4.1 Therapeutic indications
RIBEX 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
2diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4,
4.5and 5.1).

4.2 Posology and method of administration
Posology
The usual recommended initial and maintenance dose is 150 mg once daily, with or without
food.RIBEX at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control
than75 mg. However, initiation of therapy with 75 mg could be considered, particularly in
haemodialysedpatients and in the elderly over 75 years.
In patients insufficiently controlled with 150 mg once daily, the dose of RIBEX can be increased to300
mg, or other antihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). Inparticular, the
addition of a diuretic such as hydrochlorothiazide has been shown to have an additiveeffect with
RIBEX (see section 4.5).
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once dailyand
titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
The demonstration of renal benefit of RIBEX in hypertensive type 2 diabetic patients is based
onstudies where irbesartan was used in addition to other antihypertensive agents, as needed, to
reachtarget 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
lowerstarting 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
hepaticimpairment. 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
over75 years of age, dosage adjustment is not usually necessary for older people.
Paediatric population: the safety and efficacy of irbesartanin children aged 0 to 18 has not
beenestablished. Currently available data are described in section 4.8, 5.1 and 5.2 but no
recommendationon a posology can be made.
Method of Administration
For oral use.

4.4 Special warnings and precautions for use
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur
inpatients 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
RIBEX.
Renovascular hypertension: there is an increased risk of severe hypotension and renal
insufficiencywhen patients with bilateral renal artery stenosis or stenosis of the artery to a single
functioning kidneyare treated with medicinal products that affect the renin-angiotensin-aldosterone
system. While this isnot documented with RIBEX, a similar effect should be anticipated with
angiotensin-II receptorantagonists.
Renal impairment and kidney transplantation: when RIBEX is used in patients with impaired
renalfunction, a periodic monitoring of potassium and creatinine serum levels is recommended. There
is noexperience regarding the administration of RIBEX in patients with a recent kidney transplantation.
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal
andcardiovascular events were not uniform across all subgroups, in an analysis carried out in the
studywith patients with advanced renal disease. In particular, they appeared less favourable in women
andnon-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
oraliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function
(includingacute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors,
angiotensinII receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If
dualblockade therapy is considered absolutely necessary, this should only occur under
specialistsupervision 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 withdiabetic nephropathy.
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone
system,hyperkalaemia may occur during the treatment with RIBEX, especially in the presence of
renalimpairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring
ofserum potassium in patients at risk is recommended (see section 4.5).
Lithium: the combination of lithium and RIBEX 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
obstructivehypertrophic cardiomyopathy.
Primary aldosteronism: patients with primary aldosteronism generally will not respond
toantihypertensive medicinal products acting through inhibition of the renin-angiotensin
system.Therefore, the use of RIBEX is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity ofthe
renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure orunderlying
renal disease, including renal artery stenosis), treatment with angiotensin convertingenzyme inhibitors
or angiotensin-II receptor antagonists that affect this system has been associatedwith acute
hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensiveagent,
excessive blood pressure decrease in patients with ischaemiccardiopathy or ischaemiccardiovascular
disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other
angiotensinantagonists 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 (seesection 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
bechanged to alternative antihypertensive treatments which have an established safety profile for use
inpregnancy. 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
galactoseintolerance, the Lapp lactase deficiency or glucose-galactosemalabsorption should not take
thismedicinal product.
Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old
butthe current data are insufficient to support an extension of the use in children until further data
becomeavailable (see sections 4.8, 5.1 and 5.2).

4.5 Interaction with other medicinal products and other forms of interaction
Diuretics and other antihypertensive agents: other antihypertensive agents may increase thehypotensive
effects of irbesartan; however irbesartan has been safely administered with otherantihypertensive
agents, such as beta-blockers, long-acting calcium channel blockers, and thiazidediuretics. Prior
treatment with high dose diuretics may result in volume depletion and a risk ofhypotension when
initiating therapy with irbesrtan (see section 4.4).
Aliskiren-containing products and ACE-inhibitors: Clinical trial data has shown that dual blockade
ofthe renin-angiotensin-aldosterone system (RAAS) through the combined use of ACEinhibitors,
angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse
eventssuch 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
othermedicinal products that affect the renin-angiotensin system, concomitant use of potassiumsparingdiuretics,
potassium supplements, salt substitutes containing potassium or other medicinal
productsthat may increase serum potassium levels (e.g. heparin) may lead to increases in serum
potassium andis, therefore, not recommended (see section 4.4).
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported
duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar
effectshave 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 isrecommended.

Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are
administeredsimultaneously 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 effectmay occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to
anincreased risk of worsening of renal function, including possible acute renal failure, and an increase
inserum potassium, especially in patients with poor pre-existing renal function. The combination
shouldbe administered with caution, especially in the elderly. Patients should be adequately hydrated
andconsideration should be given to monitoring renal function after initiation of concomitant therapy,
andperiodically thereafter.
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of
irbesartanis not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a
lesserextent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions
wereobserved when irbesartan was coadministered with warfarin, a medicinal product metabolised
byCYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of
irbesartanhave not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration
ofirbesartan.

4.6 Fertility, pregnancy and lactation
Pregnancy:
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4).
The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see
sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE
inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in
riskcannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin
IIReceptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless
continuedAIIRA therapy is considered essential, patients planning pregnancy should be changed to
alternativeantihypertensive treatments which have an established safety profile for use in pregnancy.
Whenpregnancy 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
humanfetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and
neonataltoxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound checkof
renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (seesections 4.3
and 4.4).
Breast-feeding:Because no information is available regarding the use of irbesartan during breast-feeding, RIBEX is
notrecommended and alternative treatments with better established safety profiles during breastfeedingare
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
itsmetabolites 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
inducingthe first signs of parental toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Based on
itspharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles
oroperating machines, it should be taken into account that dizziness or weariness may occur
duringtreatment.

4.8 Undesirable effects
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events didnot
differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to
anyclinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than
forplacebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in
therecommended dose range), gender, age, race, or duration of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostaticdizziness
and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but inexcess of
placebo.
The following table presents the adverse drug reactions that were reported in placebo-controlled trialsin
which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to theadverse
reactions that were additionally reported in > 2% of diabetic hypertensive patients withchronic 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 effectsare presented in
order of decreasing seriousness.
Adverse reactions additionally reported from post–marketing experience are also listed. These
adversereactions are derived from spontaneous reports.
Blood and lymphatic system disorders
Not known: thrombocytopenia
Immune system disorders:

Not known: hypersensitivity reactions such as angioedema, rash, urticarial, anaphylactic reaction,
anaphylactic shock.
Metabolism and nutrition disorders:
Not known: hyperkalaemia
Nervous system disorders:
Common: dizziness, orthostatic dizziness*
Not known: vertigo, headache
Ear and labyrinth disorder:
Not known: tinnitus
Cardiac disorders:
Uncommon: tachycardia
Vascular disorders:
Common: orthostatic hypotension*
Uncommon: flushing
Respiratory, thoracic and mediastinal disorders:
Uncommon: cough
Gastrointestinal disorders:
Common: nausea/vomiting
Uncommon: diarrhoea, dyspepsia/heartburn
Not known: dysgeusia
Hepatobiliary disorders:
Uncommon: jaundice
Not known: hepatitis, abnormal liver function
Skin and subcutaneous tissue disorders:
Not known: leukocytoclasticvasculitis
Musculoskeletal and connective tissue disorders:
Common: musculoskeletal pain*
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine
kinaselevels), 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
followingadverse 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
frequentlaboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in
2% ofchild recipients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
Itallows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting
system.

Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
o Toll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

4.9 Overdose
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The
mostlikely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia
mightalso occur from overdose. No specific information is available on the treatment of overdose
withirbesartan. The patient should be closely monitored, and the treatment should be symptomatic
andsupportive. Suggested measures include induction of emesis and/or gastric lavage. Activated
charcoalmay be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis.

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin-II antagonists, plain.
ATC code: C09C A04.
Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin-II receptor (type
AT1)antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1
receptor,regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of
theangiotensin-II (AT1) receptors results in increases in plasma renin levels and angiotensin-II levels,
anda decrease in plasma aldosterone concentration. Serum potassium levels are not significantly
affectedby irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II),
anenzyme 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
isdose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses
of150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing)
byan 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 bloodpressure
was 60-70% of the corresponding peak diastolic and systolic responses at the recommendeddoses.
Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twicedaily
dosing on the same total dose.
The blood pressure lowering effect of RIBEX is evident within 1-2 weeks, with the maximal
effectoccurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during
longterm therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline.
Reboundhypertension has not been observed.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patientsnot
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 attrough of 7-
10/3-6 mm Hg (systolic/diastolic).
The efficacy of RIBEX is not influenced by age or gender. As is the case with other medicinalproducts
that affect the renin-angiotensin system, black hypertensive patients have notably lessresponse to
irbesartanmonotherapy. When irbesartan is administered concomitantly with a low doseof
hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients
approachesthat 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)
targettitrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history
ofhypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of
thethree weeks the mean reduction from baseline in the primary efficacy variable, trough seated
systolicblood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg

(highdose). No significant difference was apparent between these doses. Adjusted mean change of
troughseated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg
(mediumdose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were rerandomizedto
either active medicinal product or placebo, patients on placebo had increases of 2.4 and
2.0 mmHgin SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all
doses ofirbesartan (see section 4.2).
Hypertension and type 2 diabetes with renal disease
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progressionof
renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a
doubleblind, controlled, morbidity and mortality trial comparing irbesaratn, amlodipine and placebo.
In1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum
creatinineranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of irbesaratn on the
progression ofrenal disease and all-cause mortality were examined. Patients were titrated from 75 mg
to amaintenance dose of 300 mg irbesaratn, 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
mmHgor a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%)
ofpatients 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
riskin the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or
allcausemortality. Approximately 33% of patients in the irbesartan group reached the primary
renalcomposite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20%
relativerisk 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 analyzed, no
effect in allcause mortality was observed, while a positive trend in the reduction in ESRD and a
significantreduction in doubling of serum creatinine were observed.
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure,
serumcreatinine, and albumin excretion rate were assessed for treatment effect. In the female and
blacksubgroups which represented 32% and 26% of the overall study population respectively, a
renalbenefit was not evident, although the confidence intervals do not exclude it. As for the
secondaryendpoint of fatal and non-fatal cardiovascular events, there was no difference among the
three groupsin the overall population, although an increased incidence of non-fatal MI was seen for
women and adecreased incidence of non-fatal MI was seen in males in the irbesartan group versus the
placebo-basedregimen. An increased incidence of non-fatal MI and stroke was seen in females in
theirbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to
heartfailure was reduced in the overall population. However, no proper explanation for these findings
inwomen has been identified.
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type
2Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria
inpatients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study
in590 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-termeffects (2 years) of irbesaratn on the progression to clinical (overt) proteinuria (urinary
albuminexcretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline).
Thepredefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents
(excludingACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers)

were addedas needed to help achieve the blood pressure goal. While similar blood pressure was
achieved in alltreatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the
placebo (14.9%) orin 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
accompanyingimprovement in the glomerular filtration rate (GFR) was not observed during the first
three months oftreatment. The slowing in the progression to clinical proteinuria was evident as early as
three monthsand continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was
morefrequent in the irbesaratn 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 (ONgoingTelmisartan Alone and incombination
with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans AffairsNephropathy in
Diabetes)) have examined the use of the combination of an ACE-inhibitor with anangiotensin II
receptor blocker. ONTARGET was a study conducted in patients with a history ofcardiovascular or
cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence ofend-organ damage. VA
NEPHRON-D was a study in patients with type 2 diabetes mellitus anddiabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes
andmortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension
ascompared to monotherapy was observed. Given their similar pharmacodynamic properties,
theseresults are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.ACEinhibitors
and angiotensin II receptor blockers should therefore not be used concomitantly inpatients
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 ACEinhibitoror
an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic
kidneydisease, cardiovascular disease, or both. The study was terminated early because of an increased
riskof adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in
thealiskiren 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
aliskirengroup than in the placebo group.

After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values
ofapproximately 60-80%. Concomitant food intake does not significantly influence the bioavailability
ofirbesartan. Plasma protein binding is approximately 96%, with negligible binding to cellular
bloodcomponents. The volume of distribution is 53 - 93 litres. Following oral or intravenous
administrationof 14C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to
unchangedirbesartan. Irbesartan is metabolised by the liver via glucuronide conjugation and oxidation.
The majorcirculating metabolite is irbesartanglucuronide (approximately 6%). In vitro studies indicate
thatirbesartan is primarily oxidised by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4
hasnegligible 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
maximalrecommended dose) was observed; the mechanism for this is unknown. Peak plasma
concentrationsare 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
dosingregimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once

dailydosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in
femalehypertensive patients. However, there was no difference in the half-life and accumulation
ofirbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax
valueswere 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
inolder people.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or
IVadministration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and
theremainder 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
administrationof single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of
150 mg forfour 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, AUCand clearance rates were comparable to those observed in adult patients receiving 150 mg
irbesartandaily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated
once dailydosing.
Renal impairment: in patients with renal impairment or those undergoing haemodialysis,
thepharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed
byhaemodialysis.
Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters
ofirbesartan 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. Innonclinical
safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day
inmacaques) 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
interstitialnephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea
andcreatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to
thehypotensive 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, inmacaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by
thepharmacological 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 atoral
doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), includingmortality at
the highest dose. No significant effects on the number of corpora lutea, implants, or livefetuses 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,
includingmortality. No teratogenic effects were observed in the rat or rabbit.

6.1 List of excipients
Tablet core:
Microcrystalline cellulose
Starch pregelatinised
Lactose monohydrate
Poloxamer 188
Croscarmellose sodium
Magnesium Stearate
Film-coating:
Opadry white 20A28735
consisting of:
Hydroxypropyl cellulose
Hypromellose 6cP
Titanium dioxide
Talc

Not applicable.

Do not store above 30°C.

Cartons of 14 film-coated tablets in PVC/PE/PVDC/Aluminium blisters.
Cartons of 28 film-coated tablets in PVC/PE/PVDC/Aluminium blisters.

Not all pack sizes may be marketed.

RIBEX/VEPRAN 150MG/SPC/SK/SOTHEMA MAJ 12/18/REF RMP 11/18 

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