Irbetel is indicated in adults for the treatment of essential hypertension.
Treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus
as part of an antihypertensive medicinal product regimen (see section 5.1).

The usual recommended initial and maintenance dose is 150 mg once daily, with or without
food.
Irbetel 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 Irbetel can be increased
to
300 mg, or other antihypertensive agents can be added. In particular, the addition of a diuretic
such as hydrochlorothiazide has been shown to have an additive effect with Irbetel (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 Irbetel 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 section 5.1).
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).
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.
Elderly patients: 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 the elderly.
Paediatric patients: irbesartan is not recommended for use in children and adolescents
due to insufficient data on safety and efficacy (see sections 4.8, 5.1 and 5.2).

Paediatric patients: irbesartan is not recommended for use in children and adolescents
due to insufficient data on safety and efficacy (see sections 4.8, 5.1 and 5.2).

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 Irbetel.
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-angiotensinaldosterone
system. While this is not documented with Irbetel, a similar effect should be
anticipated with angiotensin-II receptor antagonists.
Renal impairment and kidney transplantation: when Irbetel 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 Irbetel 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).
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone
system, hyperkalaemia may occur during the treatment with Irbetel, 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 Irbetel 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 reninangiotensin
system. Therefore, the use of Irbetel is not recommended.
General: in patients whose vascular tone and renal function depend predominantly on the
activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart
failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin
converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has
been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As
with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic
cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or
stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin

antagonists are apparently less effective in lowering blood pressure in black people than in
non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive
population (see section 5.1).
Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during
pregnancy. Unless continued AIIRA therapy is considered essential, patients planning
pregnancy should be changed to alternative antihypertensive treatments which have an
established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped
immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and
4.6).
Lactose: this medicinal product contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should
not take this medicinal product.
Paediatric patients: 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).

Diuretics and other antihypertensive agents: other antihypertensive agents may increase the
hypotensive effects of irbesartan; however Irbetel 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 Irbetel (see section 4.4).
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.

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).

Pregnancy category D
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.
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 fetotoxicity (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).
Lactation:
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).
Because no information is available regarding the use of Irbetel during breast-feeding, Irbetel
is not recommended and alternative treatments with better established safety profiles during
breast-feeding are preferable, especially while nursing a newborn or preterm infant.

No studies on the effects on the ability to drive and use machines have been performed.
Based on its pharmacodynamic properties, irbesartan is unlikely to affect this ability. When
driving vehicles or operating machines, it should be taken into account that dizziness or
weariness may occur during treatment.

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 placebocontrolled
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, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥
1/10,000,
< 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are
presented in order of decreasing seriousness.
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.
Cardiac disorders:
Uncommon: tachycardia
Nervous system disorders:
Common: dizziness, orthostatic dizziness*
Respiratory, thoracic and mediastinal disorders:
Uncommon: cough
Gastrointestinal disorders:
Common: nausea/vomiting
Uncommon: diarrhoea, dyspepsia/heartburn
Musculoskeletal and connective tissue disorders:
Common: musculoskeletal pain*
Vascular disorders:
Common: orthostatic
hypotension* Uncommon: flushing
General disorders and administration site conditions:
Common: fatigue
Uncommon: chest pain
Reproductive system and breast disorders:
Uncommon: sexual dysfunction
The following additional adverse reactions have been reported during post–
marketing experience; they are derived from spontaneous reports and therefore, the
frequency of these adverse reactions is not known:
Nervous system disorders:
Headache
Ear and labyrinth disorders:
Tinnitus
Gastrointestinal disorders:
Dysgeusia
Renal and urinary disorders:
Impaired renal function including cases of renal failure in patients at risk (see section 4.4)
Skin and subcutaneous tissue disorders:
Leukocytoclastic vasculitis

Musculoskeletal and connective tissue disorders:
Arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels),
muscle cramps
Metabolism and nutrition disorders:
Hyperkalaemia
Immune system disorders:
Hypersensitivity reactions such as angioedema, rash, urticaria
Hepato-biliary disorders:
Hepatitis, abnormal liver function
Hepatobiliary disorders Uncommon jaundice
Paediatric patients: in a randomised trial of 318 hypertensive children and adolescents aged 6
to
16 years, the following related adverse events occurred in the 3-week double-blind phase:
headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week openlabel
period of this trial the most frequent laboratory abnormalities observed were creatinine
increases (6.5%) and elevated CK values in 2% of child recipients.

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 Irbetel. 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.

Pharmacotherapeutic group: Angiotensin-II antagonists,
plain. ATC code: C09C A04.
Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin-II receptor
(type AT1) antagonist. It is expected to block all actions of angiotensin-II mediated by the
AT1 receptor, regardless of the source or route of synthesis of angiotensin-II. The selective
antagonism of the
angiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II
levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not

significantly affected by irbesartan alone at the recommended doses. Irbesartan does not
inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades
bradykinin into inactive metabolites.
Irbesartan does not require metabolic activation for its
activity. Clinical efficacy:
Hypertension
Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood
pressure is dose-related for once a day doses with a tendency towards plateau at doses above
300 mg. Doses of
150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after
dosing) by an average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated
with placebo.
Peak reduction of blood pressure is achieved within 3-6 hours after administration and the
blood pressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction
of blood pressure was 60-70% of the corresponding peak diastolic and systolic responses at
the recommended doses. Once daily dosing with 150 mg produced trough and mean 24 hour
responses similar to twice daily dosing on the same total dose.

The blood pressure lowering effect of Irbetel 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 Irbetel 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.
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 Irbetel,
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 Irbetel 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 Irbetel, from 2.5 mg to 10 mg amlodipine, or
placebo as tolerated. Patients in all treatment groups typically received between 2 and 4
antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined
blood pressure goal of ≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if
baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this
target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine
groups respectively. Irbesartan significantly reduced the relative risk
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease
(ESRD) or all- cause mortality. Approximately 33% of patients in the irbesartan group reached
the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine
groups [20% relative
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to
amlodipine
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no
effect in all cause mortality was observed, while a positive trend in the reduction in ESRD
and a significant reduction in doubling of serum creatinine were observed.

Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure,
serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female
and black subgroups which represented 32% and 26% of the overall study population
respectively, a renal benefit was not evident, although the confidence intervals do not exclude
it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no
difference among the three groups in the overall population, although an increased incidence
of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in
males in the irbesartan group versus the placebo- based regimen. An increased incidence of
non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the
amlodipine-based regimen, while hospitalization due to heart

failure was reduced in the overall population. However, no proper explanation for these
findings in women has been identified.
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type
2
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt
proteinuria in patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind
morbidity study in
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the
long-term effects (2 years) of Irbetel 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 Irbetel 300 mg group (34%) than in the placebo group
(21%).

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. Plasma protein binding is approximately 96%, with negligible
binding to cellular blood components. The volume of distribution is 53 - 93 litres. 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.
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 elderly 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 elderly patients.
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.
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the
administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum
daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison
of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12
years). Results showed that Cmax, AUC and clearance rates were comparable to those
observed in adult patients receiving 150 mg irbesartan

daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated
once daily dosing.
Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the
pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not
removed by haemodialysis.
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic
parameters of irbesartan are not significantly altered.
Studies have not been performed in patients with severe hepatic impairment.

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.
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.

Tablet core:
Lactose monohydrate
Microcrystalline
cellulose
Croscarmellose sodium
Hypromellose
Silicon dioxide
Magnesium stearate.
Film-coating:
Lactose
monohydrate
Hypromellose
Titanium dioxide

Macrogol 3000
Carnauba wax.

Not applicable.

Do not store above 30°C.

Cartons of 14 film-coated tablets: 1 blister card of 14 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 28 film-coated tablets: 2 blister cards of 14 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 30 film-coated tablets: 2 blister cards of 15 film-coated tablets in
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Cartons of 56 film-coated tablets: 4 blister cards of 14 film-coated tablets in
PVC/PVDC/Aluminium blisters.
Cartons of 84 film-coated tablets: 6 blister cards of 14 film-coated tablets in
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Cartons of 90 film-coated tablets: 6 blister cards of 15 film-coated tablets in
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Cartons of 98 film-coated tablets: 7 blister cards of 14 film-coated tablets in
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Cartons of 56 x 1 film-coated tablet; 7 blister cards of 8 x 1 film-coated tablet each in
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Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local
requirements.