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IRBESARTAN JUBILANT 300 MG FILM-COATED TABLETS

Active substance(s): IRBESARTAN

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Irbesartan Jubilant 300 mg film-coated tablets.

2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet Irbesartan Jubilant 300 mg contains 300 mg of
irbesartan.
Excipient with known effect:
128 mg of lactose monohydrate per film-coated tablet (for the 300 mg filmcoated tablet).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
White to off-white, oval-shaped, film-coated tablets of 17.3 mm with a “J” debossed
on one side and “300” on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Irbesartan Jubilant is indicated in adults for the treatment of essential
hypertension.
It is also indicated for the treatment of renal disease in adult patients with
hypertension and type 2 diabetes mellitus as part of an antihypertensive
medicinal product regimen (see sections 4.3, 4.4, 4.5 and 5.1).

4.2

Posology and method of administration
Posology
The usual recommended initial and maintenance dose is 150 mg once daily,
with or without food.
Irbesartan Jubilant 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 Jubilant 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 Irbesartan
Jubilant (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 Jubilant 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 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 Jubilant in children
aged 0 to 18 has not been established. Currently available data are described in
section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Method of Administration
For oral use.
4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.
Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
The concomitant use of Irbesartan Jubilant with aliskiren-containing products
is contraindicated in patients with diabetes mellitus or renal impairment (GFR
< 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4

Special warnings and precautions for use
Intravascular volume depletion: symptomatic hypotension, especially after the
first dose, may occur in patients who are volume and/or sodium depleted by
vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such
conditions should be corrected before the administration of Irbesartan Jubilant.
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 Jubilant, a similar effect should be anticipated
with angiotensin-II receptor antagonists.
Renal impairment and kidney transplantation: when Irbesartan Jubilant 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 Jubilant 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 nonwhite 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 reninangiotensin-aldosterone system, hyperkalaemia may occur during the
treatment with Irbesartan Jubilant, 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 Jubilant 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 Jubilant 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 glucosegalactose 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).
4.5

Interaction with other medicinal products and other forms of interaction
Diuretics and other antihypertensive agents: other antihypertensive agents may
increase the hypotensive effects of irbesartan; however Irbesartan Jubilant has
been safely administered with other antihypertensive agents, such as betablockers, 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 Jubilant (see section 4.4).
Clinical trial data has shown that dual blockade of the renin-angiotensinaldosterone-system (RAAS) through the combined use of ACE-inhibitors,
angiotensin II receptor blockers or aliskiren is associated with a higher
frequency of adverse events such as hypotension, hyperkalaemia and

decreased renal function (including acute renal failure) compared to the use of
a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Potassium supplements and potassium-sparing diuretics: based on experience
with the use of other medicinal products that affect the renin-angiotensin
system, concomitant use of potassium-sparing diuretics, potassium
supplements, salt substitutes containing potassium or other medicinal products
that may increase serum potassium levels (e.g. heparin) may lead to increases
in serum potassium and is, therefore, not recommended (see section 4.4).
Lithium: reversible increases in serum lithium concentrations and toxicity
have been reported during concomitant administration of lithium with
angiotensin converting enzyme inhibitors. Similar effects have been very
rarely reported with irbesartan so far. Therefore, this combination is not
recommended (see section 4.4). If the combination proves necessary, careful
monitoring of serum lithium levels is recommended.
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are
administered simultaneously with non-steroidal anti-inflammatory drugs (i.e.
selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective
NSAIDs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and
NSAIDs may lead to an increased risk of worsening of renal function,
including possible acute renal failure, and an increase in serum potassium,
especially in patients with poor pre-existing renal function. The combination
should be administered with caution, especially in the elderly. Patients should
be adequately hydrated and consideration should be given to monitoring renal
function after initiation of concomitant therapy, and periodically thereafter.

Additional information on irbesartan interactions: in clinical studies, the
pharmacokinetic of irbesartan is not affected by hydrochlorothiazide.
Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by
glucuronidation. No significant pharmacokinetic or pharmacodynamic
interactions were observed when irbesartan was coadministered with warfarin,
a medicinal product metabolised by CYP2C9. The effects of CYP2C9
inducers such as rifampicin on the pharmacokinetic of irbesartan have not
been evaluated. The pharmacokinetic of digoxin was not altered by
coadministration of irbesartan.
4.6

Fertility, pregnancy and lactation
Pregnancy:
The use of AIIRAs is not recommended during the first trimester of pregnancy
(see section 4.4). The use of AIIRAs is contraindicated during the second and
third trimesters of pregnancy (see sections 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following
exposure to ACE inhibitors during the first trimester of pregnancy has not
been conclusive; however a small increase in risk cannot be excluded. Whilst
there is no controlled epidemiological data on the risk with Angiotensin II
Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs.
Unless continued AIIRA therapy is considered essential, patients planning
pregnancy should be changed to alternative antihypertensive treatments which
have an established safety profile for use in pregnancy. When pregnancy is
diagnosed, treatment with AIIRAs should be stopped immediately, and, if
appropriate, alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to
induce human 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 Jubilant
during breast-feeding, Irbesartan Jubilant is not recommended and alternative
treatments with better established safety profiles during breast-feeding are
preferable, especially while nursing a newborn or preterm infant.
It is unknown whether irbesartan or its metabolites are excreted in human
milk.
Available pharmacodynamic/toxicological data in rats have shown excretion
of irbesartan or its metabolites in milk (for details see 5.3).
Fertility

Irbesartan had no effect upon fertility of treated rats and their offspring up to
the dose levels inducing the first signs of parental toxicity (see section 5.3).
4.7

Effects on ability to drive and use machines
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.

4.8

Undesirable effects
In placebo-controlled trials in patients with hypertension, the overall incidence
of adverse events did not differ between the irbesartan (56.2%) and the
placebo groups (56.5%). Discontinuation due to any clinical or laboratory
adverse event was less frequent for irbesartan-treated patients (3.3%) than for
placebo-treated patients (4.5%). The incidence of adverse events was not
related to dose (in the recommended dose range), gender, age, race, or duration
of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal
function, orthostatic dizziness and orthostatic hypotension were reported in
0.5% of the patients (i.e., uncommon) but in excess of placebo.
The following table presents the adverse drug reactions that were reported in
placebo-controlled trials in which 1,965 hypertensive patients received
irbesartan. Terms marked with a star (*) refer to the adverse reactions that
were additionally reported in > 2% of diabetic hypertensive patients with
chronic renal insufficiency and overt proteinuria and in excess of placebo.
The frequency of adverse reactions listed below is defined using the following
convention:
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to
< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each
frequency grouping, undesirable effects are presented in order of decreasing
seriousness.
Adverse reactions additionally reported from post–marketing experience are
also listed. These adverse reactions are derived from spontaneous reports.
Immune system disorders:
Not known:
hypersensitivity reactions such as angioedema, rash,
urticaria
Metabolism and nutrition disorders:
Not known:
hyperkalaemia
Nervous system disorders:

Common:
Not known:

dizziness, orthostatic dizziness*
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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via www.mhra.gov.uk/yellowcard.
4.9

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

5

PHARMACOLOGICAL PROPERTIES

5.1

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

which generates 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 Jubilant 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 Jubilant 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 Jubilant, 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 Jubilant 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 Jubilant, 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
allcause 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
placebobased 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 Jubilant 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 Jubilant 300 mg group (34%)
than in the placebo group (21%).
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan
Alone and in combination with Ramipril Global Endpoint Trial) and VA
NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have
examined the use of the combination of an ACE-inhibitor with an angiotensin
II receptor blocker.
ONTARGET was a study conducted in patients with a history of
cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus
accompanied by evidence of end-organ damage. VA NEPHRON-D was a
study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or
cardiovascular outcomes and mortality, while an increased risk of
hyperkalaemia, acute kidney injury and/or hypotension as compared to
monotherapy was observed. Given their similar pharmacodynamic properties,
these results are also relevant for other ACE-inhibitors and angiotensin II
receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be
used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and
Renal Disease Endpoints) was a study designed to test the benefit of adding
aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II
receptor blocker in patients with type 2 diabetes mellitus and chronic kidney
disease, cardiovascular disease, or both. The study was terminated early
because of an increased risk of adverse outcomes. Cardiovascular death and
stroke were both numerically more frequent in the aliskiren group than in the
placebo group and adverse events and serious adverse events of interest
(hyperkalaemia, hypotension and renal dysfunction) were more frequently
reported in the aliskiren group than in the placebo group.

5.2

Pharmacokinetic properties
After oral administration, irbesartan is well absorbed: studies of absolute
bioavailability gave values of approximately 60-80%. Concomitant food
intake does not significantly influence the bioavailability of irbesartan. Plasma
protein binding is approximately 96%, with negligible binding to cellular
blood components. The volume of distribution is 53 - 93 litres. Following oral
or intravenous administration of 14C irbesartan, 80-85% of the circulating
plasma radioactivity is attributable to unchanged irbesartan. Irbesartan is
metabolised by the liver via glucuronide conjugation and oxidation. The major
circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro
studies indicate that irbesartan is primarily oxidised by the cytochrome P450
enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the
dose range of 10 to 600 mg.
A less than proportional increase in oral absorption at doses beyond 600 mg
(twice the maximal recommended dose) was observed; the mechanism for this
is unknown. Peak plasma concentrations are attained at 1.5 - 2 hours after oral
administration. The total body and renal clearance are 157 - 176 and 3 - 3.5
ml/min, respectively. The terminal elimination half-life of irbesartan is 11 - 15
hours.
Steady-state plasma concentrations are attained within 3 days after initiation of
a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is
observed in plasma upon repeated once-daily dosing. In a study, somewhat
higher plasma concentrations of irbesartan were observed in female
hypertensive patients. However, there was no difference in the half-life and
accumulation of irbesartan. No dosage adjustment is necessary in female
patients. Irbesartan AUC and Cmax values were also somewhat greater in
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 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.
5.3

Preclinical safety data
There was no evidence of abnormal systemic or target organ toxicity at
clinically relevant doses. In non-clinical safety studies, high doses of
irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day in macaques) caused
a reduction of red blood cell parameters (erythrocytes, haemoglobin,
haematocrit).
At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney
(such as interstitial nephritis, tubular distension, basophilic tubules, increased
plasma concentrations of urea and creatinine) were induced by irbesartan in
the rat and the macaque and are considered secondary to the hypotensive
effects of the medicinal product which led to decreased renal perfusion.
Furthermore, irbesartan induced hyperplasia/hypertrophy of the
juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, in macaques at ≥ 10
mg/kg/day). All of these changes were considered to be caused by the
pharmacological action of irbesartan. For therapeutic doses of irbesartan in
humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does
not appear to have any relevance.
There was no evidence of mutagenicity, clastogenicity or carcinogenicity.
Fertility and reproductive performance were not affected in studies of male
and female rats even at oral doses of irbesartan causing some parental toxicity
(from 50 to 650 mg/kg/day), including mortality at the highest dose. No
significant effects on the number of corpora lutea, implants, or live 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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Lactose, monohydrate

Silica, colloidal anhydrous (E551)
Microcrystalline cellulose (E460)
Croscarmellose sodium (E468)
Hypromellose (E464)
Starch, pregelatinized
Magnesium stearate. (E572)
Film-coating:
Lactose, monohydrate
Hypromellose (E464)
Macrogol 4000
Titanium dioxide (E171)

6.2

Incompatibilities
Not applicable

6.3.

Shelf life
3 years.

6.4

Special precautions for storage
Store in the original package in order to protect from moisture.
This medicinal product does not require any special temperature storage conditions.

6.5

Nature and contents of container
28 film-coated tablets
56 film-coated tablets
84 film-coated tablets
98 film-coated tablets
PVC/PVDC/Aluminium blisters.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Jubilant Pharmaceuticals nv
Axxes Business Park
Guldensporenpark 22 – Block C
9820 Merelbeke
Belgium

8

MARKETING AUTHORISATION NUMBER(S)
PL 19156/0090

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/07/2015

10

DATE OF REVISION OF THE TEXT
27/07/2015

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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