Irovel 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 section 5.1).

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

Hypersensitivity to the active substance, or to any of the excipients (see section 6.1). -Second and third trimesters of pregnancy (see sections 4.6). -Severe hepatic impairment Do not co-administer Irovel with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (glomerular filtration rate (GFR) <60 ml/min/1.73 m²) (see sections 4.4 and 4.5)

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 Irovel.

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

Renal impairment and kidney transplantation: when Irovel 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 Irovel 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):

Dual blockade of the RAAS by combining Irovel with aliskiren is not recommended since there is an

increased risk of hypotension, hyperkalaemia, and changes in renal function. The use of Irovel in

combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR

<60 ml/min/1.73 mÇ) (see section 4.5).

Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system,

hyperkalaemia may occur during the treatment with Irovel, 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 Irovel 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 Irovel 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).

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 Irovel 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 Irovel

(see section 4.4).

 Add Dual Blockade of the Renin-Angiotensin System (RAS): 􀀃 Dual blockade of the RAS with angiotensin

receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope,

hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Closely monitor blood pressure, renal function, and electrolytes in patients on [drug] and other agents that

affect the RAS.

Do not co-administer aliskiren with [drug] in patients with diabetes. Avoid use of aliskiren with [drug] in

patients with renal impairment (GFR &amp;amp;lt;60 ml/min).

Aliskiren-containing products: the combination of Irovel with aliskiren-containing medicinal products is

contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR <60

ml/min/1.73 mÇ) and is not recommended in other patients.

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,

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 Irovel during breast-feeding, Irovel 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).

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.

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 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

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 Center (NPC):
Fax: +966-11-205-7662
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa
• 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 Irovel. 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 doserelated

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 Irovel 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 Irovel 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, 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 nonfatal

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 Irovel 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 Irovel 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 oncedaily

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.

Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV

administration of14C 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.

Lactose Monohydrate fine. Colloidal Silicon Dioxide Microcrystalline Cellulose. Croscarmellose Sodium. Hypromellose 6 cps. Magnesium stearate. Opadry OY 7300. Simethicone Emulsion.

Not applicable.

3 years.

 store below30°C.

Three white PVC /PVDC blisters packed with aluminum foil each blister contains 10 tablets packed

in carton with folded leaflet.

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

requirements.