particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive 
effect with Aprovel (see section 4.5). 
 
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily 
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease. 
The demonstration of renal benefit of Aprovel in hypertensive type 2 diabetic patients is based on 
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach 
target blood pressure (see sections 4.3, 4.4, 4.5 and 5.1). 
 
Special Populations 
 
Renal impairment 
 
No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose 
(75 mg) should be considered for patients undergoing haemodialysis (see section 4.4). 



 68 

 
Hepatic impairment 
 
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no 
clinical experience in patients with severe hepatic impairment. 
 
Older people 
 
Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of 
age, dosage adjustment is not usually necessary for older people. 
 
Paediatric population 
 
The safety and efficacy of Aprovel in children aged 0 to 18 has not been established. Currently 
available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be 
made. 
 
Method of Administration 
 
For oral use. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Second and third trimesters of pregnancy (see sections 4.4 and 4.6). 
 
The concomitant use of Aprovel with aliskiren-containing products is contraindicated in patients with 
diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m2) (see 
sections 4.5 and 5.1). 
 
4.4 Special warnings and precautions for use 
 
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in 
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, 
diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel. 
 
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency 
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney 
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is 
not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor 
antagonists. 
 
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal 
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no 
experience regarding the administration of Aprovel in patients with a recent kidney transplantation. 
 
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and 
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study 
with patients with advanced renal disease. In particular, they appeared less favourable in women and 
non-white subjects (see section 5.1). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the 
concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of 
hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual 
blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or 
aliskiren is therefore not recommended (see sections 4.5 and 5.1).  If dual blockade therapy is 
considered absolutely necessary, this should only occur under specialist supervision and subject to 



 69 

frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and 
angiotensin II receptor blockers should not be used concomitantly in patients with diabetic 
nephropathy. 
 
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, 
hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal 
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of 
serum potassium in patients at risk is recommended (see section 4.5). 
 
Lithium: the combination of lithium and Aprovel is not recommended (see section 4.5). 
 
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, 
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive 
hypertrophic cardiomyopathy. 
 
Primary aldosteronism: patients with primary aldosteronism generally will not respond to 
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. 
Therefore, the use of Aprovel is not recommended. 
 
General: in patients whose vascular tone and renal function depend predominantly on the activity of 
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or 
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting 
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated 
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any 
antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or 
ischaemic cardiovascular disease could result in a myocardial infarction or stroke. 
 
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin 
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, 
possibly because of higher prevalence of low-renin states in the black hypertensive population (see 
section 5.1). 
 
Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be 
changed to alternative antihypertensive treatments which have an established safety profile for use in 
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, 
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). 
 
Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old but 
the current data are insufficient to support an extension of the use in children until further data become 
available (see sections 4.8, 5.1 and 5.2). 
 
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicine 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Diuretics and other antihypertensive agents: other antihypertensive agents may increase the 
hypotensive effects of irbesartan; however Aprovel has been safely administered with other 
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide 
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of 
hypotension when initiating therapy with Aprovel (see section 4.4). 
 
Aliskiren-containing products and ACE-inhibitors: 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 a higher frequency of adverse events 



 70 

such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) 
compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). 
 
 
Potassium supplements and potassium-sparing diuretics: based on experience with the use of other 
medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing 
diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products 
that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and 
is, therefore, not recommended (see section 4.4). 
 
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during 
concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects 
have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended 
(see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels is 
recommended. 
 
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered 
simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, 
acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect 
may occur. 
 
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an 
increased risk of worsening of renal function, including possible acute renal failure, and an increase in 
serum potassium, especially in patients with poor pre-existing renal function. The combination should 
be administered with caution, especially in the elderly. Patients should be adequately hydrated and 
consideration should be given to monitoring renal function after initiation of concomitant therapy, and 
periodically thereafter. 
 
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartan 
is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser 
extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were 
observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by 
CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan 
have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of 
irbesartan. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The 
use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 
and 4.4). 
 
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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II 
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued 
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative 
antihypertensive treatments which have an established safety profile for use in pregnancy. When 
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, 
alternative therapy should be started. 
 
Exposure to AIIRA therapy during the second and third trimesters is known to induce human 
foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal 
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). 
 



 71 

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 
 
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 
sections 4.3 and 4.4). 
 
Breast-feeding 
 
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel is not 
recommended and alternative treatments with better established safety profiles during breast-feeding 
are preferable, especially while nursing a newborn or preterm infant. 
 
It is unknown whether irbesartan or its metabolites are excreted in human milk.  
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its 
metabolites in milk (for details see 5.3). 
 
Fertility 
 
Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing 
the first signs of parental toxicity (see section 5.3).  
 
4.7 Effects on ability to drive and use machines 
 
Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and use 
machines. When driving vehicles or operating machines, it should be taken into account that dizziness 
or weariness may occur during treatment. 
 
4.8 Undesirable effects 
 
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did 
not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any 
clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for 
placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the 
recommended dose range), gender, age, race, or duration of treatment. 
 
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic 
dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in 
excess of placebo. 
 
The following table presents the adverse drug reactions that were reported in placebo-controlled trials 
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the 
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with 
chronic renal insufficiency and overt proteinuria and in excess of placebo. 
 
The frequency of adverse reactions listed below is defined using the following convention: 
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 
(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects 
are presented in order of decreasing seriousness. 
 
Adverse reactions additionally reported from post–marketing experience are also listed. These adverse 
reactions are derived from spontaneous reports. 
 



 72 

Blood and lymphatic system disorders 
 
Not known:  thrombocytopenia 
 
Immune system disorders 
 
Not known:  hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction, 

anaphylactic shock 
 
Metabolism and nutrition disorders 
 
Not known:  hyperkalaemia 
 
Nervous system disorders 
 
Common: dizziness, orthostatic dizziness* 
Not known: vertigo, headache 
 
Ear and labyrinth disorder 
 
Not known: tinnitus 
 
Cardiac disorders 
 
Uncommon: tachycardia 
 
Vascular disorders 
 
Common: orthostatic hypotension* 
Uncommon: flushing 
 
Respiratory, thoracic and mediastinal disorders 
 
Uncommon: cough 
 
Gastrointestinal disorders 
 
Common: nausea/vomiting 
Uncommon: diarrhoea, dyspepsia/heartburn 
Not known: dysgeusia 
 
Hepatobiliary disorders 
 
Uncommon: jaundice 
Not known: hepatitis, abnormal liver function 
 
Skin and subcutaneous tissue disorders 
 
Not known: leukocytoclastic vasculitis 
 
Musculoskeletal and connective tissue disorders 
 
Common: musculoskeletal pain* 
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase 

levels), muscle cramps 
 



 73 

Renal and urinary disorders 
 
Not known: impaired renal function including cases of renal failure in patients at risk (see 

section 4.4) 
 
Reproductive system and breast disorders 
 
Uncommon: sexual dysfunction 
 
General disorders and administration site conditions 
 
Common: fatigue 
Uncommon: chest pain 
 
Investigations 
 
Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan than 

with placebo. In diabetic hypertensive patients with microalbuminuria and normal 
renal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in the 
irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic 
hypertensive patients with chronic renal insufficiency and overt proteinuria, 
hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group 
and 26.3% of the patients in the placebo group. 

Common: significant increases in plasma creatine kinase were commonly observed (1.7%) in 
irbesartan treated subjects. None of these increases were associated with identifiable 
clinical musculoskeletal events. 
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with 
irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been 
observed. 

 
Paediatric population 
 
In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following 
adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), 
dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent 
laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of 
child recipients. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.  
 
4.9 Overdose 
 
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most 
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might 
also occur from overdose. No specific information is available on the treatment of overdose with 
Aprovel. The patient should be closely monitored, and the treatment should be symptomatic and 
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal 
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis. 
 
 



 74 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Angiotensin-II antagonists, plain. 
 
ATC code: C09C A04. 
 
Mechanism of action: irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) 
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor, 
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the 
angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels, and 
a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected 
by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an 
enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. 
Irbesartan does not require metabolic activation for its activity. 
 
Clinical efficacy 
 
Hypertension 
 
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is 
dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 
150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by 
an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo. 
 
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the blood 
pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of blood 
pressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommended 
doses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twice 
daily dosing on the same total dose. 
 
The blood pressure lowering effect of Aprovel is evident within 1-2 weeks, with the maximal effect 
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long 
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound 
hypertension has not been observed. 
 
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients 
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide 
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at 
trough of 7-10/3-6 mm Hg (systolic/diastolic). 
 
The efficacy of Aprovel is not influenced by age or gender. As is the case with other medicinal 
products that affect the renin-angiotensin system, black hypertensive patients have notably less 
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose 
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches 
that of white patients. 
 
There is no clinically important effect on serum uric acid or urinary uric acid secretion. 
 
Paediatric population 
 
Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target 
titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of 
hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the 
three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic 
blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high 



 75 

dose). No significant difference was apparent between these doses. Adjusted mean change of trough 
seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium 
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized 
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg 
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of 
irbesartan (see section 4.2). 
 
Hypertension and type 2 diabetes with renal disease 
 
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression 
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double 
blind, controlled, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 
1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine 
ranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Aprovel on the progression of 
renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a 
maintenance dose of 300 mg Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. 
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., 
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg 
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of 
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% 
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk 
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal 
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative 
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine 
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all 
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant 
reduction in doubling of serum creatinine were observed. 
 
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum 
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black 
subgroups which represented 32% and 26% of the overall study population respectively, a renal 
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary 
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups 
in the overall population, although an increased incidence of non-fatal MI was seen for women and a 
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the 
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart 
failure was reduced in the overall population. However, no proper explanation for these findings in 
women has been identified. 
 
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in 
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function 
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term 
effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin 
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The 
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding 
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added 
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all 
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or 
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% 
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying 
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of 
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months 



 76 

and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more 
frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%). 
 
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) 
 
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in 
combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs 
Nephropathy in Diabetes) have examined the use of the combination of an ACE-inhibitor with an 
angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of 
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of 
end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and 
diabetic nephropathy. 
 
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and 
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as 
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these 
results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. 
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in 
patients with diabetic nephropathy. 
 
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) 
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor 
or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney 
disease, cardiovascular disease, or both. The study was terminated early because of an increased risk 
of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the 
aliskiren group than in the placebo group and adverse events and serious adverse events of interest 
(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren 
group than in the placebo group. 
 
 
5.2 Pharmacokinetic properties 
 
AbsorptionAfter oral administration, irbesartan is well absorbed: studies of absolute bioavailability 
gave values of approximately 60-80%. Concomitant food intake does not significantly influence the 
bioavailability of irbesartan.  
 
Distribution 
 
Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. 
The volume of distribution is 53 - 93 litres.  
 
Biotransformation 
 
Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasma 
radioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver via 
glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide 
(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by the 
cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 
 
Linearity/non-linearity 
 
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. 
A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal 
recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations 
are attained at 1.5 - 2 hours after oral administration. The total body and renal clearance are 157 -
 176 and 3 - 3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15 hours. 
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing 



 77 

regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily 
dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female 
hypertensive patients. However, there was no difference in the half-life and accumulation of 
irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values 
were also somewhat greater in older subjects (≥ 65 years) than those of young subjects (18 - 40 years). 
However the terminal half-life was not significantly altered. No dosage adjustment is necessary in 
older people. 
 
Elimination 
 
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV 
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the 
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan. 
 
Paediatric population 
 
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration 
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for 
four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults 
(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC 
and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan 
daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily 
dosing. 
 
Renal impairment  
 
In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters 
of irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis. 
 
Hepatic impairment  
 
In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not 
significantly altered.  
 
Studies have not been performed in patients with severe hepatic impairment. 
 
5.3 Preclinical safety data 
 
There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In 
non-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in 
macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). 
At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial 
nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and 
creatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to the 
hypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore, 
irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in 
macaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by the 
pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ 
hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance. 
 
There was no evidence of mutagenicity, clastogenicity or carcinogenicity. 
 
Fertility and reproductive performance were not affected in studies of male and female rats even at 
oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including 
mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live 
foetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring. 



 78 

Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses. 
Irbesartan is excreted in the milk of lactating rats. 
 
Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, 
hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, 
abortion or early resorption were noted at doses causing significant maternal toxicity, including 
mortality. No teratogenic effects were observed in the rat or rabbit. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Lactose monohydrate 
Microcrystalline cellulose 
Croscarmellose sodium 
Hypromellose 
Silicon dioxide 
Magnesium stearate. 
 
Film-coating: 
Lactose monohydrate 
Hypromellose 
Titanium dioxide 
Macrogol 3000 
Carnauba wax. 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
Cartons of 14 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 28 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 30 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 84 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 90 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 98 film-coated tablets in PVC/PVDC/Aluminium blisters. 
Cartons of 56 x 1 film-coated tablet in PVC/PVDC/Aluminium perforated unit dose blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 



 79 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/97/046/026-030 
EU/1/97/046/033 
EU/1/97/046/036 
EU/1/97/046/039 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 August 1997 
Date of latest renewal: 27 August 2007 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 



 80 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 



 81 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Sanofi Winthrop Industrie 
1 rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex 
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel, BP 7166 
F-37071 Tours Cedex 2 
France 
 
Chinoin Private Co. Ltd. 
Lévai u.5. 
2112 Veresegyhaz 
Hungary 
 
SANOFI-AVENTIS, S.A. 
Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 
17404 Riells i Viabrea (Girona) - Spain 
 
 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 

 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 

 
Not applicable. 
 
 



 82 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



 83 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 84 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 75 mg tablets 
irbesartan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains: irbesartan 75 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 



 85 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/97/046/010 - 14 tablets 
EU/1/97/046/001 - 28 tablets 
EU/1/97/046/002 - 56 tablets 
EU/1/97/046/013 - 56 x 1 tablets 
EU/1/97/046/003 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Aprovel 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 86 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 75 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
56 x 1 tablets: 



 87 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 150 mg tablets 
irbesartan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains: irbesartan 150 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 



 88 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/97/046/011 - 14 tablets 
EU/1/97/046/004 - 28 tablets 
EU/1/97/046/005 - 56 tablets 
EU/1/97/046/014 - 56 x 1 tablets 
EU/1/97/046/006 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Aprovel 150 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 89 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 150 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
56 x 1 tablets: 



 90 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 300 mg tablets 
irbesartan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains: irbesartan 300 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
56 tablets 
56 x 1 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 



 91 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/97/046/012 - 14 tablets 
EU/1/97/046/007 - 28 tablets 
EU/1/97/046/008 - 56 tablets 
EU/1/97/046/015 - 56 x 1 tablets 
EU/1/97/046/009 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Aprovel 300 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 92 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 300 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
56 x 1 tablets: 



 93 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 75 mg film-coated tablets 
irbesartan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains: irbesartan 75 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
56 tablets 
56 x 1 tablets 
84 tablets 
90 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 94 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/97/046/016 - 14 tablets 
EU/1/97/046/017 - 28 tablets 
EU/1/97/046/034 - 30 tablets 
EU/1/97/046/018 - 56 tablets 
EU/1/97/046/019 - 56 x 1 tablets 
EU/1/97/046/031 - 84 tablets 
EU/1/97/046/037 - 90 tablets 
EU/1/97/046/020 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Aprovel 75 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 95 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 75 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 84 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
30 - 56 x 1 - 90 tablets: 



 96 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 150 mg film-coated tablets 
irbesartan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains: irbesartan 150 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
56 tablets 
56 x 1 tablets 
84 tablets 
90 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 97 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/97/046/021 - 14 tablets 
EU/1/97/046/022 - 28 tablets 
EU/1/97/046/035 - 30 tablets 
EU/1/97/046/023 - 56 tablets 
EU/1/97/046/024 - 56 x 1 tablets 
EU/1/97/046/032 - 84 tablets 
EU/1/97/046/038 - 90 tablets 
EU/1/97/046/025 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Aprovel 150 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 98 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 150 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 84 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
30 - 56 x 1 - 90 tablets: 



 99 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 300 mg film-coated tablets 
irbesartan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains: irbesartan 300 mg 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: also contains lactose monohydrate. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets 
28 tablets 
30 tablets 
56 tablets 
56 x 1 tablets 
84 tablets 
90 tablets 
98 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 100 

9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/97/046/026 - 14 tablets 
EU/1/97/046/027 - 28 tablets 
EU/1/97/046/036 - 30 tablets 
EU/1/97/046/028 - 56 tablets 
EU/1/97/046/029 - 56 x 1 tablets 
EU/1/97/046/033 - 84 tablets 
EU/1/97/046/039 - 90 tablets 
EU/1/97/046/030 - 98 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Aprovel 300 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
 



 101 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Aprovel 300 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
sanofi-aventis groupe 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
14 - 28 - 56 - 84 - 98 tablets: 
Mon 
Tue 
Wed 
Thu 
Fri 
Sat 
Sun 
 
30 - 56 x 1 - 90 tablets: 
 



 102 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 103 

 
Package leaflet: Information for the user 

Aprovel 75 mg tablets 
irbesartan 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Aprovel is and what it is used for 
2. What you need to know before you take Aprovel 
3. How to take Aprovel 
4. Possible side effects 
5. How to store Aprovel 
6. Contents of the pack and other information 
 
 
1. What Aprovel is and what it is used for 
 
Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II 
is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. 
This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these 
receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the 
decrease of kidney function in patients with high blood pressure and type 2 diabetes. 
 
Aprovel is used in adult patients 
 to treat high blood pressure (essential hypertension) 
 to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory 

evidence of impaired kidney function. 
 
 
2. What you need to know before you take Aprovel 
 
Do not take Aprovel 
 if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) 
 if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy 

– see pregnancy section) 
 if you have diabetes or impaired kidney function and you are treated with a blood pressure 

lowering medicine containing aliskiren 
 
Warning and precautions 
Talk to your doctor before taking Aprovel and if any of the following apply to you: 
 if you get excessive vomiting or diarrhoea 
 if you suffer from kidney problems 
 if you suffer from heart problems 
 if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform 

regular blood tests, especially for measuring blood potassium levels in case of poor kidney 
function 

 if you are going to have an operation (surgery) or be given anaesthetics 
 if you are taking any of the following medicines used to treat high blood pressure: 



 104 

o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 
diabetes-related kidney problems. 

o aliskiren. 
 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Aprovel”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not 
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it 
may cause serious harm to your baby if used at that stage (see pregnancy section). 
 
Children and adolescents 
This medicinal product should not be used in children and adolescents because the safety and efficacy 
have not yet been fully established. 
 
Other medicines and Aprovel 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Your doctor may need to change your dose and/or to take other precautions: 
If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Aprovel” and “Warnings and precautions”). 
 
You may need to have blood checks if you take: 
 potassium supplements 
 salt substitutes containing potassium 
 potassium-sparing medicines (such as certain diuretics) 
 medicines containing lithium 
 
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan 
may be reduced. 
 
Aprovel with food and drink 
Aprovel can be taken with or without food. 
 
Pregnancy and breast-feeding 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Aprovel before you become pregnant or as soon as you know you are 
pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not 
recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may 
cause serious harm to your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended 
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish 
to breast-feed, especially if your baby is newborn, or was born prematurely. 
 
Driving and using machines 
Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or 
weariness may occur during treatment of high blood pressure. If you experience these, talk to your 
doctor before attempting to drive or use machines. 
 
Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some 
sugars (e.g. lactose), contact your doctor before taking this medicinal product. 



 105 

 
 
3. How to take Aprovel 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Method of administration 
Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). 
You can take Aprovel with or without food. Try to take your daily dose at about the same time each 
day. It is important that you continue to take Aprovel until your doctor tells you otherwise. 
 
 Patients with high blood pressure 

The usual dose is 150 mg once a day (two tablets a day). The dose may later be increased to 
300 mg (four tablets a day) once daily depending on blood pressure response. 

 
 Patients with high blood pressure and type 2 diabetes with kidney disease 

In patients with high blood pressure and type 2 diabetes, 300 mg (four tablets a day) once daily 
is the preferred maintenance dose for the treatment of associated kidney disease. 

 
The doctor may advise a lower dose, especially when starting treatment in certain patients such as 
those on haemodialysis, or those over the age of 75 years. 
 
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. 
 
Use in children and adolescents 
Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, 
contact your doctor immediately. 
 
If you take more Aprovel than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Aprovel 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised 
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any 
of these symptoms or get short of breath, stop taking Aprovel and contact your doctor 
immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Very common:  may affect more than 1 in 10 people 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Aprovel were: 
 Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and 

type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 



 106 

 
 Common (may affect up to 1 in 10 people): dizziness, feeling sick/vomiting, fatigue and blood 

tests may show raised levels of an enzyme that measures the muscle and heart function (creatine 
kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, 
dizziness when getting up from a lying or sitting position, low blood pressure when getting up 
from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the 
red blood cells (haemoglobin) were also reported. 

 
 Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, 

indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. 
 
Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where 
the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, 
muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, 
increased blood potassium levels, impaired kidney function, inflammation of small blood vessels 
mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic 
reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of 
the eyes) have also been reported. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Aprovel 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Aprovel contains 
 The active substance is irbesartan. Each tablet of Aprovel 75 mg contains 75 mg irbesartan. 
 The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose 

monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and 
poloxamer 188.  Please see section 2 “Aprovel contains lactose”. 

 
What Aprovel looks like and contents of the pack 
Aprovel 75 mg tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on one 
side and the number 2771 engraved on the other side. 
 
Aprovel 75 mg tablets are supplied in blister packs of 14, 28, 56 or 98 tablets. Unidose blister packs of 
56 x 1 tablet for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 



 107 

Marketing Authorisation Holder: 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
Manufacturer: 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel, BP 7166 
F-37071 Tours Cedex 2 – France 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB sanofi-aventis Lietuva 
Tel: +370 5 2755224 
 

България 
Sanofi Bulgaria EOOD 
Тел.: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel.: +36 1 505 0050 
 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.p.A. 
Tel: +39 02 39394275 
 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 
 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 34 88 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda 
Tel: +351 21 35 89 400 
 



 108 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 
 

Italia 
Sanofi S.p.A. 
Tel:  800 536389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 
 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0) 845 372 7101 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 



 109 

 
Package leaflet: Information for the user 

Aprovel 150 mg tablets 
irbesartan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Aprovel is and what it is used for 
2. What you need to know before you take Aprovel 
3. How to take Aprovel 
4. Possible side effects 
5. How to store Aprovel 
6. Contents of the pack and other information 
 
 
1. What Aprovel is and what it is used for 
 
Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II 
is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. 
This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these 
receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the 
decrease of kidney function in patients with high blood pressure and type 2 diabetes. 
 
Aprovel is used in adult patients 
 to treat high blood pressure (essential hypertension) 
 to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory 

evidence of impaired kidney function. 
 
 
2. What you need to know before you take Aprovel 
 
Do not take Aprovel 
 if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) 
 if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy 

– see pregnancy section) 
 if you have diabetes or impaired kidney function and you are treated with  a blood pressure 

lowering medicine containing aliskiren  
 
Warning and precautions 
Talk to your doctor before taking Aprovel and if any of the following apply to you: 
 if you get excessive vomiting or diarrhoea 
 if you suffer from kidney problems 
 if you suffer from heart problems 
 if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform 

regular blood tests, especially for measuring blood potassium levels in case of poor kidney 
function 

 if you are going to have an operation (surgery) or be given anaesthetics 
 if you are taking any of the following medicines used to treat high blood pressure: 



 110 

o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 
diabetes-related kidney problems. 

o aliskiren 
 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Aprovel”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not 
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it 
may cause serious harm to your baby if used at that stage (see pregnancy section). 
 
Children and adolescents 
This medicinal product should not be used in children and adolescents because the safety and efficacy 
have not yet been fully established. 
 
Other medicines and Aprovel 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Your doctor may need to change your dose and/or to take other precautions: 
If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Aprovel” and “Warnings and precautions”). 
 
You may need to have blood checks if you take: 
 potassium supplements 
 salt substitutes containing potassium 
 potassium-sparing medicines (such as certain diuretics) 
 medicines containing lithium 
 
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan 
may be reduced. 
 
Aprovel with food and drink 
Aprovel can be taken with or without food. 
 
Pregnancy and breast-feeding 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Aprovel before you become pregnant or as soon as you know you are 
pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not 
recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may 
cause serious harm to your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended 
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish 
to breast-feed, especially if your baby is newborn, or was born prematurely. 
 
Driving and using machines 
Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or 
weariness may occur during treatment of high blood pressure. If you experience these, talk to your 
doctor before attempting to drive or use machines. 
 
Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some 
sugars (e.g. lactose), contact your doctor before taking this medicinal product. 



 111 

 
 
3. How to take Aprovel 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Method of administration 
Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). 
You can take Aprovel with or without food. Try to take your daily dose at about the same time each 
day. It is important that you continue to take Aprovel until your doctor tells you otherwise. 
 
 Patients with high blood pressure 

The usual dose is 150 mg once a day. The dose may later be increased to 300 mg (two tablets a 
day) once daily depending on blood pressure response. 

 
 Patients with high blood pressure and type 2 diabetes with kidney disease 

In patients with high blood pressure and type 2 diabetes, 300 mg (two tablets a day) once daily 
is the preferred maintenance dose for the treatment of associated kidney disease. 

 
The doctor may advise a lower dose, especially when starting treatment in certain patients such as 
those on haemodialysis, or those over the age of 75 years. 
 
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. 
 
Use in children and adolescents 
Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, 
contact your doctor immediately. 
 
If you take more Aprovel than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Aprovel 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised 
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any 
of these symptoms or get short of breath, stop taking Aprovel and contact your doctor 
immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Very common:  may affect more than 1 in 10 people 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Aprovel were: 
 Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and 

type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 



 112 

 
 Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood 

tests may show raised levels of an enzyme that measures the muscle and heart function (creatine 
kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, 
dizziness when getting up from a lying or sitting position, low blood pressure when getting up 
from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the 
red blood cells (haemoglobin) were also reported. 

 
 Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, 

indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. 
 
Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where 
the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, 
muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, 
increased blood potassium levels, impaired kidney function, inflammation of small blood vessels 
mainly affecting the skin (a condition known as leukocytoclastic vasculitis),and severe allergic 
reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of 
the eyes) have also been reported. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Aprovel 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Aprovel contains 
 The active substance is irbesartan. Each tablet of Aprovel 150 mg contains 150 mg irbesartan. 
 The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose 

monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and 
poloxamer 188. Please see section 2 “Aprovel contains lactose”. 

 
What Aprovel looks like and contents of the pack 
Aprovel 150 mg tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on 
one side and the number 2772 engraved on the other side. 
 
Aprovel 150 mg tablets are supplied in blister packs of 14, 28, 56 or 98 tablets. Unidose blister packs 
of 56 x 1 tablet for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 



 113 

Marketing Authorisation Holder: 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
Manufacturer: 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel, BP 7166 
F-37071 Tours Cedex 2 - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB sanofi-aventis Lietuva 
Tel: +370 5 2755224 
 

България 
Sanofi Bulgaria EOOD 
Тел.: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel.: +36 1 505 0050 
 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.p.A. 
Tel: +39 02 39394275 
 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 34 88 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 



 114 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda 
Tel: +351 21 35 89 400 
 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 
 

Italia 
Sanofi S.p.A. 
Tel:  800 536389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 
 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi- 
Tel: +44 (0) 845 372 7101 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 



 115 

 
Package leaflet: Information for the user 

Aprovel 300 mg tablets 
irbesartan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Aprovel is and what it is used for 
2. What you need to know before you take Aprovel 
3. How to take Aprovel 
4. Possible side effects 
5. How to store Aprovel 
6. Contents of the pack and other information 
 
 
1. What Aprovel is and what it is used for 
 
Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II 
is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. 
This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these 
receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the 
decrease of kidney function in patients with high blood pressure and type 2 diabetes. 
 
Aprovel is used in adult patients 
 to treat high blood pressure (essential hypertension) 
 to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory 

evidence of impaired kidney function. 
 
 
2. What you need to know before you take Aprovel 
 
Do not take Aprovel 
 if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) 
 if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy 

– see pregnancy section) 
 if you have diabetes or impaired kidney function and you are treated with  a blood pressure 

lowering medicine containing aliskiren 
 
Warning and precautions 
Talk to your doctor before taking Aprovel and if any of the following apply to you: 
 if you get excessive vomiting or diarrhoea 
 if you suffer from kidney problems 
 if you suffer from heart problems 
 if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform 

regular blood tests, especially for measuring blood potassium levels in case of poor kidney 
function 

 if you are going to have an operation (surgery) or be given anaesthetics 
 if you are taking any of the following medicines used to treat high blood pressure: 



 116 

o an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have 
diabetes-related kidney problems. 

o aliskiren 
 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Aprovel”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not 
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it 
may cause serious harm to your baby if used at that stage (see pregnancy section). 
 
Children and adolescents 
This medicinal product should not be used in children and adolescents because the safety and efficacy 
have not yet been fully established. 
 
Other medicines and Aprovel 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Your doctor may need to change your dose and/or to take other precautions: 
If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Aprovel” and “Warnings and precautions”). 
 
You may need to have blood checks if you take: 
 potassium supplements 
 salt substitutes containing potassium 
 potassium-sparing medicines (such as certain diuretics) 
 medicines containing lithium 
 
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan 
may be reduced. 
 
Aprovel with food and drink 
Aprovel can be taken with or without food. 
 
Pregnancy and breast-feeding 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Aprovel before you become pregnant or as soon as you know you are 
pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not 
recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may 
cause serious harm to your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended 
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish 
to breast-feed, especially if your baby is newborn, or was born prematurely. 
 
Driving and using machines 
Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or 
weariness may occur during treatment of high blood pressure. If you experience these, talk to your 
doctor before attempting to drive or use machines. 
 
Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some 
sugars (e.g. lactose), contact your doctor before taking this medicinal product. 



 117 

 
 
3. How to take Aprovel 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Method of administration 
Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). 
You can take Aprovel with or without food. Try to take your daily dose at about the same time each 
day. It is important that you continue to take Aprovel until your doctor tells you otherwise. 
 
 Patients with high blood pressure 

The usual dose is 150 mg once a day. The dose may later be increased to 300 mg once daily 
depending on blood pressure response. 

 
 Patients with high blood pressure and type 2 diabetes with kidney disease 

In patients with high blood pressure and type 2 diabetes, 300 mg once daily is the preferred 
maintenance dose for the treatment of associated kidney disease. 

 
The doctor may advise a lower dose, especially when starting treatment in certain patients such as 
those on haemodialysis, or those over the age of 75 years. 
 
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. 
 
Use in children and adolescents 
Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, 
contact your doctor immediately. 
 
If you take more Aprovel than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Aprovel 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised 
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any 
of these symptoms or get short of breath, stop taking Aprovel and contact your doctor 
immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Very common: may affect more than 1 in 10 people 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Aprovel were: 
 Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and 

type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 



 118 

 
 Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood 

tests may show raised levels of an enzyme that measures the muscle and heart function (creatine 
kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, 
dizziness when getting up from a lying or sitting position, low blood pressure when getting up 
from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the 
red blood cells (haemoglobin) were also reported. 

 
 Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, 

indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. 
 
Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where 
the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, 
muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, 
increased blood potassium levels, impaired kidney function, inflammation of small blood vessels 
mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic 
reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of 
the eyes) have also been reported. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Aprovel 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Aprovel contains 
 The active substance is irbesartan. Each tablet of Aprovel 300 mg contains 300 mg irbesartan. 
 The other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose 

monohydrate, magnesium stearate, colloidal hydrated silica, pregelatinised maize starch, and 
poloxamer 188. Please see section 2 “Aprovel contains lactose”. 

 
What Aprovel looks like and contents of the pack 
Aprovel 300 mg tablets are white to off-white, biconvex, and oval-shaped with a heart debossed on 
one side and the number 2773 engraved on the other side. 
 
Aprovel 300 mg tablets are supplied in blister packs of 14, 28, 56 or 98 tablets. Unidose blister packs 
of 56 x 1 tablet for delivery in hospitals are also available. 
 
Not all pack sizes may be marketed. 
 



 119 

Marketing Authorisation Holder: 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
Manufacturer: 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel, BP 7166 
F-37071 Tours Cedex 2 - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB sanofi-aventis Lietuva 
Tel: +370 5 2755224 
 

България 
Sanofi Bulgaria EOOD 
Тел.: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel.: +36 1 505 0050 
 
 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.p.A. 
Tel: +39 02 39394275 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 34 88 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 



 120 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda 
Tel: +351 21 35 89 400 
 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 
 

Italia 
Sanofi S.p.A. 
Tel:  800 536389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 
 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0) 845 372 7101 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 



 121 

 
Package leaflet: Information for the user 

Aprovel 75 mg film-coated tablets 
irbesartan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Aprovel is and what it is used for 
2. What you need to know before you take Aprovel 
3. How to take Aprovel 
4. Possible side effects 
5. How to store Aprovel 
6. Contents of the pack and other information 
 
 
1. What Aprovel is and what it is used for 
 
Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II 
is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. 
This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these 
receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the 
decrease of kidney function in patients with high blood pressure and type 2 diabetes. 
 
Aprovel is used in adult patients 
 to treat high blood pressure (essential hypertension) 
 to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory 

evidence of impaired kidney function. 
 
 
2. What you need to know before you take Aprovel 
 
Do not take Aprovel 
 if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) 
 if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy 

– see pregnancy section) 
 if you have diabetes or impaired kidney function and you are treated with  a blood pressure 

lowering medicine containing aliskiren 
 
Warnings and precautions 
Talk to your doctor before taking Aprovel and if any of the following apply to you: 
 if you get excessive vomiting or diarrhoea 
 if you suffer from kidney problems 
 if you suffer from heart problems 
 if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform 

regular blood tests, especially for measuring blood potassium levels in case of poor kidney 
function 

 if you are going to have an operation (surgery) or be given anaesthetics 
 if you are taking any of the following medicines used to treat high blood pressure: 



 122 

o an ACE-inhibitor ( for example enalapril, lisinopril, ramipril) in particular if you have 
diabetes-related kidney problems. 

o aliskiren 
 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Aprovel”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not 
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it 
may cause serious harm to your baby if used at that stage (see pregnancy section). 
 
Children and adolescents 
This medicinal product should not be used in children and adolescents because the safety and efficacy 
have not yet been fully established. 
 
Other medicines and Aprovel 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Your doctor may need to change your dose and/or to take other precautions: 
If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Aprovel” and “Warnings and precautions”). 
 
You may need to have blood checks if you take: 
 potassium supplements 
 salt substitutes containing potassium 
 potassium-sparing medicines (such as certain diuretics) 
 medicines containing lithium 
 
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan 
may be reduced. 
 
Aprovel with food and drink 
Aprovel can be taken with or without food. 
 
Pregnancy and breast-feeding 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Aprovel before you become pregnant or as soon as you know you are 
pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not 
recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may 
cause serious harm to your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended 
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish 
to breast-feed, especially if your baby is newborn, or was born prematurely. 
 
Driving and using machines 
Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or 
weariness may occur during treatment of high blood pressure. If you experience these, talk to your 
doctor before attempting to drive or use machines. 
 
Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some 
sugars (e.g. lactose), contact your doctor before taking this medicinal product. 



 123 

 
 
3. How to take Aprovel 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Method of administration 
Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). 
You can take Aprovel with or without food. Try to take your daily dose at about the same time each 
day. It is important that you continue to take Aprovel until your doctor tells you otherwise. 
 
 Patients with high blood pressure 

The usual dose is 150 mg once a day (two tablets a day). The dose may later be increased to 
300 mg (four tablets a day) once daily depending on blood pressure response. 

 
 Patients with high blood pressure and type 2 diabetes with kidney disease 

In patients with high blood pressure and type 2 diabetes, 300 mg (four tablets a day) once daily 
is the preferred maintenance dose for the treatment of associated kidney disease. 

 
The doctor may advise a lower dose, especially when starting treatment in certain patients such as 
those on haemodialysis, or those over the age of 75 years. 
 
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. 
 
Use in children and adolescents 
Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, 
contact your doctor immediately. 
 
If you take more Aprovel than you should: 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Aprovel: 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised 
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any 
of these symptoms or get short of breath, stop taking Aprovel and contact your doctor 
immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Very common: may affect more than 1 in 10 people 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Aprovel were: 
 Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and 

type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 



 124 

 
 Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood 

tests may show raised levels of an enzyme that measures the muscle and heart function (creatine 
kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, 
dizziness when getting up from a lying or sitting position, low blood pressure when getting up 
from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the 
red blood cells (haemoglobin) were also reported. 

 
 Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, 

indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. 
 
Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where 
the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, 
muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, 
increased blood potassium levels, impaired kidney function, inflammation of small blood vessels 
mainly affecting the skin (a condition known as leukocytoclastic vasculitis),and severe allergic 
reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of 
the eyes) have also been reported. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Aprovel 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Aprovel contains 
 The active substance is irbesartan. Each tablet of Aprovel 75 mg contains 75 mg irbesartan. 
 The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose 

sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, 
carnauba wax. Please see section 2 “Aprovel contains lactose”. 

 
What Aprovel looks like and contents of the pack 
Aprovel 75 mg film-coated tablets are white to off-white, biconvex, and oval-shaped with a heart 
debossed on one side and the number 2871 engraved on the other side. 
 
Aprovel 75 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or 98 film-
coated tablets. Unidose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are also 
available. 
 
Not all pack sizes may be marketed. 
 



 125 

Marketing Authorisation Holder: 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
Manufacturer: 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel, BP 7166 
F-37071 Tours Cedex 2 - France 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB sanofi-aventis Lietuva 
Tel: +370 5 2755224 
 

България 
Sanofi Bulgaria EOOD 
Тел.: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel.: +36 1 505 0050 
 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.p.A. 
Tel: +39 02 39394275 
 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 34 88 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda 
Tel: +351 21 35 89 400 
 



 126 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 
 

Italia 
Sanofi S.p.A. 
Tel:  800 536389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 
 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0) 845 372 7101 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 



 127 

 
Package leaflet: Information for the user 

Aprovel 150 mg film-coated tablets 
irbesartan 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Aprovel is and what it is used for 
2. What you need to know before you take Aprovel 
3. How to take Aprovel 
4. Possible side effects 
5. How to store Aprovel 
6. Contents of the pack and other information 
 
 
1. What Aprovel is and what it is used for 
 
Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II 
is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. 
This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these 
receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the 
decrease of kidney function in patients with high blood pressure and type 2 diabetes. 
 
Aprovel is used in adult patients 
 to treat high blood pressure (essential hypertension) 
 to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory 

evidence of impaired kidney function. 
 
 
2. What you need to know before you take Aprovel 
 
Do not take Aprovel 
 if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) 
 if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy 

– see pregnancy section) 
 if you have diabetes or impaired kidney function and you are treated with a blood pressure 

lowering medicine containing aliskiren 
 
Warnings and precautions 
Talk to your doctor before taking Aprovel and if any of the following apply to you: 
 if you get excessive vomiting or diarrhoea 
 if you suffer from kidney problems 
 if you suffer from heart problems 
 if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform 

regular blood tests, especially for measuring blood potassium levels in case of poor kidney 
function 

 if you are going to have an operation (surgery) or be given anaesthetics 
 if you are taking any of the following medicines used to treat high blood pressure: 



 128 

o an ACE-inhibitor ( for example enalapril, lisinopril, ramipril) in particular if you have 
diabetes-related kidney problems. 

o aliskiren 
 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Aprovel”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not 
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it 
may cause serious harm to your baby if used at that stage (see pregnancy section). 
 
Children and adolescents 
This medicinal product should not be used in children and adolescents because the safety and efficacy 
have not yet been fully established. 
 
Other medicines and Aprovel 
Tell your doctor or pharmacist if you are taking,have recently taken or might take any other medicines. 
 
Your doctor may need to change your dose and/or to take other precautions: 
 If you are taking an ACE-inhibitor or aliskiren  (see also information under the headings “Do not take 
Aprovel” and “Warnings and precautions”). 
 
You may need to have blood checks if you take: 
 potassium supplements 
 salt substitutes containing potassium 
 potassium-sparing medicines (such as certain diuretics) 
 medicines containing lithium 
 
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan 
may be reduced. 
 
Aprovel with food and drink 
Aprovel can be taken with or without food. 
 
Pregnancy and breast-feeding 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Aprovel before you become pregnant or as soon as you know you are 
pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not 
recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may 
cause serious harm to your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended 
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish 
to breast-feed, especially if your baby is newborn, or was born prematurely. 
 
Driving and using machines 
Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or 
weariness may occur during treatment of high blood pressure. If you experience these, talk to your 
doctor before attempting to drive or use machines. 
 
Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some 
sugars (e.g. lactose), contact your doctor before taking this medicinal product. 
 



 129 

 
3. How to take Aprovel 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Method of administration 
Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). 
You can take Aprovel with or without food. Try to take your daily dose at about the same time each 
day. It is important that you continue to take Aprovel until your doctor tells you otherwise. 
 
 Patients with high blood pressure 

The usual dose is 150 mg once a day. The dose may later be increased to 300 mg (two tablets a 
day) once daily depending on blood pressure response. 

 
 Patients with high blood pressure and type 2 diabetes with kidney disease 

In patients with high blood pressure and type 2 diabetes, 300 mg (two tablets a day) once daily 
is the preferred maintenance dose for the treatment of associated kidney disease. 

 
The doctor may advise a lower dose, especially when starting treatment in certain patients such as 
those on haemodialysis, or those over the age of 75 years. 
 
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. 
 
Use in children and adolescents 
Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, 
contact your doctor immediately. 
 
If you take more Aprovel than you should: 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Aprovel: 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised 
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any 
of these symptoms or get short of breath, stop taking Aprovel and contact your doctor 
immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Very common: may affect more than 1 in 10 people 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Aprovel were: 
 Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and 

type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 
 



 130 

 Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood 
tests may show raised levels of an enzyme that measures the muscle and heart function (creatine 
kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, 
dizziness when getting up from a lying or sitting position, low blood pressure when getting up 
from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the 
red blood cells (haemoglobin) were also reported. 

 
 Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, 

indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. 
 
Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where 
the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, 
muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, 
increased blood potassium levels, impaired kidney function, inflammation of small blood vessels 
mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic 
reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of 
the eyes) have also been reported. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Aprovel 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Aprovel contains 
 The active substance is irbesartan. Each tablet of Aprovel 150 mg contains 150 mg irbesartan. 
 The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose 

sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, 
carnauba wax. Please see section 2 “Aprovel contains lactose”. 

 
What Aprovel looks like and contents of the pack 
Aprovel 150 mg film-coated tablets are white to off-white, biconvex, and oval-shaped with a heart 
debossed on one side and the number 2872 engraved on the other side. 
 
Aprovel 150 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or 98 film-
coated tablets. Unidose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are also 
available. 
 
Not all pack sizes may be marketed. 
 



 131 

Marketing Authorisation Holder: 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
Manufacturer: 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel, BP 7166 
F-37071 Tours Cedex 2 - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház – Hungary 
 
SANOFI-AVENTIS, S.A. 
Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 
17404 Riells i Viabrea (Girona) - Spain 
 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB sanofi-aventis Lietuva 
Tel: +370 5 2755224 
 

България 
Sanofi Bulgaria EOOD 
Тел.: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel.: +36 1 505 0050 
 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.p.A. 
Tel: +39 02 39394275 
 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 34 88 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 



 132 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda 
Tel: +351 21 35 89 400 
 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 
 

Italia 
Sanofi S.p.A. 
Tel:  800 536389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 
 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0) 845 372 7101 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 



 133 

Package leaflet: Information for the user 
Aprovel 300 mg film-coated tablets 

irbesartan 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Aprovel is and what it is used for 
2. What you need to know before you take Aprovel 
3. How to take Aprovel 
4. Possible side effects 
5. How to store Aprovel 
6. Contents of the pack and other information 
 
 
1. What Aprovel is and what it is used for 
 
Aprovel belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II 
is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. 
This results in an increase in blood pressure. Aprovel prevents the binding of angiotensin-II to these 
receptors, causing the blood vessels to relax and the blood pressure to lower. Aprovel slows the 
decrease of kidney function in patients with high blood pressure and type 2 diabetes. 
 
Aprovel is used in adult patients 
 to treat high blood pressure (essential hypertension) 
 to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory 

evidence of impaired kidney function. 
 
 
2. What you need to know before you take Aprovel 
 
Do not take Aprovel 
 if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) 
 if you are more than 3 months pregnant. (It is also better to avoid Aprovel in early pregnancy 

– see pregnancy section) 
 if you have diabetes or impaired kidney function and you are treated with  a blood pressure 

lowering medicine containing aliskiren 
 
Warnings and precautions 
Talk to your doctor before taking Aprovel and if any of the following apply to you: 
 if you get excessive vomiting or diarrhoea 
 if you suffer from kidney problems 
 if you suffer from heart problems 
 if you receive Aprovel for diabetic kidney disease. In this case your doctor may perform 

regular blood tests, especially for measuring blood potassium levels in case of poor kidney 
function 

 if you are going to have an operation (surgery) or be given anaesthetics 
 if you are taking any of the following medicines used to treat high blood pressure: 

o an ACE-inhibitor ( for example enalapril, lisinopril, ramipril) in particular if you have 
diabetes-related kidney problems. 



 134 

o aliskiren 
 
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. 
potassium) in your blood at regular intervals. 
 
See also information under the heading “Do not take Aprovel”. 
 
 
You must tell your doctor if you think you are (or might become) pregnant. Aprovel is not 
recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it 
may cause serious harm to your baby if used at that stage (see pregnancy section). 
 
Children and adolescents 
This medicinal product should not be used in children and adolescents because the safety and efficacy 
have not yet been fully established. 
 
Other medicines and Aprovel 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Your doctor may need to change your dose and/or to take other precautions:  
If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Aprovel” and “Warnings and precautions”). 
 
You may need to have blood checks if you take: 
 potassium supplements 
 salt substitutes containing potassium 
 potassium-sparing medicines (such as certain diuretics) 
 medicines containing lithium 
 
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan 
may be reduced. 
 
Aprovel with food and drink 
Aprovel can be taken with or without food. 
 
Pregnancy and breast-feeding 
Pregnancy 
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally 
advise you to stop taking Aprovel before you become pregnant or as soon as you know you are 
pregnant and will advise you to take another medicine instead of Aprovel. Aprovel is not 
recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may 
cause serious harm to your baby if used after the third month of pregnancy. 
 
Breast-feeding 
Tell your doctor if you are breast-feeding or about to start breast-feeding. Aprovel is not recommended 
for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish 
to breast-feed, especially if your baby is newborn, or was born prematurely. 
 
Driving and using machines 
Aprovel is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or 
weariness may occur during treatment of high blood pressure. If you experience these, talk to your 
doctor before attempting to drive or use machines. 
 
Aprovel contains lactose. If you have been told by your doctor that you have an intolerance to some 
sugars (e.g. lactose), contact your doctor before taking this medicinal product. 
 



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3. How to take Aprovel 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Method of administration 
Aprovel is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). 
You can take Aprovel with or without food. Try to take your daily dose at about the same time each 
day. It is important that you continue to take Aprovel until your doctor tells you otherwise. 
 
 Patients with high blood pressure 

The usual dose is 150 mg once a day. The dose may later be increased to 300 mg once daily 
depending on blood pressure response. 

 
 Patients with high blood pressure and type 2 diabetes with kidney disease 

In patients with high blood pressure and type 2 diabetes, 300 mg once daily is the preferred 
maintenance dose for the treatment of associated kidney disease. 

 
The doctor may advise a lower dose, especially when starting treatment in certain patients such as 
those on haemodialysis, or those over the age of 75 years. 
 
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment. 
 
Use in children and adolescents 
Aprovel should not be given to children under 18 years of age. If a child swallows some tablets, 
contact your doctor immediately. 
 
If you take more Aprovel than you should: 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Aprovel: 
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to 
make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Some of these effects may be serious and may require medical attention. 
 
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised 
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any 
of these symptoms or get short of breath, stop taking Aprovel and contact your doctor 
immediately. 
 
The frequency of the side effects listed below is defined using the following convention: 
Very common: may affect more than 1 in 10 people 
Common: may affect up to 1 in 10 people 
Uncommon: may affect up to 1 in 100 people 
 
Side effects reported in clinical studies for patients treated with Aprovel were: 
 Very common (may affect more than 1 in 10 people): if you suffer from high blood pressure and 

type 2 diabetes with kidney disease, blood tests may show an increased level of potassium. 
 



 136 

 Common (may affect up to 1 10 people): dizziness, feeling sick/vomiting, fatigue and blood 
tests may show raised levels of an enzyme that measures the muscle and heart function (creatine 
kinase enzyme). In patients with high blood pressure and type 2 diabetes with kidney disease, 
dizziness when getting up from a lying or sitting position, low blood pressure when getting up 
from a lying or sitting position, pain in joints or muscles and decreased levels of a protein in the 
red blood cells (haemoglobin) were also reported. 

 
 Uncommon (may affect up to 1 in 100 people): heart rate increased, flushing, cough, diarrhoea, 

indigestion/heartburn, sexual dysfunction (problems with sexual performance), chest pain. 
 
Some undesirable effects have been reported since marketing of Aprovel. Undesirable effects where 
the frequency is not known are: feeling of spinning, headache, taste disturbance, ringing in the ears, 
muscle cramps, pain in joints and muscles, reduced number of platelets, abnormal liver function, 
increased blood potassium levels, impaired kidney function, inflammation of small blood vessels 
mainly affecting the skin (a condition known as leukocytoclastic vasculitis), and severe allergic 
reactions (anaphylactic shock). Uncommon cases of jaundice (yellowing of the skin and/or whites of 
the eyes) have also been reported. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Aprovel 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on the blister after 
EXP. The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Aprovel contains 
 The active substance is irbesartan. Each tablet of Aprovel 300 mg contains 300 mg irbesartan. 
 The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose 

sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000, 
carnauba wax. Please see section 2 “Aprovel contains lactose”. 

 
What Aprovel looks like and contents of the pack 
Aprovel 300 mg film-coated tablets are white to off-white, biconvex, and oval-shaped with a heart 
debossed on one side and the number 2873 engraved on the other side. 
 
Aprovel 300 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or 98 film-
coated tablets. Unidose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are also 
available. 
 
Not all pack sizes may be marketed. 
 



 137 

Marketing Authorisation Holder: 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris - France 
 
Manufacturer: 
SANOFI WINTHROP INDUSTRIE 
1, rue de la Vierge 
Ambarès & Lagrave 
F-33565 Carbon Blanc Cedex - France 
 
SANOFI WINTHROP INDUSTRIE 
30-36 Avenue Gustave Eiffel, BP 7166 
F-37071 Tours Cedex 2 - France 
 
CHINOIN PRIVATE CO. LTD. 
Lévai u.5. 
2112 Veresegyház - Hungary 
 
SANOFI-AVENTIS, S.A. 
Ctra. C-35 (La Batlloria-Hostalric), km. 63.09 
17404 Riells i Viabrea (Girona) - Spain 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Sanofi Belgium 
Tél/Tel: +32 (0)2 710 54 00 
 

Lietuva 
UAB sanofi-aventis Lietuva 
Tel: +370 5 2755224 
 

България 
Sanofi Bulgaria EOOD 
Тел.: +359 (0)2 970 53 00 
 

Luxembourg/Luxemburg 
Sanofi Belgium  
Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 
 

Česká republika 
sanofi-aventis, s.r.o. 
Tel: +420 233 086 111 
 

Magyarország 
SANOFI-AVENTIS Zrt. 
Tel.: +36 1 505 0050 
 

Danmark 
Sanofi A/S 
Tlf: +45 45 16 70 00 
 

Malta 
Sanofi S.p.A. 
Tel: +39 02 39394275 
 

Deutschland 
Sanofi-Aventis Deutschland GmbH 
Tel: 0800 52 52 010 
Tel. aus dem Ausland: +49 69 305 21 131 

Nederland 
sanofi-aventis Netherlands B.V. 
Tel: +31 20 245 4000 
 

Eesti 
sanofi-aventis Estonia OÜ 
Tel: +372 627 34 88 
 

Norge 
sanofi-aventis Norge AS 
Tlf: +47 67 10 71 00 
 

Ελλάδα 
sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 
 

Österreich 
sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 
 



 138 

España 
sanofi-aventis, S.A. 
Tel: +34 93 485 94 00 
 

Polska 
sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 
 

France 
sanofi-aventis France 
Tél: 0 800 222 555 
Appel depuis l’étranger: +33 1 57 63 23 23 
 

Portugal 
Sanofi - Produtos Farmacêuticos, Lda 
Tel: +351 21 35 89 400 
 

Hrvatska 
sanofi-aventis Croatia d.o.o. 
Tel: +385 1 600 34 00 

România 
Sanofi Romania SRL 
Tel: +40 (0) 21 317 31 36 
 

Ireland 
sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 
 

Slovenija 
sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 
 
 

Ísland 
Vistor hf. 
Sími: +354 535 7000 
 

Slovenská republika 
sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 
 

Italia 
Sanofi S.p.A. 
Tel: 800.536389 
 

Suomi/Finland 
Sanofi Oy 
Puh/Tel: +358 (0) 201 200 300 

Κύπρος 
sanofi-aventis Cyprus Ltd. 
Τηλ: +357 22 871600 
 

Sverige 
Sanofi AB 
Tel: +46 (0)8 634 50 00 
 

Latvija 
sanofi-aventis Latvia SIA 
Tel: +371 67 33 24 51 
 

United Kingdom 
Sanofi 
Tel: +44 (0) 845 372 7101 
 

 
This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET