ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Aprovel 75 mg tablets.
2.
Each tablet contains 75 mg of irbesartan.
Excipient: 15.37 mg of lactose monohydrate per tablet.
For a full list of excipients, see section 6.1.
3.
Tablet.
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2771
engraved on the other side.
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.
Aprovel 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 Aprovel can be increased to
300 mg, or other antihypertensive agents can be added. In particular, the addition of a diuretic such as
hydrochlorothiazide has been shown to have an additive effect with Aprovel (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 Aprovel 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.
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).
2
Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).
Second and third trimesters of pregnancy (see sections 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 Aprovel.
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 Aprovel, a similar effect should be anticipated with angiotensin-II receptor
antagonists.
Renal impairment and kidney transplantation
: when Aprovel 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 Aprovel 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 Aprovel, 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 Aprovel 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 Aprovel is not recommended.
General
: in patients whose vascular tone and renal function depend predominantly on the activity of
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or
underlying renal disease, including renal artery stenosis), treatment with angiotensin
converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive
agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic
cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks,
possibly because of higher prevalence of low-renin states in the black hypertensive population (see
section 5.1).
Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be
changed to alternative antihypertensive treatments which have an established safety profile for use in
3
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Lactose
:
this medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Paediatric 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 Aprovel 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 Aprovel (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 trimesters 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 Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check
of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see
sections 4.3 and 4.4).
Lactation
:
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel 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 table presents the adverse drug reactions that were reported in placebo-controlled trials
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with
chronic renal insufficiency and overt proteinuria and in excess of placebo.
The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000,
< 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 patients in the
5
Common:
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.
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
6
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.
Musculoskeletal and connective tissue disorders:
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
Aprovel. 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 Aprovel 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 Aprovel 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 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high
dose). No significant difference was apparent between these doses. Adjusted mean change of trough
seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of
irbesartan (see section 4.2).
Hypertension and type 2 diabetes with renal disease
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double
blind, controlled, morbidity and mortality trial comparing Aprovel, 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 Aprovel 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 Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g.,
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78%
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant
reduction in doubling of serum creatinine were observed.
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black
subgroups which represented 32% and 26% of the overall study population respectively, a renal
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups
in the overall population, although an increased incidence of non-fatal MI was seen for women and a
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart
8
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 Aprovel on the progression to clinical (overt) proteinuria (urinary albumin
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70%
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more
frequent in the Aprovel 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
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
9
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
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Colloidal hydrated silica
Pregelatinised maize starch
Poloxamer 188
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
10
6.5 Nature and contents of container
Cartons of 14 tablets: 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 28 tablets: 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 tablets: 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 98 tablets: 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 x 1 tablet; 7 blister cards of 8 x 1 tablet each in PVC/PVDC/Aluminium perforated unit
dose blisters.
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.
SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC
174 avenue de France
F-75013 Paris - France
8.
EU/1/97/046/001-003
EU/1/97/046/010
EU/1/97/046/013
9.
Date of first authorisation: 27 August 1997
Date of latest renewal: 27 August 2007
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/
11
1.
Aprovel 150 mg tablets.
2.
Each tablet contains 150 mg of irbesartan.
Excipient: 30.75 mg of lactose monohydrate per tablet.
For a full list of excipients, see section 6.1.
3.
Tablet.
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2772
engraved on the other side.
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.
Aprovel 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 Aprovel can be increased to
300 mg, or other antihypertensive agents can be added. In particular, the addition of a diuretic such as
hydrochlorothiazide has been shown to have an additive effect with Aprovel (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 Aprovel 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.
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).
12
Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).
Second and third trimesters of pregnancy (see sections 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 Aprovel.
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 Aprovel, a similar effect should be anticipated with angiotensin-II receptor
antagonists.
Renal impairment and kidney transplantation
: when Aprovel 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 Aprovel 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 Aprovel, 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 Aprovel 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 Aprovel is not recommended.
General
: in patients whose vascular tone and renal function depend predominantly on the activity of
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or
underlying renal disease, including renal artery stenosis), treatment with angiotensin
converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive
agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic
cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks,
possibly because of higher prevalence of low-renin states in the black hypertensive population (see
section 5.1).
Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be
changed to alternative antihypertensive treatments which have an established safety profile for use in
13
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Lactose
:
this medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Paediatric 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 Aprovel 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 Aprovel (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 trimesters 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 Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check
of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see
sections 4.3 and 4.4).
Lactation
:
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel 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 table presents the adverse drug reactions that were reported in placebo-controlled trials
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with
chronic renal insufficiency and overt proteinuria and in excess of placebo.
The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000,
< 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 patients in the
15
Common:
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.
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
16
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.
Musculoskeletal and connective tissue disorders:
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
Aprovel. 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 Aprovel 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 Aprovel 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 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high
dose). No significant difference was apparent between these doses. Adjusted mean change of trough
seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of
irbesartan (see section 4.2).
Hypertension and type 2 diabetes with renal disease
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double
blind, controlled, morbidity and mortality trial comparing Aprovel, 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 Aprovel 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 Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g.,
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78%
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant
reduction in doubling of serum creatinine were observed.
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black
subgroups which represented 32% and 26% of the overall study population respectively, a renal
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups
in the overall population, although an increased incidence of non-fatal MI was seen for women and a
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart
18
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 Aprovel on the progression to clinical (overt) proteinuria (urinary albumin
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70%
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more
frequent in the Aprovel 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
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
19
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
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Colloidal hydrated silica
Pregelatinised maize starch
Poloxamer 188
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
20
6.5 Nature and contents of container
Cartons of 14 tablets: 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 28 tablets: 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 tablets: 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 98 tablets: 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 x 1 tablet; 7 blister cards of 8 x 1 tablet each in PVC/PVDC/Aluminium perforated unit
dose blisters.
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.
SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC
174 avenue de France
F-75013 Paris - France
8.
EU/1/97/046/004-006
EU/1/97/046/011
EU/1/97/046/014
9.
Date of first authorisation: 27 August 1997
Date of latest renewal: 27 August 2007
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/
21
1.
Aprovel 300 mg tablets.
2.
Each tablet contains 300 mg of irbesartan.
Excipient: 61.50 mg of lactose monohydrate per tablet.
For a full list of excipients, see section 6.1.
3.
Tablet.
White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2773
engraved on the other side.
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.
Aprovel 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 Aprovel can be increased to
300 mg, or other antihypertensive agents can be added. In particular, the addition of a diuretic such as
hydrochlorothiazide has been shown to have an additive effect with Aprovel (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 Aprovel 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.
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).
22
Hypersensitivity to the active substance, or to any of the excipients (see section 6.1).
Second and third trimesters of pregnancy (see sections 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 Aprovel.
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 Aprovel, a similar effect should be anticipated with angiotensin-II receptor
antagonists.
Renal impairment and kidney transplantation
: when Aprovel 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 Aprovel 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 Aprovel, 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 Aprovel 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 Aprovel is not recommended.
General
: in patients whose vascular tone and renal function depend predominantly on the activity of
the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or
underlying renal disease, including renal artery stenosis), treatment with angiotensin
converting
enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated
with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive
agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic
cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin
antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks,
possibly because of higher prevalence of low-renin states in the black hypertensive population (see
section 5.1).
Pregnancy:
Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be
changed to alternative antihypertensive treatments which have an established safety profile for use in
23
pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Lactose
:
this medicinal product contains lactose. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.
Paediatric 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 Aprovel 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 Aprovel (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 trimesters 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 Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued
AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,
alternative therapy should be started.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human
fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal
toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check
of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see
sections 4.3 and 4.4).
Lactation
:
Because no information is available regarding the use of Aprovel during breast-feeding, Aprovel 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 table presents the adverse drug reactions that were reported in placebo-controlled trials
in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the
adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with
chronic renal insufficiency and overt proteinuria and in excess of placebo.
The frequency of adverse reactions listed below is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000,
< 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 patients in the
25
Common:
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.
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
26
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.
Musculoskeletal and connective tissue disorders:
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
Aprovel. 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 Aprovel 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 Aprovel 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 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high
dose). No significant difference was apparent between these doses. Adjusted mean change of trough
seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium
dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized
to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg
in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of
irbesartan (see section 4.2).
Hypertension and type 2 diabetes with renal disease
The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression
of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double
blind, controlled, morbidity and mortality trial comparing Aprovel, 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 Aprovel 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 Aprovel, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.
Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g.,
diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHg
or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of
patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78%
in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk
in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-
cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal
composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative
risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine
(p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all
cause mortality was observed, while a positive trend in the reduction in ESRD and a significant
reduction in doubling of serum creatinine were observed.
Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum
creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black
subgroups which represented 32% and 26% of the overall study population respectively, a renal
benefit was not evident, although the confidence intervals do not exclude it. As for the secondary
endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups
in the overall population, although an increased incidence of non-fatal MI was seen for women and a
decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-
based regimen. An increased incidence of non-fatal MI and stroke was seen in females in the
irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart
28
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 Aprovel on the progression to clinical (overt) proteinuria (urinary albumin
excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The
predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding
ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added
as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all
treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or
in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70%
relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying
improvement in the glomerular filtration rate (GFR) was not observed during the first three months of
treatment. The slowing in the progression to clinical proteinuria was evident as early as three months
and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more
frequent in the Aprovel 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
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
29
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
Microcrystalline cellulose
Croscarmellose sodium
Lactose monohydrate
Magnesium stearate
Colloidal hydrated silica
Pregelatinised maize starch
Poloxamer 188
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
30
6.5 Nature and contents of container
Cartons of 14 tablets: 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 28 tablets: 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 tablets: 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 98 tablets: 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.
Cartons of 56 x 1 tablet; 7 blister cards of 8 x 1 tablet each in PVC/PVDC/Aluminium perforated unit
dose blisters.
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.
SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC
174 avenue de France
F-75013 Paris - France
8.
EU/1/97/046/007-009
EU/1/97/046/012
EU/1/97/046/015
9.
Date of first authorisation: 27 August 1997
Date of latest renewal: 27 August 2007
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA) http://www.emea.europa.eu/
31
1.
FURTHER INFORMATION
What Aprovel contains
The active substance is irbesartan. Each tablet of Aprovel 300 mg contains 300 mg irbesartan.
The other ingredients are lactose monohydrate, microcrystalline cellulose, croscarmellose
sodium, hypromellose, silicon dioxide, magnesium stearate, titanium dioxide, macrogol 3000,
carnauba wax.
What Aprovel looks like and contents of the pack
Aprovel 300 mg film-coated tablets are white to off-white, biconvex, and oval-shaped with a heart
debossed on one side and the number 2873 engraved on the other side.
Aprovel 300 mg film-coated tablets are supplied in blister packs of 14, 28, 30, 56, 84, 90 or 98 film-
coated tablets. Unidose blister packs of 56 x 1 film-coated tablet for delivery in hospitals are also
available.
Not all pack sizes may be marketed.
Marketing Authorisation Holder:
SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC
174 avenue de France
F-75013 Paris - France
Manufacturer:
SANOFI WINTHROP INDUSTRIE
1, rue de la Vierge
Ambarès & Lagrave
F-33565 Carbon Blanc Cedex - France
SANOFI SYNTHELABO LIMITED
Edgefield Avenue - Fawdon
Newcastle Upon Tyne, Tyne & Wear NE3 3TT - United Kingdom
SANOFI WINTHROP INDUSTRIE
30-36 Avenue Gustave Eiffel, BP 7166
F-37071 Tours Cedex 2 - France
CHINOIN PRIVATE CO. LTD.
Lévai u.5.
2112 Veresegyház - Hungary
121
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
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122
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This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
123
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