Irbesartan Zentiva

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

 2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
Irbesartan Zentiva 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. 
Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 Irbesartan Zentiva 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). 
 



 

 3 

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 Irbesartan Zentiva 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 Irbesartan Zentiva with aliskiren-containing products is contraindicated in 
patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 
ml/min/1.73m2) (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 Irbesartan 
Zentiva. 
 

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 Irbesartan Zentiva, a similar effect should be anticipated with angiotensin-II 
receptor antagonists. 
 

Renal impairment and kidney transplantation: when Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 4 

aliskirenis 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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 



 

 5 

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). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 



 

 6 

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 Irbesartan Zentiva during breast-feeding, 
Irbesartan Zentiva 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. 
 



 

 7 

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 
 
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 
 



 

 8 

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 
Irbesartan Zentiva. 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. 
 
 
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 



 

 9 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 
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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva, 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 



 

 10 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 11 

(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 
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 



 

 12 

 
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. 
 
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. 
 



 

 13 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/376/001-005 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
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 
 



 

 14 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
Irbesartan Zentiva 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. 
Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 Irbesartan Zentiva 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). 
 



 

 15 

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 forolder people. 
 
Paediatric population 
 
The safety and efficacy of Irbesartan Zentiva 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 Irbesartan Zentiva with aliskiren-containing products is contraindicated in 
patients with diabetes mellitus or moderate to severe renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73m2) (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 Irbesartan 
Zentiva. 
 

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 Irbesartan Zentiva, a similar effect should be anticipated with angiotensin-II 
receptor antagonists. 
 

Renal impairment and kidney transplantation: when Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 16 

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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 



 

 17 

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). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 



 

 18 

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 Irbesartan Zentiva during breast-feeding, 
Irbesartan Zentiva 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. 
 



 

 19 

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 
 
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 
 



 

 20 

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 
Irbesartan Zentiva. 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. 
 
 
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 



 

 21 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 
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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva, 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 



 

 22 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 23 

(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 
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. 
 



 

 24 

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. 
 
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. 
 



 

 25 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/376/006-010 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
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 
 



 

 26 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
Irbesartan Zentiva 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. 
Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 Irbesartan Zentiva 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). 
 



 

 27 

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 forolder people. 
 
Paediatric population 
 
The safety and efficacy of Irbesartan Zentiva 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 Irbesartan Zentiva with aliskiren-containing products is contraindicated in 
patients with diabetes mellitus or moderate to severe renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73m2) (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 Irbesartan 
Zentiva. 
 

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 Irbesartan Zentiva, a similar effect should be anticipated with angiotensin-II 
receptor antagonists. 
 

Renal impairment and kidney transplantation: when Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 28 

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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (see section 4.4). 
 



 

 29 

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. 
 



 

 30 

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 Irbesartan Zentiva during breast-feeding, 
Irbesartan Zentiva 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. 
 



 

 31 

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 
 
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 
 



 

 32 

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 
Irbesartan Zentiva. 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. 
 
 
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 



 

 33 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 
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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva, 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 



 

 34 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 35 

(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 
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. 
 



 

 36 

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. 
 
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. 
 



 

 37 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/376/011-015 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
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 
 



 

 38 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
Irbesartan Zentiva 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. 
Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 Irbesartan Zentiva 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). 
 



 

 39 

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 forolder people. 
 
Paediatric population 
 
The safety and efficacy of Irbesartan Zentiva 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 Irbesartan Zentiva with aliskiren-containing products is contraindicated in 
patients with diabetes mellitus or moderate to severe renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73m2) (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 Irbesartan 
Zentiva. 
 
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 Irbesartan Zentiva, a similar effect should be anticipated with angiotensin-II 
receptor antagonists. 
 
Renal impairment and kidney transplantation: when Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 40 

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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (see section 4.4). 
 



 

 41 

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. 
 



 

 42 

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 Irbesartan Zentiva during breast-feeding, 
Irbesartan Zentiva 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. 
 



 

 43 

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 
 
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 
 



 

 44 

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 
Irbesartan Zentiva. 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. 
 
 
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 



 

 45 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 
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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva, 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 



 

 46 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 47 

(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 
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. 
 



 

 48 

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. 
 
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 



 

 49 

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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/376/016-021 
EU/1/06/376/034-035 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
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 



 

 50 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
Irbesartan Zentiva 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. 
Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 Irbesartan Zentiva 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). 
 



 

 51 

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 forolder people. 
 
Paediatric population 
 
The safety and efficacy of Irbesartan Zentiva 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 Irbesartan Zentiva with aliskiren-containing products is contraindicated in 
patients with diabetes mellitus or moderate to severe renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73m2) (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 Irbesartan 
Zentiva. 
 
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 Irbesartan Zentiva, a similar effect should be anticipated with angiotensin-II 
receptor antagonists. 
 
Renal impairment and kidney transplantation: when Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 52 

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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (see section 4.4). 
 



 

 53 

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. 
 
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). 



 

 54 

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 Irbesartan Zentiva during breast-feeding, 
Irbesartan Zentiva 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. 
 



 

 55 

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 
 
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 
 



 

 56 

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 
Irbesartan Zentiva. 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. 
 
 
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 



 

 57 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 
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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva, 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 



 

 58 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 59 

(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 
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. 
 



 

 60 

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. 
 
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 



 

 61 

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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/376/022-027 
EU/1/06/376/036-037 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
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 



 

 62 

1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
Irbesartan Zentiva 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. 
Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 Irbesartan Zentiva 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). 
 



 

 63 

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 forolder people. 
 
Paediatric population 
 
The safety and efficacy of Irbesartan Zentiva 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 Irbesaratn Zentiva with aliskiren-containing products is contraindicated in 
patients with diabetes mellitus or moderate to severe renal impairment (glomerular filtration rate 
(GFR) <60 ml/min/1.73m2) (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 Irbesartan 
Zentiva. 
 
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 Irbesartan Zentiva, a similar effect should be anticipated with angiotensin-II 
receptor antagonists. 
 
Renal impairment and kidney transplantation: when Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 64 

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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva (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 



 

 65 

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). 
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 
of renal function and skull is recommended. 



 

 66 

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 Irbesartan Zentiva during breast-feeding, 
Irbesartan Zentiva 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. 
 



 

 67 

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 
 
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 
 



 

 68 

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 
Irbesartan Zentiva. 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. 
 
 
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 



 

 69 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 
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 Irbesartan Zentiva, 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 Irbesartan Zentiva 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 Irbesartan Zentiva, 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 



 

 70 

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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 



 

 71 

(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 
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 oldersubjects (≥ 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. 
 



 

 72 

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. 
 
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 



 

 73 

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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/06/376/028-033 
EU/1/06/376/038-039 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19 January 2007 
Date of latest renewal: 19 January 2012 
 
 
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 



 

 74 

 
 
 
 
 
 

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 



 

 75 

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 et Lagrave 
33 565 Carbon Blanc cedex 
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel 
37 100 Tours 
France 
 
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. 
The PSUR cycle of Irbesartan Zentiva is aligned with the cross-referred product, APROVEL, until 
otherwise specified. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

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

 
Not applicable. 
 
 



 

 76 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



 

 77 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

 78 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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. 
 
 



 

 79 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/376/001 - 14 tablets 
EU/1/06/376/002 - 28 tablets 
EU/1/06/376/003 - 56 tablets 
EU/1/06/376/004 - 56 x 1 tablets 
EU/1/06/376/005 - 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 
 
Irbesartan Zentiva 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 

 80 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 75 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s. 
 
 
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: 



 

 81 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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. 
 
 



 

 82 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/376/006 - 14 tablets 
EU/1/06/376/007 - 28 tablets 
EU/1/06/376/008 - 56 tablets 
EU/1/06/376/009 - 56 x 1 tablets 
EU/1/06/376/010 - 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 
 
Irbesartan Zentiva 150 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 

 83 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 150 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s. 
 
 
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: 



 

 84 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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. 
 
 



 

 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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/376/011 - 14 tablets 
EU/1/06/376/012 - 28 tablets 
EU/1/06/376/013 - 56 tablets 
EU/1/06/376/014 - 56 x 1 tablets 
EU/1/06/376/015 - 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 
 
Irbesartan Zentiva 300 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 
 
Irbesartan Zentiva 300 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s. 
 
 
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 
 
Irbesartan Zentiva 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 
 
 



 

 88 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/376/016 - 14 tablets 
EU/1/06/376/017 - 28 tablets 
EU/1/06/376/034 - 30 tablets 
EU/1/06/376/018 - 56 tablets 
EU/1/06/376/019 - 56 x 1 tablets 
EU/1/06/376/020 - 84 tablets 
EU/1/06/376/035 - 90 tablets 
EU/1/06/376/021 - 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 
 
Irbesartan Zentiva 75 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 

 89 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 

 90 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 75 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s. 
 
 
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: 



 

 91 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
 



 

 92 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/376/022 - 14 tablets 
EU/1/06/376/023 - 28 tablets 
EU/1/06/376/036 - 30 tablets 
EU/1/06/376/024 - 56 tablets 
EU/1/06/376/025 - 56 x 1 tablets 
EU/1/06/376/026 - 84 tablets 
EU/1/06/376/037 - 90 tablets 
EU/1/06/376/027 - 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 
 
Irbesartan Zentiva 150 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 

 93 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 

 94 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 150 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s. 
 
 
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: 



 

 95 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 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 
 
 



 

 96 

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 
 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/376/028 - 14 tablets 
EU/1/06/376/029 - 28 tablets 
EU/1/06/376/038 - 30 tablets 
EU/1/06/376/030 - 56 tablets 
EU/1/06/376/031 - 56 x 1 tablets 
EU/1/06/376/032 - 84 tablets 
EU/1/06/376/039 - 90 tablets 
EU/1/06/376/033 - 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 
 
Irbesartan Zentiva 300 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



 

 97 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN: 
NN: 



 

 98 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Irbesartan Zentiva 300 mg tablets 
irbesartan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva k.s. 
 
 
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 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 

 100 

Package leaflet: Information for the user 
Irbesartan Zentiva 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 Irbesartan Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Zentiva 
3. How to take Irbesartan Zentiva 
4. Possible side effects 
5. How to store Irbesartan Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Zentiva is and what it is used for 
 
Irbesartan Zentiva 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. Irbesartan Zentiva prevents the binding 
of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Irbesartan Zentiva slows the decrease of kidney function in patients with high blood pressure and 
type 2 diabetes. 
 
Irbesartan Zentiva 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 Irbesartan Zentiva 
 
Do not take Irbesartan Zentiva 
▪ 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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: 



 

 101 

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 Irbesartan Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan Zentiva 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 Irbesartan Zentiva 
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 
Irbesartan Zentiva ” 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. 
 
Irbesartan Zentiva with food and drink 
Irbesartan Zentiva 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 Irbesartan Zentiva before you become pregnant or as soon as you know you 
are pregnant and will advise you to take another medicine instead of Irbesartan Zentiva. Irbesartan 
Zentiva 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. Irbesartan Zentiva 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 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 



 

 102 

 
 
3. How to take Irbesartan Zentiva 
 
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 
Irbesartan Zentiva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass 
of water). You can take Irbesartan Zentiva 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 Irbesartan Zentiva 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 
Irbesartan Zentiva 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 Irbesartan Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Zentiva 
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 Irbesartan Zentiva 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 Irbesartan Zentiva were: 



 

 103 

▪ 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. 

 
▪ 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 Irbesartan Zentiva. 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 Irbesartan Zentiva 
 
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 Irbesartan Zentiva contains 
▪ The active substance is irbesartan. Each tablet of Irbesartan Zentiva 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 “Irbesartan Zentiva contains lactose”. 

 
What Irbesartan Zentiva looks like and contents of the pack 
Irbesartan Zentiva 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. 
 



 

 104 

Irbesartan Zentiva 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. 
 
Marketing Authorisation Holder: 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1 Rue de la vierge 
Ambarès et Lagrave 
33 565 Carbon Blanc cedex 
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel 
37 100 Tours  
France 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 



 

 105 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

România 
ZENTIVA S.A. 
Tel: +4 021 304 7597 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 800 090 2408 
PV-United-Kingdom@zentiva.com 

  
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/ 



 

 106 

Package leaflet: Information for the user 
Irbesartan Zentiva 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 Irbesartan Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Zentiva 
3. How to take Irbesartan Zentiva 
4. Possible side effects 
5. How to store Irbesartan Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Zentiva is and what it is used for 
 
Irbesartan Zentiva 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. Irbesartan Zentiva prevents the binding 
of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Irbesartan Zentiva slows the decrease of kidney function in patients with high blood pressure and 
type 2 diabetes. 
 
Irbesartan Zentiva 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 Irbesartan Zentiva 
 
Do not take Irbesartan Zentiva 
▪ 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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: 



 

 107 

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 Irbesartan Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan Zentiva 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 Irbesartan Zentiva 
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 
Irbesartan Zentiva” 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. 
 
Irbesartan Zentiva with food and drink 
Irbesartan Zentiva 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 Irbesartan Zentiva before you become pregnant or as soon as you know you 
are pregnant and will advise you to take another medicine instead of Irbesartan Zentiva. Irbesartan 
Zentiva 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. Irbesartan Zentiva 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 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 



 

 108 

 
 
3. How to take Irbesartan Zentiva 
 
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 
Irbesartan Zentiva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass 
of water). You can take Irbesartan Zentiva 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 Irbesartan Zentiva 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 
Irbesartan Zentiva 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 Irbesartan Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Zentiva 
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 Irbesartan Zentiva 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 Irbesartan Zentiva were: 



 

 109 

▪ 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. 

 
▪ 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 Irbesartan Zentiva. 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 Irbesartan Zentiva 
 
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 Irbesartan Zentiva contains 
▪ The active substance is irbesartan. Each tablet of Irbesartan Zentiva 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 “Irbesartan Zentiva contains lactose”. 

 
What Irbesartan Zentiva looks like and contents of the pack 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 
 



 

 110 

Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder: 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1 Rue de la vierge 
Ambarès et Lagrave 
33 565 Carbon Blanc cedex  
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel 
37 100 Tours 
France 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 



 

 111 

 
España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

România 
ZENTIVA S.A. 
Tel: +4 021 304 7597 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 800 090 2408 
PV-United-Kingdom@zentiva.com 

  
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/ 



 

 112 

Package leaflet: Information for the user 
Irbesartan Zentiva 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 Irbesartan Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Zentiva 
3. How to take Irbesartan Zentiva 
4. Possible side effects 
5. How to store Irbesartan Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Zentiva is and what it is used for 
 
Irbesartan Zentiva 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. Irbesartan Zentiva prevents the binding 
of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Irbesartan Zentiva slows the decrease of kidney function in patients with high blood pressure and 
type 2 diabetes. 
 
Irbesartan Zentiva 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 Irbesartan Zentiva 
 
Do not take Irbesartan Zentiva 
▪ 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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: 



 

 113 

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 Irbesartan Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan Zentiva 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 Irbesartan Zentiva 
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 
Irbesartan Zentiva” 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. 
 
Irbesartan Zentiva with food and drink 
Irbesartan Zentiva 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 Irbesartan Zentiva before you become pregnant or as soon as you know you 
are pregnant and will advise you to take another medicine instead of Irbesartan Zentiva. Irbesartan 
Zentiva 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. Irbesartan Zentiva 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 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 



 

 114 

 
 
3. How to take Irbesartan Zentiva 
 
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 
Irbesartan Zentiva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass 
of water). You can take Irbesartan Zentiva 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 Irbesartan Zentiva 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 
Irbesartan Zentiva 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 Irbesartan Zentiva than you should 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Zentiva 
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 Irbesartan Zentiva 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 Irbesartan Zentiva were: 



 

 115 

▪ 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. 

 
▪ 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 Irbesartan Zentiva. 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 Irbesartan Zentiva 
 
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 Irbesartan Zentiva contains 
▪ The active substance is irbesartan. Each tablet of Irbesartan Zentiva 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 “Irbesartan Zentiva contains lactose”. 

 
What Irbesartan Zentiva looks like and contents of the pack 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 
 



 

 116 

Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder: 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1 Rue de la vierge 
Ambarès et Lagrave 
33 565 Carbon Blanc cedex 
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel 
37 100 Tours 
France 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 



 

 117 

 
España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

România 
ZENTIVA S.A. 
Tel: +4 021 304 7597 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 800 090 2408 
PV-United-Kingdom@zentiva.com 

  
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/ 



 

 118 

Package leaflet: Information for the user 
Irbesartan Zentiva 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 Irbesartan Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Zentiva 
3. How to take Irbesartan Zentiva 
4. Possible side effects 
5. How to store Irbesartan Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Zentiva is and what it is used for 
 
Irbesartan Zentiva 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. Irbesartan Zentiva prevents the binding 
of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Irbesartan Zentiva slows the decrease of kidney function in patients with high blood pressure and 
type 2 diabetes. 
 
Irbesartan Zentiva 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 Irbesartan Zentiva 
 
Do not take Irbesartan Zentiva 
▪ 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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: 



 

 119 

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 Irbesartan Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan Zentiva 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 Irbesartan Zentiva 
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: 
Iif you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take 
Irbesartan Zentiva” 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. 
 
Irbesartan Zentiva with food and drink 
Irbesartan Zentiva 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 Irbesartan Zentiva before you become pregnant or as soon as you know you 
are pregnant and will advise you to take another medicine instead of Irbesartan Zentiva. Irbesartan 
Zentiva 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. Irbesartan Zentiva 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 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 
 
 



 

 120 

3. How to take Irbesartan Zentiva 
 
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 
Irbesartan Zentiva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass 
of water). You can take Irbesartan Zentiva 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 Irbesartan Zentiva 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 
Irbesartan Zentiva 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 Irbesartan Zentiva than you should: 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Zentiva: 
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 Irbesartan Zentiva 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 Irbesartan Zentiva 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. 
 



 

 121 

▪ 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 Irbesartan Zentiva. 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 Irbesartan Zentiva 
 
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 Irbesartan Zentiva contains 
▪ The active substance is irbesartan. Each tablet of Irbesartan Zentiva 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 “Irbesartan Zentiva  contains lactose”. 

 
What Irbesartan Zentiva looks like and contents of the pack 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 
 



 

 122 

Marketing Authorisation Holder: 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1 Rue de la vierge 
Ambarès et Lagrave 
33 565 Carbon Blanc cedex 
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel 
37 100 Tours 
France 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder. 
 
België/Belgique/Belgien 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 



 

 123 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

România 
ZENTIVA S.A. 
Tel: +4 021 304 7597 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 800 090 2408 
PV-United-Kingdom@zentiva.com 

  
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/ 



 

 124 

Package leaflet: Information for the user 
Irbesartan Zentiva 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 Irbesartan Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Zentiva 
3. How to take Irbesartan Zentiva 
4. Possible side effects 
5. How to store Irbesartan Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Zentiva is and what it is used for 
 
Irbesartan Zentiva 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. Irbesartan Zentiva prevents the binding 
of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Irbesartan Zentiva slows the decrease of kidney function in patients with high blood pressure and 
type 2 diabetes. 
 
Irbesartan Zentiva 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 Irbesartan Zentiva 
 
Do not take Irbesartan Zentiva 
▪ 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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: 



 

 125 

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 Irbesartan Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan Zentiva 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 Irbesartan Zentiva 
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 
Irbesartan Zentiva” 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. 
 
Irbesartan Zentiva with food and drink 
Irbesartan Zentiva 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 Irbesartan Zentiva before you become pregnant or as soon as you know you 
are pregnant and will advise you to take another medicine instead of Irbesartan Zentiva. Irbesartan 
Zentiva 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. Irbesartan Zentiva 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 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 
 



 

 126 

 
3. How to take Irbesartan Zentiva 
 
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 
Irbesartan Zentiva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass 
of water). You can take Irbesartan Zentiva 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 Irbesartan Zentiva 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 
Irbesartan Zentiva 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 Irbesartan Zentiva than you should: 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Zentiva: 
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 Irbesartan Zentiva 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 Irbesartan Zentiva 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. 



 

 127 

 
▪ 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 Irbesartan Zentiva. 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 Irbesartan Zentiva 
 
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 Irbesartan Zentiva contains 
▪ The active substance is irbesartan. Each tablet of Irbesartan Zentiva 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 “Irbesartan Zentiva contains lactose”. 

 
What Irbesartan Zentiva looks like and contents of the pack 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 
 



 

 128 

Marketing Authorisation Holder: 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1 Rue de la vierge 
Ambarès et Lagrave 
33 565 Carbon Blanc cedex 
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel 
37 100 Tours 
France 
 
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 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 



 

 129 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

România 
ZENTIVA S.A. 
Tel: +4 021 304 7597 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 800 090 2408 
PV-United-Kingdom@zentiva.com 

  
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/ 



 

 130 

Package leaflet: Information for the user 
Irbesartan Zentiva 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 Irbesartan Zentiva is and what it is used for 
2. What you need to know before you take Irbesartan Zentiva 
3. How to take Irbesartan Zentiva 
4. Possible side effects 
5. How to store Irbesartan Zentiva 
6. Contents of the pack and other information 
 
 
1. What Irbesartan Zentiva is and what it is used for 
 
Irbesartan Zentiva 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. Irbesartan Zentiva prevents the binding 
of angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower. 
Irbesartan Zentiva slows the decrease of kidney function in patients with high blood pressure and 
type 2 diabetes. 
 
Irbesartan Zentiva 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 Irbesartan Zentiva 
 
Do not take Irbesartan Zentiva 
▪ 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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 Irbesartan Zentiva 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: 



 

 131 

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 Irbesartan Zentiva”. 
 
You must tell your doctor if you think you are (or might become) pregnant. Irbesartan Zentiva 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 Irbesartan Zentiva 
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 
Irbesartan Zentiva” 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. 
 
Irbesartan Zentiva with food and drink 
Irbesartan Zentiva 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 Irbesartan Zentiva before you become pregnant or as soon as you know you 
are pregnant and will advise you to take another medicine instead of Irbesartan Zentiva. Irbesartan 
Zentiva 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. Irbesartan Zentiva 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 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 
 



 

 132 

 
3. How to take Irbesartan Zentiva 
 
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 
Irbesartan Zentiva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass 
of water). You can take Irbesartan Zentiva 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 Irbesartan Zentiva 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 
Irbesartan Zentiva 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 Irbesartan Zentiva than you should: 
If you accidentally take too many tablets, contact your doctor immediately. 
 
If you forget to take Irbesartan Zentiva: 
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 Irbesartan Zentiva 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 Irbesartan Zentiva 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. 



 

 133 

 
▪ 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 Irbesartan Zentiva. 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 Irbesartan Zentiva 
 
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 Irbesartan Zentiva contains 
▪ The active substance is irbesartan. Each tablet of Irbesartan Zentiva 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 “Irbesartan Zentiva contains lactose”. 

 
What Irbesartan Zentiva looks like and contents of the pack 
Irbesartan Zentiva 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. 
 
Irbesartan Zentiva 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. 



 

 134 

 
Marketing Authorisation Holder: 
Zentiva k.s.  
U kabelovny 130  
102 37 Prague 10  
Czech Republic 
 
Manufacturer: 
Sanofi Winthrop Industrie 
1 Rue de la vierge 
Ambarès et Lagrave 
33 565 Carbon Blanc cedex 
France 
 
Sanofi Winthrop Industrie 
30-36 Avenue Gustave Eiffel 
37 100 Tours 
France 
 
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 
Zentiva, k.s. 
Tél/Tel: +32 280 86 420 
PV-Belgium@zentiva.com 
 

Lietuva 
Zentiva, k.s. 
Tel: +370 52152025 
PV-Lithuania@zentiva.com 

България 
Zentiva, k.s. 
Тел: + 359 2 805 72 08 
PV-Bulgaria@zentiva.com 
 

Luxembourg/Luxemburg 
Zentiva, k.s. 
Tél/Tel: +352 208 82330 
PV-Luxembourg@zentiva.com 

Česká republika 
Zentiva, k.s. 
Tel: +420 267 241 111 
PV-Czech-Republic@zentiva.com 

Magyarország 
Zentiva, k.s. 
Tel.: +36 165 55 722 
PV-Hungary@zentiva.com 

Danmark 
Zentiva, k.s. 
Tlf: +45 787 68 400 
PV-Denmark@zentiva.com 
 

Malta 
Zentiva, k.s. 
Tel: +356 277 82 052 
PV-Malta@zentiva.com 

Deutschland 
Zentiva Pharma GmbH  
Tel: +49 (0) 800 53 53 010 
PV-Germany@zentiva.com 
 

Nederland 
Zentiva, k.s. 
Tel: +31 202 253 638 
PV-Netherlands@zentiva.com 

Eesti 
Zentiva, k.s. 
Tel: +372 52 70308 
PV-Estonia@zentiva.com 
 

Norge 
Zentiva, k.s. 
Tlf: +47 219 66 203 
PV-Norway@zentiva.com 



 

 135 

Ελλάδα 
Zentiva, k.s. 
Τηλ: +30 211 198 7510 
PV-Greece@zentiva.com 
 

Österreich 
Zentiva, k.s. 
Tel: +43 720 778 877 
PV-Austria@zentiva.com 

España 
Zentiva, k.s. 
Tel: +34 931 815 250 
PV-Spain@zentiva.com 
 

Polska 
Zentiva Polska Sp. z o.o. 
Tel: + 48 22 375 92 00 
PV-Poland@zentiva.com 

France 
Zentiva France 
Tél: +33 (0) 800 089 219  
PV-France@zentiva.com 
 

Portugal 
Zentiva Portugal, Lda 
Tel: +351210601360 
PV-Portugal@zentiva.com 

Hrvatska 
Zentiva, k.s. 
Tel: +385 155 17 772 
PV-Croatia@zentiva.com 
 
Ireland 
Zentiva, k.s. 
Tel: +353 766 803 944 
PV-Ireland@zentiva.com 
 

România 
ZENTIVA S.A. 
Tel: +4 021 304 7597 
PV-Romania@zentiva.com 
 
Slovenija 
Zentiva, k.s. 
Tel: +386 360 00 408 
PV-Slovenia@zentiva.com 

Ísland 
Zentiva, k.s. 
Sími: +354 539 0650 
PV-Iceland@zentiva.com 
 

Slovenská republika 
Zentiva, a.s. 
Tel: +421 2 3918 3010 
PV-Slovakia@zentiva.com 

Italia 
Zentiva Italia S.r.l. 
 +39-02-38598801 
PV-Italy@zentiva.com 

Suomi/Finland 
Zentiva, k.s. 
Puh/Tel: +358 942 598 648 
PV-Finland@zentiva.com 
 

Κύπρος 
Zentiva, k.s. 
Τηλ: +357 240 30 144 
PV-Cyprus@zentiva.com 
 

Sverige 
Zentiva, k.s. 
Tel: +46 840 838 822 
PV-Sweden@zentiva.com 

Latvija 
Zentiva, k.s. 
Tel: +371 67893939 
PV-Latvia@zentiva.com 

United Kingdom 
Zentiva Pharma UK Limited 
Tel: +44 (0) 800 090 2408 
PV-United-Kingdom@zentiva.com 

  
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/ 



 

 136 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

Annex IV 

Scientific conclusions  



 

 137 

Scientific conclusions  

Sartan-containing medicinal products are important treatment options of serious or potentially 

serious conditions such as hypertension or certain heart or kidney diseases. Efficacy and safety of 

sartan-containing medicines in these indications are per se well-established and are not questioned 

in this referral. The key issue of this referral concerns the detection of N-nitrosamine (esp. NDMA 

and/or NDEA) contaminations in sartans, the resulting potential long-term risk to patients and 

measures to minimise as much as possible these contaminations. 

Nitrosamines are chemically simple molecules and can be formed in pharmaceutical manufacturing 

steps whenever there is a presence of a secondary (or tertiary) amines and nitrites, usually in 

acidic conditions. This is the background to the current referral procedure. However, it should be 

noted that nitrosamines can also be formed in many other situations, including in biological 

processes.  

NDMA and NDEA are two of the most potent mutagenic carcinogens known. As soon as the 

problem of nitrosamine-contamination became known, immediate, precautionary measures were 

taken by competent authorities across the EU such as recalls of affected batches from pharmacies. 

Initially, this was only necessary for valsartan containing APIs from few manufacturers but later 

also for some other sartans with a tetrazole ring. 

Assessment of the excess risk of cancer  

The impact of NDMA and NDEA on human health is currently only extrapolated from animal studies. 

However, as the DNA damage mechanisms documented in these studies are also relevant in 

humans and in vitro data in human cells are not significantly different from those in animal cells, it 

is prudent to assume that effects seen in animals may also occur in humans after exposure to 

sufficiently large amounts of these nitrosamines.  

In addition to NDMA and NDEA, other N-nitrosamines have been detected in a few sartan-

containing medicinal products. Risks resulting from multiple exposures are considered to add up in 

patients as mutagenic carcinogens are currently considered as summation toxins. 

The ICH M7(R1) guideline sets out principles for determining limits for mutagenic / DNA-reactive 

impurities. The determination of an acceptable intake (AI) is based on extrapolation of carcinogenic 

risk from rodent carcinogenicity data, as the dose resulting in one cancer case among 100,000 

individuals exposed for a life-time to the impurity. N-nitrosamines belong to a “cohort of concern” 

compounds in this guideline. For these reasons, N-nitrosamine impurities in pharmaceuticals such 

as sartans intended for long-term use should be reduced as much as possible. 

A full risk assessment for patients previously exposed to NDMA and/or NDEA impurities in sartans, 

especially valsartan which was found to contain the highest nitrosamine contamination, is not 

possible as the real extent of exposure of patients is unknown. For an individual risk assessment, 

data on the exact drug products and batches used by each individual patient would be necessary. 

Thus, the risk assessment is based on a potential worst case scenario, which would be a partially 

combined exposure to the highest levels of NDEA for 4 years (2011 – 2015) and to NDMA for 6 

years (2012 – 2018) reported from a sartan, resulting in a cumulative theoretical excess cancer 

risk of 29.5:100,000 or 1:3390 (0.029%) when extrapolated from the available rat studies 

according to ICH M7(R1). Compared to the lifetime cancer risk in the European population of 

approximately 50%, this additional risk is considered to be very low.  

 



 

 138 

 

Considerations on monitoring of exposed patients 

The above stated very small theoretical risk has to be balanced against the risks of potential 

measures to monitor patients such as colonoscopy or gastroscopy which may exceed the 

theoretical excess cancer risk. For example, a recent review has estimated risks of perforation of 4 

per 10,000 (95% confidence interval, 2-5) and major haemorrhage of 8 per 10,000 (95% 

confidence interval, 5-14) with screening colonoscopy. In addition, advancing age, comorbidity and 

use of anticoagulants were found to be strongly associated with both gastrointestinal and non-

gastrointestinal complications. Furthermore, the target organ(s) of NDMA/NDEA toxicity in humans 

are still not sufficiently clear.  

For these reasons, CHMP could not identify cancer screening methods that patients would benefit 

from.  

 

Measures to mitigate the risk 

Appropriate regulatory actions (such as quarantine or batch recalls) have been taken where 

relevant. 

Additional measures are needed to minimise prospectively the reoccurrence of such contamination. 

Based on all available data, the CHMP requires the following: 

1. Obligatory risk assessments to be performed for manufacturing processes of the drug 

substances in order to evaluate the theoretical risk of N-nitrosamine formation and contamination 

2. Modifying manufacturing processes, where necessary, to minimise contamination as much as 

possible. 

3. Implement a control strategy to detect and control N-nitrosamine impurities in the API (or 

intermediate, if justified). 

Specifically, CHMP considered that NDMA and NDEA limits should be as low as technically possible. 

In this regard, a limit of quantification of 0.03 ppm for NDMA and NDEA would be achievable 

according to the available data on analytical methods. This limit is considered a sufficiently robust 

threshold for APIs that can technically be reached. In comparison to the daily intake levels 

calculated based on ICH M7(R1) using non-clinical toxicology, it is possible to generate additional 

safety factors ranging from 2.73 – 27.3 for NDMA and 10.0 – 100 for NDEA, by defining 0.03 ppm 

as the common technical target limit for NDEA and NDMA in tetrazole sartan APIs. The underlying 

concept of the proposed approach is to keep the amount of N-nitrosamine impurities as low as 

possible, irrespective of the type of sartan or dose. 

The limit of 0.03 ppm for NDMA and NDEA will be enforceable after a transitional period of 2 years 

from the notification of the Commission Decision. During this time period, MAHs and manufacturers 

are requested to introduce relevant changes to the manufacturing processes of the drug 

substances, as well as develop appropriate analytical methods while ensuring adequate supply of 

the market for these essential medicinal products. An interim limit based on daily intakes according 

to principles in ICH M7(R1) using toxicology data are set in order to control these impurities in the 

meantime at an acceptable level. These interim limits are based on the maximum daily dose 

authorised in the EU for each of the sartans and therefore vary between them, as outlined in the 

table below: 

 



 

 139 

 

Drug 

substance 

Max. daily 

dose (mg) 

NDEA   

Limit in ppm 
in API 

NDMA  

 Limit in ppm 
in API 

Valsartan 320 0.082  0.300 

Losartan 150 0.177 0.640 

Olmesartan 40 0.663 2.400 

Irbesartan 300 0.088 0.320 

Candesartan 32 0.820  3.000 

 

Should NDMA and NDEA be detected in parallel in an API batch, this should lead to rejection of the 

respective batch, considering that a combined contamination would translate into a combined risk, 

which may be higher than one additional case of cancer in 100.000 individuals. 

Whilst the measures are focused on NDMA and NDEA, the principles used in this procedure in terms 

of toxicology assessment, control strategy and changes to the manufacturing processes for drug 

substances should be applied by analogy to other nitrosamines. 

In case of identification of other nitrosamines, this should be forthwith reported to the competent 

authorities, together with a toxicology assessment of the impurity, a clinical assessment for the 

exposed patients, a root cause analysis and a corrective action plan (e.g. changes to the 

manufacturing process). 

 

Overall, taking into account the available data assessed in this procedure, the benefit risk balance 

of medicines containing a sartan with a tetrazole ring remains positive subject to the conditions 

imposed. 

 

Grounds for CHMP opinion 

Whereas 

• The CHMP considered the procedure under Article 31 of Directive 2001/83/EC for products 

containing sartans with a tetrazole group (candesartan, irbesartan, losartan, olmesartan, 

valsartan) 

• The CHMP reviewed data on quality regarding the manufacturing processes of sartans with 

a tetrazole group, analytical data including test results and available methods, and 

toxicological data available for the N-nitrosamines found in some of these products. The 

CHMP also carried out a risk assessment for patients previously exposed to NDMA and 

NDEA in sartans and calculated daily intake levels based on the principles of ICH M7(R1) 

which are associated with an additional lifetime risk of 1 in 100,000 patients. 

• Based on the analysis of potential root causes the CHMP considered that all the MAHs 

should perform risk assessment of the manufacturing processes used for the APIs in their 

finished products to evaluate the risk of N-nitrosamine formation and contamination. 

• A two-year transition period) is considered acceptable to change production processes to 

achieve syntheses in which N-nitrosamines are not formed, to adopt analytical methods for 

the control strategy and in order to avoid product shortages.  

• During this period, NDMA and NDEA impurities in the API should be controlled for a 

transition period at limits calculated based on the principles of ICH M7(R1) using validated 

assays 



 

 140 

• After the transition period, a limit for NDMA and NDEA of maximum 0.03 ppm should be 

implemented, which reflects the lowest quantifiable level based on capability of the 

available analytical methods. 

• In case of detection of other N-nitrosamines this should be forthwith reported to the 

competent authorities, together with a toxicology assessment of the impurity, a clinical 

assessment for the exposed patients, a root cause analysis and a corrective action plan.  

• CHMP could not identify cancer screening methods that patients would benefit from, 

considering the uncertainty of the target organ(s) of NDMA/NDEA toxicity in humans and 

the risks of measures to monitor patients such as colonoscopy or gastroscopy which may 

exceed the theoretical excess cancer risk. 

 

CHMP opinion 

The CHMP, as a consequence, considers that the benefit-risk balance of products containing 

candesartan, irbesartan, losartan, olmesartan, valsartan remains favourable subject to the 

conditions described above. 

Therefore the CHMP recommends the variation to the terms of the marketing authorisations for 

products containing candesartan, irbesartan, losartan, olmesartan, valsartan. 

 


	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 MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions