Irbesartan 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).

Posology
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food.
Irbesartan 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 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 (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 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).
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 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.

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.
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, a similar effect should be anticipated with angiotensin-II receptor
antagonists.
Renal impairment and kidney transplantation: when Irbesartan 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 in patients with recent kidney transplantation.
Hypertensive patients with type 2diabetesandrenaldisease: the effects of Irbesartan both on renal and
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study
with patients with advanced renal disease. In particular, they appeared less favourable in women and
non-white subjects (see section 5.1).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS):
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or
aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute
renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade
therapy is considered absolutely necessary, this should only occur under specialist supervision and
subject to 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, 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 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 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 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).

Diuretics and other antihypertensive agents: other antihypertensive agents may increase the hypotensive
effects of Irbesartan; however Irbesartan 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 (see section 4.4).
Aliskiren-containingproducts 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.

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
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).
Breast-feeding:
Because no information is available regarding the use of Irbesartan during breast-feeding, Irbesartan is
not recommended and alternative treatments with better established safety profiles during breastfeeding
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).

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 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.

Blood and lymphatic system disorders
Not known: thrombocytopenia
Immune system disorders:
Not known: hypersensitivity reactions such as angioedema, rash, urticaria
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 meditational 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
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.
To report any side effect(s):
 Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
 Other GCC States:
 Please contact the relevant competent authority.

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. 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 Irbesartan 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 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).
Hypertensionandtype2diabeteswithrenaldisease
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, 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 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, 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 Irbesartan 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 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 endorgan
damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic
nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and
mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as
compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results
are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in
patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints)
was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or
an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease,
cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group
than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia,
hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the
placebo group.

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. Steadystate
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 halflife
was not significantly altered. No dosage adjustment is necessary in older people.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV
administration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the
remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

Paediatric population
The pharmacokinetics of Irbesartan were evaluated in 23 hypertensive children after the administration
of single and multiple daily doses of Irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for
four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults
(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUC
and clearance rates were comparable to those observed in adult patients receiving 150 mg Irbesartan
daily. A limited accumulation of Irbesartan (18%) in plasma was observed upon repeated once daily
dosing.
Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the
pharmacokinetic parameters of Irbesartan are not significantly altered. Irbesartan is not removed by
haemodialysis.
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of
Irbesartan are not significantly altered.
Studies have not been performed in patients with severe hepatic impairment.

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In nonclinical
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 fetuses were
observed. Irbesartan did not affect survival, development, or reproduction of offspring. Studies in
animals
Indicate that the radiolabeled Irbesartan is detected in rat and rabbit fetuses. 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.

 Colloidal Silicon Dioxide-Aerosil 200
 Croscarmellose Sodium
 Lactose Anhydrus DC Gr.
 Magnesium Stearate
 Maize Starch
 Microcrystalline Cellulose PH102
 Poloxamer 188
 Purified Water

Not applicable.

Do not store above 30°C.

Primary Packing: Aluminium PVC/PVDC blisters.
Secondary Packing: Carton with PIL

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