ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Irbesartan Teva 75 mg film-coated tablets
2.
Each film-coated tablet contains 75 mg of irbesartan
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to off white capsule shaped, film coated tablet. One side of the tablet debossed with the number
“93”. The other side of the tablet debossed with number “7464”.
4.
Treatment of essential hypertension.
Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an
antihypertensive medicinal product regimen (see section 5.1).
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food.
Irbesartan at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control
than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in
haemodialysed patients and in the elderly over 75 years.
In patients insufficiently controlled with 150 mg once daily, the dose of irbesartan can be increased to
300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as
hydrochlorothiazide has been shown to have an additive effect with irbesartan (see section 4.5).
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
The demonstration of renal benefit of irbesartan in hypertensive type 2 diabetic patients is based on
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach
target blood pressure (see section 5.1).
Renal impairment:
no dosage adjustment is necessary in patients with impaired renal function. A lower
starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4).
Hepatic impairment:
no dosage adjustment is necessary in patients with mild to moderate hepatic
impairment. There is no clinical experience in patients with severe hepatic impairment.
Elderly patients:
although consideration should be given to initiating therapy with 75 mg in patients
over 75 years of age, dosage adjustment is not usually necessary for the elderly.
2
Paediatric patients:
irbesartan is not recommended for use in children and adolescents due to
insufficient data on safety and efficacy (see sections 4.8, 5.1 and 5.2).
Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).
Second and third trimester of pregnancy (see section 4.4 and 4.6).
Intravascular volume depletion:
symptomatic hypotension, especially after the first dose, may occur in
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction,
diarrhoea or vomiting. Such conditions should be corrected before the administration of irbesartan.
Renovascular hypertension:
there is an increased risk of severe hypotension and renal insufficiency
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is
not documented with irbesartan, a similar effect should be anticipated with angiotensin-II receptor
antagonists.
Renal impairment and kidney transplantation:
when irbesartan is used in patients with impaired renal
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no
experience regarding the administration of irbesartan in patients with a recent kidney transplantation.
Hypertensive patients with type 2 diabetes and renal disease:
the effects of irbesartan both on renal and
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study
with patients with advanced renal disease. In particular, they appeared less favourable in women and
non-white subjects (see section 5.1).
Hyperkalaemia:
as with other medicinal products that affect the renin-angiotensin-aldosterone system,
hyperkalaemia may occur during the treatment with irbesartan, especially in the presence of renal
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of
serum potassium in patients at risk is recommended (see section 4.5).
Lithium:
the combination of lithium and irbesartan is not recommended (see section 4.5).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
as with other vasodilators,
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive
hypertrophic cardiomyopathy.
Primary aldosteronism:
patients with primary aldosteronism generally will not respond to
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of irbesartan is not recommended.
General:
in patients whose vascular tone and renal function depend predominantly on the activity of
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive
agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic
cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks,
possibly because of higher prevalence of low-renin states in the black hypertensive population (see
section 5.1).
3
Pregnancy:
AIIRAs should not be initiated during pregnancy. Unless continued AIIRAs therapy is
considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive
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).
Paediatric patients:
irbesartan has been studied in paediatric populations aged 6 to 16 years old but the
current data are insufficient to support an extension of the use in children until further data become
available (see sections 4.8, 5.1 and 5.2).
Diuretics and other antihypertensive agents:
other antihypertensive agents may increase the
hypotensive effects of irbesartan; however irbesartan has been safely administered with other
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of
hypotension when initiating therapy with irbesartan (see section 4.4).
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 trimester of pregnancy (see sections 4.3
and 4.4).
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 Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs
therapy is considered essential, patients planning pregnancy should be changed to alternative
anti-hypertensive 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 AIIRAs 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 also
sections 4.3 and 4.4).
Lactation:
Because no information is available regarding the use of irbersartan during breast-feeding, irbesartan
is not recommended and alternative treatments with better established safety profiles during
breast-feeding are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or
operating machines, it should be taken into account that dizziness or weariness may occur during
treatment.
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did
not differ between the irbesartan (56.2 %) and the placebo groups (56.5 %). Discontinuation due to
any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3 %) than
for placebo-treated patients (4.5 %). The incidence of adverse events was not related to dose (in the
recommended dose range), gender, age, race, or duration of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic
dizziness and orthostatic hypotension were reported in 0.5 % of the patients (i.e., uncommon) but in
excess of placebo.
The following 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.
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
5
patients in the irbesartan 300 mg group and 22 % of the patients in the placebo
group. In diabetic hypertensive patients with chronic renal insufficiency and overt
proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3 % of the patients in the
irbesartan group and 26.3 % of the patients in the placebo group.
Common:
significant increases in plasma creatine kinase were commonly observed (1.7 %) in
irbesartan treated subjects. None of these increases were associated with
identifiable clinical musculoskeletal events. In 1.7 % of hypertensive patients with
advanced diabetic renal disease treated with irbesartan, a decrease in
haemoglobin*, which was not clinically significant, has been observed.
Cardiac disorders:
Uncommon:
tachycardia
Nervous system disorders:
Common:
dizziness, orthostatic dizziness*
Respiratory, thoracic and mediastinal disorders:
Uncommon:
cough
Gastrointestinal disorders:
Common:
nausea/vomiting
Uncommon:
diarrhoea, dyspepsia/heartburn
Musculoskeletal and connective tissue disorders:
Common:
musculoskeletal pain*
Vascular disorders:
Common:
orthostatic hypotension*
Uncommon:
flushing
General disorders and administration site conditions:
Common:
fatigue
Uncommon:
chest pain
Reproductive system and breast disorders:
Uncommon:
sexual dysfunction
The following additional adverse reactions have been reported during post-marketing
experience; they are derived from spontaneous reports and therefore, the frequency of these
adverse reactions is not known:
Nervous system disorders:
Headache
Ear and labyrinth disorders:
Tinnitus
Gastrointestinal disorders:
Dysgeusia
Renal and urinary disorders:
Impaired renal function including cases of renal failure in patients at risk (see section 4.4)
Skin and subcutaneous tissue disorders:
Leukocytoclastic vasculitis
Musculoskeletal and connective tissue disorders:
6
Arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle
cramps
Metabolism and nutrition disorders:
Hyperkalaemia
Immune system disorders:
Hypersensitivity reactions such as angioedema, rash, urticaria
Hepato-biliary disorders:
Hepatitis, abnormal liver function
Paediatric patients:
in a randomised trial of 318 hypertensive children and adolescents aged 6 to
16 years, the following related adverse events occurred in the 3-week double-blind phase: headache
(7.9 %), hypotension (2.2 %), dizziness (1.9 %), cough (0.9 %). In the 26-week 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.
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might
also occur from overdose. No specific information is available on the treatment of overdose with
irbesartan. The patient should be closely monitored, and the treatment should be symptomatic and
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis.
5.
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 AT
1
)
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT
1
receptor,
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the
angiotensin-II (AT
1
) 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.
7
The blood pressure lowering effect of irbesartan is evident within 1-2 weeks, with the maximal effect
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound
hypertension has not been observed.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at
trough of 7-10/3-6 mm Hg (systolic/diastolic).
The efficacy of irbesartan is not influenced by age or gender. As is the case with other medicinal
products that affect the renin-angiotensin system, black hypertensive patients have notably less
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches
that of white patients.
There is no clinically important effect on serum uric acid or urinary uric acid secretion.
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 mm Hg (low dose), 9.3 mm Hg (medium dose), 13.2 mm Hg (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 mm Hg (low dose), 3.2 mm Hg (medium
dose), 5.6 mm Hg (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 mm Hg
in SeSBP and SeDBP compared to +0.1 and -0.3 mm Hg 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 mm Hg or a
10 mm Hg reduction in systolic pressure if baseline was > 160 mm Hg. 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
8
regimen. An increased incidence of non-fatal MI and stroke was seen in females in the
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart
failure was reduced in the overall population. However, no proper explanation for these findings in
women has been identified.
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term
effects (2 years) of irbesartan on the progression to clinical (overt) proteinuria (urinary albumin
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30 % from baseline). The
predefined blood pressure goal was ≤ 135/85 mm Hg. Additional antihypertensive agents (excluding
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2 %) than in the placebo (14.9 %)
or in the irbesartan 150 mg group (9.7 %) reached the endpoint of overt proteinuria, demonstrating a
70 % relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more
frequent in the irbesartan 300 mg group (34 %) than in the placebo group (21 %).
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
14
C 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 C
max
values
were also somewhat greater in elderly subjects (≥ 65 years) than those of young subjects
(18-40 years). However the terminal half-life was not significantly altered. No dosage adjustment is
necessary in elderly patients.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV
administration of
14
C irbesartan, about 20 % of the radioactivity is recovered in the urine, and the
remainder in the faeces. Less than 2 % of the dose is excreted in the urine as unchanged irbesartan.
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for
9
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 C
max
, 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.
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.
6.1 List of excipients
Tablet Core:
Povidone
Pregelatinized starch (maize)
Poloxamer 188
Microcrystalline cellulose
Croscarmellose sodium
Silica, colloidal hydrated
Magnesium stearate
Film coating:
Polydextrose (E1200)
Titanium dioxide (E171)
Hypromellose (E464)
Macrogol 4000
6.2 Incompatibilities
10
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
PVC/PVdC white opaque – aluminium blisters. Pack sizes of 7, 14, 28, 30, 56, 60, 80, 84, 90, 98, 100
and perforated unit dose blister 50 x 1 and 56 x 1.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542DR Utrecht
The Netherlands
8.
9.
Detailed information on Irbesartan Teva is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
11
1.
Irbesartan Teva 150 mg film-coated tablets
2.
Each film-coated tablet contains 150 mg of irbesartan
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to off white capsule shaped, film coated tablet. One side of the tablet debossed with the number
“93”. The other side of the tablet debossed with number “7465”.
4.
Treatment of essential hypertension.
Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an
antihypertensive medicinal product regimen (see section 5.1).
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food.
Irbesartan at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control
than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in
haemodialysed patients and in the elderly over 75 years.
In patients insufficiently controlled with 150 mg once daily, the dose of irbesartan can be increased to
300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as
hydrochlorothiazide has been shown to have an additive effect with irbesartan (see section 4.5).
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
The demonstration of renal benefit of irbesartan in hypertensive type 2 diabetic patients is based on
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach
target blood pressure (see section 5.1).
Renal impairment:
no dosage adjustment is necessary in patients with impaired renal function. A lower
starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4).
Hepatic impairment:
no dosage adjustment is necessary in patients with mild to moderate hepatic
impairment. There is no clinical experience in patients with severe hepatic impairment.
Elderly patients:
although consideration should be given to initiating therapy with 75 mg in patients
over 75 years of age, dosage adjustment is not usually necessary for the elderly.
12
Paediatric patients:
irbesartan is not recommended for use in children and adolescents due to
insufficient data on safety and efficacy (see sections 4.8, 5.1 and 5.2).
Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).
Second and third trimester of pregnancy (see section 4.4 and 4.6).
Intravascular volume depletion:
symptomatic hypotension, especially after the first dose, may occur in
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction,
diarrhoea or vomiting. Such conditions should be corrected before the administration of irbesartan.
Renovascular hypertension:
there is an increased risk of severe hypotension and renal insufficiency
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is
not documented with irbesartan, a similar effect should be anticipated with angiotensin-II receptor
antagonists.
Renal impairment and kidney transplantation:
when irbesartan is used in patients with impaired renal
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no
experience regarding the administration of irbesartan in patients with a recent kidney transplantation.
Hypertensive patients with type 2 diabetes and renal disease:
the effects of irbesartan both on renal and
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study
with patients with advanced renal disease. In particular, they appeared less favourable in women and
non-white subjects (see section 5.1).
Hyperkalaemia:
as with other medicinal products that affect the renin-angiotensin-aldosterone system,
hyperkalaemia may occur during the treatment with irbesartan, especially in the presence of renal
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of
serum potassium in patients at risk is recommended (see section 4.5).
Lithium:
the combination of lithium and irbesartan is not recommended (see section 4.5).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
as with other vasodilators,
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive
hypertrophic cardiomyopathy.
Primary aldosteronism:
patients with primary aldosteronism generally will not respond to
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of irbesartan is not recommended.
General:
in patients whose vascular tone and renal function depend predominantly on the activity of
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive
agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic
cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks,
possibly because of higher prevalence of low-renin states in the black hypertensive population (see
section 5.1).
13
Pregnancy:
AIIRAs should not be initiated during pregnancy. Unless continued AIIRAs therapy is
considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive
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).
Paediatric patients:
irbesartan has been studied in paediatric populations aged 6 to 16 years old but the
current data are insufficient to support an extension of the use in children until further data become
available (see sections 4.8, 5.1 and 5.2).
Diuretics and other antihypertensive agents:
other antihypertensive agents may increase the
hypotensive effects of irbesartan; however irbesartan has been safely administered with other
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of
hypotension when initiating therapy with irbesartan (see section 4.4).
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 trimester of pregnancy (see sections 4.3
and 4.4).
14
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 Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs
therapy is considered essential, patients planning pregnancy should be changed to alternative
anti-hypertensive 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 AIIRAs 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 also
sections 4.3 and 4.4).
Lactation:
Because no information is available regarding the use of irbersartan during breast-feeding, irbesartan
is not recommended and alternative treatments with better established safety profiles during
breast-feeding are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or
operating machines, it should be taken into account that dizziness or weariness may occur during
treatment.
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did
not differ between the irbesartan (56.2 %) and the placebo groups (56.5 %). Discontinuation due to
any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3 %) than
for placebo-treated patients (4.5 %). The incidence of adverse events was not related to dose (in the
recommended dose range), gender, age, race, or duration of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic
dizziness and orthostatic hypotension were reported in 0.5 % of the patients (i.e., uncommon) but in
excess of placebo.
The following 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.
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
15
patients in the irbesartan 300 mg group and 22 % of the patients in the placebo
group. In diabetic hypertensive patients with chronic renal insufficiency and overt
proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3 % of the patients in the
irbesartan group and 26.3 % of the patients in the placebo group.
Common:
significant increases in plasma creatine kinase were commonly observed (1.7 %) in
irbesartan treated subjects. None of these increases were associated with
identifiable clinical musculoskeletal events. In 1.7 % of hypertensive patients with
advanced diabetic renal disease treated with irbesartan, a decrease in
haemoglobin*, which was not clinically significant, has been observed.
Cardiac disorders:
Uncommon:
tachycardia
Nervous system disorders:
Common:
dizziness, orthostatic dizziness*
Respiratory, thoracic and mediastinal disorders:
Uncommon:
cough
Gastrointestinal disorders:
Common:
nausea/vomiting
Uncommon:
diarrhoea, dyspepsia/heartburn
Musculoskeletal and connective tissue disorders:
Common:
musculoskeletal pain*
Vascular disorders:
Common:
orthostatic hypotension*
Uncommon:
flushing
General disorders and administration site conditions:
Common:
fatigue
Uncommon:
chest pain
Reproductive system and breast disorders:
Uncommon:
sexual dysfunction
The following additional adverse reactions have been reported during post-marketing
experience; they are derived from spontaneous reports and therefore, the frequency of these
adverse reactions is not known:
Nervous system disorders:
Headache
Ear and labyrinth disorders:
Tinnitus
Gastrointestinal disorders:
Dysgeusia
Renal and urinary disorders:
Impaired renal function including cases of renal failure in patients at risk (see section 4.4)
Skin and subcutaneous tissue disorders:
Leukocytoclastic vasculitis
Musculoskeletal and connective tissue disorders:
16
Arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle
cramps
Metabolism and nutrition disorders:
Hyperkalaemia
Immune system disorders:
Hypersensitivity reactions such as angioedema, rash, urticaria
Hepato-biliary disorders:
Hepatitis, abnormal liver function
Paediatric patients:
in a randomised trial of 318 hypertensive children and adolescents aged 6 to
16 years, the following related adverse events occurred in the 3-week double-blind phase: headache
(7.9 %), hypotension (2.2 %), dizziness (1.9 %), cough (0.9 %). In the 26-week 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.
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might
also occur from overdose. No specific information is available on the treatment of overdose with
irbesartan. The patient should be closely monitored, and the treatment should be symptomatic and
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis.
5.
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 AT
1
)
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT
1
receptor,
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the
angiotensin-II (AT
1
) 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.
17
The blood pressure lowering effect of irbesartan is evident within 1-2 weeks, with the maximal effect
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound
hypertension has not been observed.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at
trough of 7-10/3-6 mm Hg (systolic/diastolic).
The efficacy of irbesartan is not influenced by age or gender. As is the case with other medicinal
products that affect the renin-angiotensin system, black hypertensive patients have notably less
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches
that of white patients.
There is no clinically important effect on serum uric acid or urinary uric acid secretion.
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 mm Hg (low dose), 9.3 mm Hg (medium dose), 13.2 mm Hg (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 mm Hg (low dose), 3.2 mm Hg (medium
dose), 5.6 mm Hg (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 mm Hg
in SeSBP and SeDBP compared to +0.1 and -0.3 mm Hg 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 mm Hg or a
10 mm Hg reduction in systolic pressure if baseline was > 160 mm Hg. 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
18
regimen. An increased incidence of non-fatal MI and stroke was seen in females in the
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart
failure was reduced in the overall population. However, no proper explanation for these findings in
women has been identified.
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term
effects (2 years) of irbesartan on the progression to clinical (overt) proteinuria (urinary albumin
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30 % from baseline). The
predefined blood pressure goal was ≤ 135/85 mm Hg. Additional antihypertensive agents (excluding
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2 %) than in the placebo (14.9 %)
or in the irbesartan 150 mg group (9.7 %) reached the endpoint of overt proteinuria, demonstrating a
70 % relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more
frequent in the irbesartan 300 mg group (34 %) than in the placebo group (21 %).
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
14
C 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 C
max
values
were also somewhat greater in elderly subjects (≥ 65 years) than those of young subjects
(18-40 years). However the terminal half-life was not significantly altered. No dosage adjustment is
necessary in elderly patients.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV
administration of
14
C irbesartan, about 20 % of the radioactivity is recovered in the urine, and the
remainder in the faeces. Less than 2 % of the dose is excreted in the urine as unchanged irbesartan.
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for
19
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 C
max
, 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.
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.
6.1 List of excipients
Tablet Core:
Povidone
Pregelatinized starch (maize)
Poloxamer 188
Microcrystalline cellulose
Croscarmellose sodium
Silica, colloidal hydrated
Magnesium stearate
Film coating:
Polydextrose (E1200)
Titanium dioxide (E171)
Hypromellose (E464)
Macrogol 4000
6.2 Incompatibilities
20
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVdC white opaque – aluminium blisters. Pack sizes of 7, 14, 28, 30, 56, 60, 80, 84, 90, 98, 100
and perforated unit dose blister 50 x 1 and 56 x 1.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542DR Utrecht
The Netherlands
8.
9.
Detailed information on Irbesartan Teva is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
21
1.
Irbesartan Teva 300 mg film-coated tablets
2.
Each film-coated tablet contains 300 mg of irbesartan
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
White to off white capsule shaped, film coated tablet. One side of the tablet debossed with the number
“93”. The other side of the tablet debossed with number “7466”.
4.
Treatment of essential hypertension.
Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an
antihypertensive medicinal product regimen (see section 5.1).
The usual recommended initial and maintenance dose is 150 mg once daily, with or without food.
Irbesartan at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control
than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in
haemodialysed patients and in the elderly over 75 years.
In patients insufficiently controlled with 150 mg once daily, the dose of irbesartan can be increased to
300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as
hydrochlorothiazide has been shown to have an additive effect with irbesartan (see section 4.5).
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily
and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
The demonstration of renal benefit of irbesartan in hypertensive type 2 diabetic patients is based on
studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach
target blood pressure (see section 5.1).
Renal impairment:
no dosage adjustment is necessary in patients with impaired renal function. A lower
starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4).
Hepatic impairment:
no dosage adjustment is necessary in patients with mild to moderate hepatic
impairment. There is no clinical experience in patients with severe hepatic impairment.
Elderly patients:
although consideration should be given to initiating therapy with 75 mg in patients
over 75 years of age, dosage adjustment is not usually necessary for the elderly.
22
Paediatric patients:
irbesartan is not recommended for use in children and adolescents due to
insufficient data on safety and efficacy (see sections 4.8, 5.1 and 5.2).
Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).
Second and third trimester of pregnancy (see section 4.4 and 4.6).
Intravascular volume depletion:
symptomatic hypotension, especially after the first dose, may occur in
patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction,
diarrhoea or vomiting. Such conditions should be corrected before the administration of irbesartan.
Renovascular hypertension:
there is an increased risk of severe hypotension and renal insufficiency
when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is
not documented with irbesartan, a similar effect should be anticipated with angiotensin-II receptor
antagonists.
Renal impairment and kidney transplantation:
when irbesartan is used in patients with impaired renal
function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no
experience regarding the administration of irbesartan in patients with a recent kidney transplantation.
Hypertensive patients with type 2 diabetes and renal disease:
the effects of irbesartan both on renal and
cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study
with patients with advanced renal disease. In particular, they appeared less favourable in women and
non-white subjects (see section 5.1).
Hyperkalaemia:
as with other medicinal products that affect the renin-angiotensin-aldosterone system,
hyperkalaemia may occur during the treatment with irbesartan, especially in the presence of renal
impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of
serum potassium in patients at risk is recommended (see section 4.5).
Lithium:
the combination of lithium and irbesartan is not recommended (see section 4.5).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
as with other vasodilators,
special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive
hypertrophic cardiomyopathy.
Primary aldosteronism:
patients with primary aldosteronism generally will not respond to
antihypertensive medicinal products acting through inhibition of the renin-angiotensin system.
Therefore, the use of irbesartan is not recommended.
General:
in patients whose vascular tone and renal function depend predominantly on the activity of
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or
underlying renal disease, including renal artery stenosis), treatment with angiotensin converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive
agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic
cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks,
possibly because of higher prevalence of low-renin states in the black hypertensive population (see
section 5.1).
23
Pregnancy:
AIIRAs should not be initiated during pregnancy. Unless continued AIIRAs therapy is
considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive
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).
Paediatric patients:
irbesartan has been studied in paediatric populations aged 6 to 16 years old but the
current data are insufficient to support an extension of the use in children until further data become
available (see sections 4.8, 5.1 and 5.2).
Diuretics and other antihypertensive agents:
other antihypertensive agents may increase the
hypotensive effects of irbesartan; however irbesartan has been safely administered with other
antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide
diuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk of
hypotension when initiating therapy with irbesartan (see section 4.4).
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 trimester of pregnancy (see sections 4.3
and 4.4).
24
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 Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs
therapy is considered essential, patients planning pregnancy should be changed to alternative
anti-hypertensive 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 AIIRAs 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 also
sections 4.3 and 4.4).
Lactation:
Because no information is available regarding the use of irbersartan during breast-feeding, irbesartan
is not recommended and alternative treatments with better established safety profiles during
breast-feeding are preferable, especially while nursing a newborn or preterm infant.
No studies on the effects on the ability to drive and use machines have been performed. Based on its
pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or
operating machines, it should be taken into account that dizziness or weariness may occur during
treatment.
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did
not differ between the irbesartan (56.2 %) and the placebo groups (56.5 %). Discontinuation due to
any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3 %) than
for placebo-treated patients (4.5 %). The incidence of adverse events was not related to dose (in the
recommended dose range), gender, age, race, or duration of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic
dizziness and orthostatic hypotension were reported in 0.5 % of the patients (i.e., uncommon) but in
excess of placebo.
The following 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.
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
25
patients in the irbesartan 300 mg group and 22 % of the patients in the placebo
group. In diabetic hypertensive patients with chronic renal insufficiency and overt
proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3 % of the patients in the
irbesartan group and 26.3 % of the patients in the placebo group.
Common:
significant increases in plasma creatine kinase were commonly observed (1.7 %) in
irbesartan treated subjects. None of these increases were associated with
identifiable clinical musculoskeletal events. In 1.7 % of hypertensive patients with
advanced diabetic renal disease treated with irbesartan, a decrease in
haemoglobin*, which was not clinically significant, has been observed.
Cardiac disorders:
Uncommon:
tachycardia
Nervous system disorders:
Common:
dizziness, orthostatic dizziness*
Respiratory, thoracic and mediastinal disorders:
Uncommon:
cough
Gastrointestinal disorders:
Common:
nausea/vomiting
Uncommon:
diarrhoea, dyspepsia/heartburn
Musculoskeletal and connective tissue disorders:
Common:
musculoskeletal pain*
Vascular disorders:
Common:
orthostatic hypotension*
Uncommon:
flushing
General disorders and administration site conditions:
Common:
fatigue
Uncommon:
chest pain
Reproductive system and breast disorders:
Uncommon:
sexual dysfunction
The following additional adverse reactions have been reported during post-marketing
experience; they are derived from spontaneous reports and therefore, the frequency of these
adverse reactions is not known:
Nervous system disorders:
Headache
Ear and labyrinth disorders:
Tinnitus
Gastrointestinal disorders:
Dysgeusia
Renal and urinary disorders:
Impaired renal function including cases of renal failure in patients at risk (see section 4.4)
Skin and subcutaneous tissue disorders:
Leukocytoclastic vasculitis
Musculoskeletal and connective tissue disorders:
26
Arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle
cramps
Metabolism and nutrition disorders:
Hyperkalaemia
Immune system disorders:
Hypersensitivity reactions such as angioedema, rash, urticaria
Hepato-biliary disorders:
Hepatitis, abnormal liver function
Paediatric patients:
in a randomised trial of 318 hypertensive children and adolescents aged 6 to
16 years, the following related adverse events occurred in the 3-week double-blind phase: headache
(7.9 %), hypotension (2.2 %), dizziness (1.9 %), cough (0.9 %). In the 26-week 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.
Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most
likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might
also occur from overdose. No specific information is available on the treatment of overdose with
irbesartan. The patient should be closely monitored, and the treatment should be symptomatic and
supportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal
may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis.
5.
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 AT
1
)
antagonist. It is expected to block all actions of angiotensin-II mediated by the AT
1
receptor,
regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the
angiotensin-II (AT
1
) 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.
27
The blood pressure lowering effect of irbesartan is evident within 1-2 weeks, with the maximal effect
occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long
term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound
hypertension has not been observed.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients
not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide
(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at
trough of 7-10/3-6 mm Hg (systolic/diastolic).
The efficacy of irbesartan is not influenced by age or gender. As is the case with other medicinal
products that affect the renin-angiotensin system, black hypertensive patients have notably less
response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose
of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches
that of white patients.
There is no clinically important effect on serum uric acid or urinary uric acid secretion.
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 mm Hg (low dose), 9.3 mm Hg (medium dose), 13.2 mm Hg (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 mm Hg (low dose), 3.2 mm Hg (medium
dose), 5.6 mm Hg (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 mm Hg
in SeSBP and SeDBP compared to +0.1 and -0.3 mm Hg 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 mm Hg or a
10 mm Hg reduction in systolic pressure if baseline was > 160 mm Hg. 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
28
regimen. An increased incidence of non-fatal MI and stroke was seen in females in the
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart
failure was reduced in the overall population. However, no proper explanation for these findings in
women has been identified.
The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2
Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in
patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in
590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function
(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term
effects (2 years) of irbesartan on the progression to clinical (overt) proteinuria (urinary albumin
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30 % from baseline). The
predefined blood pressure goal was ≤ 135/85 mm Hg. Additional antihypertensive agents (excluding
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2 %) than in the placebo (14.9 %)
or in the irbesartan 150 mg group (9.7 %) reached the endpoint of overt proteinuria, demonstrating a
70 % relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more
frequent in the irbesartan 300 mg group (34 %) than in the placebo group (21 %).
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
14
C 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 C
max
values
were also somewhat greater in elderly subjects (≥ 65 years) than those of young subjects
(18-40 years). However the terminal half-life was not significantly altered. No dosage adjustment is
necessary in elderly patients.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV
administration of
14
C irbesartan, about 20 % of the radioactivity is recovered in the urine, and the
remainder in the faeces. Less than 2 % of the dose is excreted in the urine as unchanged irbesartan.
The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration
of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for
29
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 C
max
, 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.
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.
6.1 List of excipients
Tablet Core:
Povidone
Pregelatinized starch (maize)
Poloxamer 188
Microcrystalline cellulose
Croscarmellose sodium
Silica, colloidal hydrated
Magnesium stearate
Film coating:
Polydextrose (E1200)
Titanium dioxide (E171)
Hypromellose (E464)
Macrogol 4000
6.2 Incompatibilities
30
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVdC white opaque – aluminium blisters. Pack sizes of 7, 14, 28, 30, 56, 60, 80, 84, 90, 98, 100
and perforated unit dose blister 50 x 1 and 56 x 1.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Teva Pharma B.V.
Computerweg 10
3542DR Utrecht
The Netherlands
8.
9.
Detailed information on Irbesartan Teva is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
31
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
32
A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
HU-4042 Debrecen
Hungary
TEVA Pharmaceutical Works Private Limited Company
Táncsics Mihály út 82
H-2100 Gödöllő
Hungary
Pharmachemie B.V.
Swensweg 5, Postbus 552
2003 RN Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
TEVA UK Ltd.
Brampton Road
Hampden Park, Eastbourne,
East Sussex, BN22 9AG
United Kingdom
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
33
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 dated
28 May 2009 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management plan
Not applicable.
The application is based on a reference medicinal product for which no safety concerns requiring
specific risk minimization activities have been identified.
PSURs
The PSUR submission schedule should follow the PSUR schedule for the reference product.
34
ANNEX III
LABELLING AND PACKAGE LEAFLET
35
A. LABELLING
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Irbesartan Teva 75 mg film-coated tablets
Irbesartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 75 mg irbesartan
3.
LIST OF EXCIPIENTS
4.
Film-coated tablets
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
60 film-coated tablets
80 film-coated tablets
84 film-coated tablets
90 film-coated tablets
98 film-coated tablets
100 film-coated tablets
50 x 1 film-coated tablets
56 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Swallow tablets whole. Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
37
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Irbesartan Teva 75 mg film-coated tablets
38
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Irbesartan Teva 75 mg film-coated tablets
Irbesartan
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Irbesartan Teva 150 mg film-coated tablets
Irbesartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 150 mg irbesartan
3.
LIST OF EXCIPIENTS
4.
Film-coated tablets
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
60 film-coated tablets
80 film-coated tablets
84 film-coated tablets
90 film-coated tablets
98 film-coated tablets
100 film-coated tablets
50 x 1 film-coated tablets
56 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Swallow tablets whole. Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
40
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Irbesartan Teva 150 mg film-coated tablets
41
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Irbesartan Teva 150 mg film-coated tablets
Irbesartan
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Carton
1.
Irbesartan Teva 300 mg film-coated tablets
Irbesartan
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 300 mg irbesartan
3.
LIST OF EXCIPIENTS
4.
Film-coated tablets
7 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
56 film-coated tablets
60 film-coated tablets
80 film-coated tablets
84 film-coated tablets
90 film-coated tablets
98 film-coated tablets
100 film-coated tablets
50 x 1 film-coated tablets
56 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use. Swallow tablets whole. Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
43
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
EU/0/00/000/000
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Irbesartan Teva 300 mg film-coated tablets
44
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
Irbesartan Teva 300 mg film-coated tablets
Irbesartan
2.
Teva Pharma B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
45
B. PACKAGE LEAFLET
46
PACKAGE LEAFLET: INFORMATION FOR THE USER
Irbesartan Teva 75 mg Film-Coated Tablets
Irbesartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Irbesartan Teva is and what it is used for
2. Before you take Irbesartan Teva
3. How to take Irbesartan Teva
4. Possible side effects
5.
How to store Irbesartan Teva
6.
Further information
1.
WHAT IRBESARTAN TEVA IS AND WHAT IT IS USED FOR
Irbesartan Teva belongs to a group of medicines known as angiotensin-II receptor antagonists.
Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing
them to tighten. This results in an increase in blood pressure. Irbesartan Teva prevents the binding of
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower.
Irbesartan Teva slows the decrease of kidney function in patients with high blood pressure and type 2
diabetes.
Irbesartan Teva is used
•
to treat high blood pressure (essential hypertension)
•
to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory
evidence of impaired kidney function.
2.
BEFORE YOU TAKE IRBESARTAN TEVA
Do not take Irbesartan Teva
•
If you are allergic (hypersensitive) to irbesartan or to any of the other ingredients of this
medicine.
•
If you are more than 3 months pregnant (it is also better to avoid Irbesartan Teva in early
pregnancy - see pregnancy section).
Irbesartan Teva should not be given to children and adolescents (under 18 years).
Take special care with Irbesartan Teva
Tell your doctor if any of the following apply to you:
•
If you get excessive diarrhoea or vomiting.
•
If you suffer from kidney problems.
•
If you suffer from heart problems.
•
If you receive Irbesartan Teva for diabetic kidney disease. In this case your doctor may perform
regular blood tests, especially for measuring blood potassium levels in case of poor kidney
function.
•
If you are going to have an operation (surgery) or be given anaesthetics.
47
-
If you have any further questions, ask your doctor or pharmacist.
You must tell your doctor if you think that you are (or might become) pregnant. Irbesartan Teva is not
recommended in early pregnancy and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see pregnancy section).
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Irbesartan Teva does not usually interact with other medicines.
You may need to have blood checks if you take:
•
potassium supplements
•
salt substitutes containing potassium
•
potassium-sparing medicines (such as certain diuretics)
•
medicines containing lithium
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan
may be reduced.
Taking Irbesartan Teva with food and drink
Irbesartan Teva can be taken with or without food.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think that you are (or might become) pregnant. Your doctor will
normally advise you to stop taking Irbesartan Teva before you become pregnant or as soon as you
know you are pregnant and will advise you to take another medicine instead of Irbesartan Teva.
Irbesartan Teva is not recommended in early pregnancy, and must not be taken when more than 3
months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.
Breastfeeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan Teva is not
recommended for mothers who are breast-feeding, and your doctor may choose another treatment for
you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan
Teva is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or
weariness may occur during treatment of high blood pressure. If you experience these, talk to your
doctor before attempting to drive or use machines.
3.
HOW TO TAKE
IRBESARTAN TEVA
Always take Irbesartan Teva exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure.
Method of administration
Irbesartan Teva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of
water). You can take Irbesartan Teva with or without food. Try to take your daily dose at about the
same time each day. It is important that you continue to take Irbesartan Teva until your doctor tells
you otherwise.
•
Patients with high blood pressure
The usual dose is 150 mg once a day. The dose may later be increased to 300 mg once daily
depending on blood pressure response.
48
•
Patients with high blood pressure and type 2 diabetes with kidney disease
In patients with high blood pressure and type 2 diabetes, 300 mg once daily is the preferred
maintenance dose for the treatment of associated kidney disease.
The doctor may advise a lower dose, especially when starting treatment in certain patients such as
those on haemodialysis, or those over the age of 75 years.
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment.
If you take more Irbesartan Teva than you should
If you accidentally take too many tablets, contact your doctor immediately.
Children should not take Irbesartan Teva
Irbesartan Teva should not be given to children under 18 years of age. If a child swallows some
tablets, contact your doctor immediately.
If you forget to take Irbesartan Teva
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to
make up for a forgotten dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Irbesartan Teva can cause side effects, although not everybody gets them. Some of
these effects may be serious and may require medical attention.
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any
of these symptoms or get short of breath, stop taking Irbesartan Teva and contact your doctor
immediately.
The frequency of the side effects listed below is defined using the following convention:
Very common: at least 1 in 10 patients or more
Common: at least 1 in 100 and less than 1 in 10 patients
Uncommon: at least 1 in 1000 and less than 1 in 100 patients
Side effects reported in clinical studies for patients treated with irbesartan were:
•
Very common: if you suffer from high blood pressure and type 2 diabetes with kidney disease,
blood tests may show an increased level of potassium.
•
Common: dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an
enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with
high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from
lying or sitting position, low blood pressure when getting up from a lying or sitting position,
pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin)
were also reported.
•
Uncommon: heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual
dysfunction (problems with sexual performance), chest pain.
Some undesirable effects have been reported since marketing of irbesartan but the frequency for them
to occur is not known. These undesirable effects are: headache, taste disturbance, ringing in the ears,
muscle cramps, pain in joints and muscles, abnormal liver function, increased blood potassium levels,
impaired kidney function, and inflammation of small blood vessels mainly affecting the skin (a
condition known as leukocytoclastic vasculitis).
49
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE IRBESARTAN TEVA
Keep out of the reach and sight of children.
Do not use Irbesartan Teva after the expiry date that is stated on the outer carton or foil. The expiry
date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Irbesartan Teva contains
-
The active substance is irbesartan.
•
Each Irbesartan Teva 75 mg film-coated tablet contains 75 mg irbesartan.
-
The other ingredients are:
•
Tablet core: povidone, pregelatinized starch (maize), poloxamer 188, microcrystalline
cellulose, croscarmellose sodium, colloidal hydrated silica and magnesium stearate.
•
Tablet coating: polydextrose, titanium dioxide, hypromellose and macrogol 4000.
What Irbesartan Teva looks like and contents of the pack
Irbesartan 75 mg film-coated tablets are white to off white capsule shaped, film coated tablet. One side
of the tablet debossed with the number “93”. The other side of the tablet debossed with number
“7464”.
Irbesartan Teva is available in pack sizes of 7, 14, 28, 30, 56, 60, 80, 84, 90, 98 and 100 film-coated
tablets and perforated unit dose blister 50 x 1 and 56 x 1 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturers:
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
Debrecen H-4042
Hungary
50
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
51
Tél: +(34) 91 387 32 80
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on Irbesartan Teva is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
52
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
PACKAGE LEAFLET: INFORMATION FOR THE USER
Irbesartan Teva 150 mg Film-Coated Tablets
Irbesartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Irbesartan Teva is and what it is used for
2. Before you take Irbesartan Teva
3. How to take Irbesartan Teva
4. Possible side effects
6.
How to store Irbesartan Teva
6.
Further information
1.
WHAT IRBESARTAN TEVA IS AND WHAT IT IS USED FOR
Irbesartan Teva belongs to a group of medicines known as angiotensin-II receptor antagonists.
Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing
them to tighten. This results in an increase in blood pressure. Irbesartan Teva prevents the binding of
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower.
Irbesartan Teva slows the decrease of kidney function in patients with high blood pressure and type 2
diabetes.
Irbesartan Teva is used
•
to treat high blood pressure (essential hypertension)
•
to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory
evidence of impaired kidney function.
2.
BEFORE YOU TAKE IRBESARTAN TEVA
Do not take Irbesartan Teva
a.
If you are allergic (hypersensitive) to irbesartan or to any of the other ingredients of this
medicine.
b.
If you are more than 3 months pregnant (it is also better to avoid Irbesartan Teva in early
pregnancy - see pregnancy section).
Irbesartan Teva should not be given to children and adolescents (under 18 years).
Take special care with Irbesartan Teva
Tell your doctor if any of the following apply to you:
•
If you get excessive diarrhoea or vomiting.
•
If you suffer from kidney problems.
•
If you suffer from heart problems.
•
If you receive Irbesartan Teva for diabetic kidney disease. In this case your doctor may perform
regular blood tests, especially for measuring blood potassium levels in case of poor kidney
function.
•
If you are going to have an operation (surgery) or be given anaesthetics.
53
-
If you have any further questions, ask your doctor or pharmacist.
You must tell your doctor if you think that you are (or might become) pregnant. Irbesartan Teva is not
recommended in early pregnancy and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see pregnancy section).
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Irbesartan Teva does not usually interact with other medicines.
You may need to have blood checks if you take:
•
potassium supplements
•
salt substitutes containing potassium
•
potassium-sparing medicines (such as certain diuretics)
•
medicines containing lithium
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan
may be reduced.
Taking Irbesartan Teva with food and drink
Irbesartan Teva can be taken with or without food.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think that you are (or might become) pregnant. Your doctor will
normally advise you to stop taking Irbesartan Teva before you become pregnant or as soon as you
know you are pregnant and will advise you to take another medicine instead of Irbesartan Teva.
Irbesartan Teva is not recommended in early pregnancy, and must not be taken when more than 3
months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.
Breastfeeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan Teva is not
recommended for mothers who are breast-feeding, and your doctor may choose another treatment for
you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan
Teva is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or
weariness may occur during treatment of high blood pressure. If you experience these, talk to your
doctor before attempting to drive or use machines.
3.
HOW TO TAKE
IRBESARTAN TEVA
Always take Irbesartan Teva exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure.
Method of administration
Irbesartan Teva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of
water). You can take Irbesartan Teva with or without food. Try to take your daily dose at about the
same time each day. It is important that you continue to take Irbesartan Teva until your doctor tells
you otherwise.
•
Patients with high blood pressure
The usual dose is 150 mg once a day. The dose may later be increased to 300 mg once daily
depending on blood pressure response.
54
•
Patients with high blood pressure and type 2 diabetes with kidney disease
In patients with high blood pressure and type 2 diabetes, 300 mg once daily is the preferred
maintenance dose for the treatment of associated kidney disease.
The doctor may advise a lower dose, especially when starting treatment in certain patients such as
those on haemodialysis, or those over the age of 75 years.
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment.
If you take more Irbesartan Teva than you should
If you accidentally take too many tablets, contact your doctor immediately.
Children should not take Irbesartan Teva
Irbesartan Teva should not be given to children under 18 years of age. If a child swallows some
tablets, contact your doctor immediately.
If you forget to take Irbesartan Teva
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to
make up for a forgotten dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Irbesartan Teva can cause side effects, although not everybody gets them. Some of
these effects may be serious and may require medical attention.
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any
of these symptoms or get short of breath, stop taking Irbesartan Teva and contact your doctor
immediately.
The frequency of the side effects listed below is defined using the following convention:
Very common: at least 1 in 10 patients or more
Common: at least 1 in 100 and less than 1 in 10 patients
Uncommon: at least 1 in 1000 and less than 1 in 100 patients
Side effects reported in clinical studies for patients treated with irbesartan were:
•
Very common: if you suffer from high blood pressure and type 2 diabetes with kidney disease,
blood tests may show an increased level of potassium.
•
Common: dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an
enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with
high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from
lying or sitting position, low blood pressure when getting up from a lying or sitting position,
pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin)
were also reported.
•
Uncommon: heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual
dysfunction (problems with sexual performance), chest pain.
Some undesirable effects have been reported since marketing of irbesartan but the frequency for them
to occur is not known. These undesirable effects are: headache, taste disturbance, ringing in the ears,
muscle cramps, pain in joints and muscles, abnormal liver function, increased blood potassium levels,
impaired kidney function, and inflammation of small blood vessels mainly affecting the skin (a
condition known as leukocytoclastic vasculitis).
55
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE IRBESARTAN TEVA
Keep out of the reach and sight of children.
Do not use Irbesartan Teva after the expiry date that is stated on the outer carton or foil. The expiry
date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Irbesartan Teva contains
-
The active substance is irbesartan.
•
Each Irbesartan Teva 150 mg film-coated tablet contains 150 mg irbesartan.
-
The other ingredients are:
•
Tablet core: povidone, pregelatinized starch (maize), poloxamer 188, microcrystalline
cellulose, croscarmellose sodium, colloidal hydrated silica and magnesium stearate.
•
Tablet coating: polydextrose, titanium dioxide, hypromellose and macrogol 4000.
What Irbesartan Teva looks like and contents of the pack
Irbesartan 150 mg film-coated tablets are white to off white capsule shaped, film coated tablet. One
side of the tablet debossed with the number “93”. The other side of the tablet debossed with number
“7465”.
Irbesartan Teva is available in pack sizes of 7, 14, 28, 30, 56, 60, 80, 84, 90, 98 and 100 film-coated
tablets and perforated unit dose blister 50 x 1 and 56 x 1 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturers:
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
Debrecen H-4042
Hungary
56
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
57
Tél: +(34) 91 387 32 80
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on Irbesartan Teva is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
58
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
PACKAGE LEAFLET: INFORMATION FOR THE USER
Irbesartan Teva 300 mg Film-Coated Tablets
Irbesartan
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1. What Irbesartan Teva is and what it is used for
2. Before you take Irbesartan Teva
3. How to take Irbesartan Teva
4. Possible side effects
7.
How to store Irbesartan Teva
6.
Further information
1.
WHAT IRBESARTAN TEVA IS AND WHAT IT IS USED FOR
Irbesartan Teva belongs to a group of medicines known as angiotensin-II receptor antagonists.
Angiotensin-II is a substance produced in the body which binds to receptors in blood vessels causing
them to tighten. This results in an increase in blood pressure. Irbesartan Teva prevents the binding of
angiotensin-II to these receptors, causing the blood vessels to relax and the blood pressure to lower.
Irbesartan Teva slows the decrease of kidney function in patients with high blood pressure and type 2
diabetes.
Irbesartan Teva is used
•
to treat high blood pressure (essential hypertension)
•
to protect the kidney in patients with high blood pressure, type 2 diabetes and laboratory
evidence of impaired kidney function.
2.
BEFORE YOU TAKE IRBESARTAN TEVA
Do not take Irbesartan Teva
a.
If you are allergic (hypersensitive) to irbesartan or to any of the other ingredients of this
medicine.
b.
If you are more than 3 months pregnant (it is also better to avoid Irbesartan Teva in early
pregnancy - see pregnancy section).
Irbesartan Teva should not be given to children and adolescents (under 18 years).
Take special care with Irbesartan Teva
Tell your doctor if any of the following apply to you:
•
If you get excessive diarrhoea or vomiting.
•
If you suffer from kidney problems.
•
If you suffer from heart problems.
•
If you receive Irbesartan Teva for diabetic kidney disease. In this case your doctor may perform
regular blood tests, especially for measuring blood potassium levels in case of poor kidney
function.
•
If you are going to have an operation (surgery) or be given anaesthetics.
59
-
If you have any further questions, ask your doctor or pharmacist.
You must tell your doctor if you think that you are (or might become) pregnant. Irbesartan Teva is not
recommended in early pregnancy and must not be taken if you are more than 3 months pregnant, as it
may cause serious harm to your baby if used at that stage (see pregnancy section).
Using other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Irbesartan Teva does not usually interact with other medicines.
You may need to have blood checks if you take:
•
potassium supplements
•
salt substitutes containing potassium
•
potassium-sparing medicines (such as certain diuretics)
•
medicines containing lithium
If you take certain painkillers, called non-steroidal anti-inflammatory drugs, the effect of irbesartan
may be reduced.
Taking Irbesartan Teva with food and drink
Irbesartan Teva can be taken with or without food.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think that you are (or might become) pregnant. Your doctor will
normally advise you to stop taking Irbesartan Teva before you become pregnant or as soon as you
know you are pregnant and will advise you to take another medicine instead of Irbesartan Teva.
Irbesartan Teva is not recommended in early pregnancy, and must not be taken when more than 3
months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.
Breastfeeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Irbesartan Teva is not
recommended for mothers who are breast-feeding, and your doctor may choose another treatment for
you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. Irbesartan
Teva is unlikely to affect your ability to drive or use machines. However, occasionally dizziness or
weariness may occur during treatment of high blood pressure. If you experience these, talk to your
doctor before attempting to drive or use machines.
3.
HOW TO TAKE
IRBESARTAN TEVA
Always take Irbesartan Teva exactly as your doctor has told you. You should check with your doctor
or pharmacist if you are not sure.
Method of administration
Irbesartan Teva is for oral use. Swallow the tablets with a sufficient amount of fluid (e.g. one glass of
water). You can take Irbesartan Teva with or without food. Try to take your daily dose at about the
same time each day. It is important that you continue to take Irbesartan Teva until your doctor tells
you otherwise.
•
Patients with high blood pressure
The usual dose is 150 mg once a day. The dose may later be increased to 300 mg once daily
depending on blood pressure response.
60
•
Patients with high blood pressure and type 2 diabetes with kidney disease
In patients with high blood pressure and type 2 diabetes, 300 mg once daily is the preferred
maintenance dose for the treatment of associated kidney disease.
The doctor may advise a lower dose, especially when starting treatment in certain patients such as
those on haemodialysis, or those over the age of 75 years.
The maximal blood pressure lowering effect should be reached 4-6 weeks after beginning treatment.
If you take more Irbesartan Teva than you should
If you accidentally take too many tablets, contact your doctor immediately.
Children should not take Irbesartan Teva
Irbesartan Teva should not be given to children under 18 years of age. If a child swallows some
tablets, contact your doctor immediately.
If you forget to take Irbesartan Teva
If you accidentally miss a daily dose, just take the next dose as normal. Do not take a double dose to
make up for a forgotten dose.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Irbesartan Teva can cause side effects, although not everybody gets them. Some of
these effects may be serious and may require medical attention.
As with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as localised
swelling of the face, lips and/or tongue have been reported in patients taking irbesartan. If you get any
of these symptoms or get short of breath, stop taking Irbesartan Teva and contact your doctor
immediately.
The frequency of the side effects listed below is defined using the following convention:
Very common: at least 1 in 10 patients or more
Common: at least 1 in 100 and less than 1 in 10 patients
Uncommon: at least 1 in 1000 and less than 1 in 100 patients
Side effects reported in clinical studies for patients treated with irbesartan were:
•
Very common: if you suffer from high blood pressure and type 2 diabetes with kidney disease,
blood tests may show an increased level of potassium.
•
Common: dizziness, feeling sick/vomiting, fatigue and blood tests may show raised levels of an
enzyme that measures the muscle and heart function (creatine kinase enzyme). In patients with
high blood pressure and type 2 diabetes with kidney disease, dizziness when getting up from
lying or sitting position, low blood pressure when getting up from a lying or sitting position,
pain in joints or muscles and decreased levels of a protein in the red blood cells (haemoglobin)
were also reported.
•
Uncommon: heart rate increased, flushing, cough, diarrhoea, indigestion/heartburn, sexual
dysfunction (problems with sexual performance), chest pain.
Some undesirable effects have been reported since marketing of irbesartan but the frequency for them
to occur is not known. These undesirable effects are: headache, taste disturbance, ringing in the ears,
muscle cramps, pain in joints and muscles, abnormal liver function, increased blood potassium levels,
impaired kidney function, and inflammation of small blood vessels mainly affecting the skin (a
condition known as leukocytoclastic vasculitis).
61
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE IRBESARTAN TEVA
Keep out of the reach and sight of children.
Do not use Irbesartan Teva after the expiry date that is stated on the outer carton or foil. The expiry
date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Irbesartan Teva contains
-
The active substance is irbesartan.
•
Each Irbesartan Teva 300 mg film-coated tablet contains 300 mg irbesartan.
-
The other ingredients are:
•
Tablet core: povidone, pregelatinized starch (maize), poloxamer 188, microcrystalline
cellulose, croscarmellose sodium, colloidal hydrated silica and magnesium stearate.
•
Tablet coating: polydextrose, titanium dioxide, hypromellose and macrogol 4000.
What Irbesartan Teva looks like and contents of the pack
Irbesartan 300 mg film-coated tablets are white to off white capsule shaped, film coated tablet. One
side of the tablet debossed with the number “93”. The other side of the tablet debossed with number
“7466”.
Irbesartan Teva is available in pack sizes of 7, 14, 28, 30, 56, 60, 80, 84, 90, 98 and 100 film-coated
tablets and perforated unit dose blister 50 x 1 and 56 x 1 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Teva Pharma B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
Manufacturers:
TEVA Kutno SA
Sienkiewicza Str. 25
99-300 Kutno
Poland
Teva Pharmaceutical Works Private Limited Company
Pallagi út 13
Debrecen H-4042
Hungary
62
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllö
Táncsics Mihály út 82
Hungary
TEVA UK Ltd
Brampton Road
Hampden Park
Eastbourne, East Sussex
BN22 9AG UK
Pharmachemie B.V.
Swensweg 5
2031 GA Haarlem
The Netherlands
TEVA Santé SA
Rue Bellocier
89107 Sens
France
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech
Eesti filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
España
Teva Genéricos Española, S.L.U
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
63
Tél: +(34) 91 387 32 80
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 212 08 90
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on Irbesartan Teva is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
64
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Source: European Medicines Agency
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