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Sabervel (irbesartan) – Summary of product characteristics - C09CA04

Updated on site: 10-Oct-2017

Medication nameSabervel
ATC CodeC09CA04
Substanceirbesartan
ManufacturerPharmathen S.A.

1.NAME OF THE MEDICINAL PRODUCT

Sabervel 75 mg film-coated tablets

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 75 mg of irbesartan

Excipient with known effect:

20 mg of lactose monohydrate per film-coated tablet

For the full list of excipients, see section 6.1.

authorised

 

3.

PHARMACEUTICAL FORM

 

Film-coated tablet.

 

White, concave, round, film-coated tablet with 7 mm diameter.

 

4.

CLINICAL PARTICULARS

 

4.1 Therapeutic indications

and 5.1).

longer

Sabervel is indicated in adults for the treatment of essential hypertension.

It is also indicated for the treatment of renal disease in adu t patients with hypertension and type 2

diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 no product

4.2 Posology and method of administra ion

Posology

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Sabervel at a dose of 150 mg nce 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.

particular, the add t on of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Sabervel (see section 4.5).

InMedicinalpatients insufficie tly controlled with 150 mg once daily, the dose of Sabervel can be increased to 300 mg, or other a tihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In

In hyp rt nsive 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 Sabervel 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 sections 4.3, 4.4, 4.5 and 5.1).

Special Populations

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A 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 population:the safety and efficacy of Sabervel in children aged 0 to 18 has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Method of Administration

For oral use.

4.3 Contraindications

authorised

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).

The concomitant use of Sabervel with aliskiren-containing products is contraindica ed in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Renovascular hypertension: there is an increased risk oflongersevere hypotension and renal insufficiency when patients with bilateral renal artery stenosis r sten sis of the artery to a single functioning kidney

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 Sabervel.

are treated with medicinal products that affect the re in-angiotensin-aldosterone system. While this is

not documented with Sabervel, a similar effect should be anticipated with angiotensin-II receptor

antagonists.

no

product

 

Renal impairment and kidney transplantation: when Sabervel is used in patients with impaired renal function, a periodic monitoring f p tassium and creatinine serum levels is recommended. There is no experience regarding the administ ati n of Sabervel in patients with a recent kidney transplantation.

non-white subjects (see section 5.1).

Hypertensive patients with ty e 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascularMedicinalevents were not uniform across all subgroups, in an analysis carried out in the study with patients with dv nced renal disease. In particular, they appeared less favourable in women and

Dual blocka e of the renin-angiotensin-aldosterone system (RAAS)

There is evi ence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskir n increases the risk of hypotension, hyperkalaemia and decreased renal function (including

acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Sabervel, 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 Sabervel 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 Sabervel 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 associat d with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any ant hypertensive

Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be authorisedinitiated during pregnancy.

agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaem c cardiovascular disease could result in a myocardial infarction or stroke.

As observed for angiotensin converting enzyme inhibitors, irbesartan and the ot er angi tensin antagonists are apparently less effective in lowering blood pressure in black people an in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1).

Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in

pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,

and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

 

 

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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.

no

 

Paediatric population: irbesartanproducthas been studied in paediatric populations aged 6 to 16 years old but Diuretics and other ntihypertensive agents: other antihypertensive agents may increase the

the current data are insufficient to s pport an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

Medicinalhypotensive effects of irbesartan; however irbesartan has been safely administered with other antihypertens ve age ts, such as beta-blockers, long-acting calcium channel blockers, and thiazide

diuretics. Pr or treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Sabervel (see section 4.4).

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS)

through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal

function (including acute renalfailure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing

diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and

is, therefore, not recommended (see section 4.4).

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during

Pregnancy:

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, carefulmonitoring 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 beauthorisedadequately hydrated and

consideration should be given to monitoring renal function after initiation of concomitant th rapy, and periodically thereafter.

Additional information on irbesartan interactions: in clinical studies, the pharmac kinetic 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 in eractions were observed when irbesartan was coadministered with warfarin, a medicinal prod ct metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the ph rm cokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not alte ed by coadministration of irbesartan.

4.6 Fertility, pregnancy and lactation

longer The use of AIIRAs is not recommended during nothe first trimester of pregnancy (see section 4.4). The

use of AIIRAs is contraindicated during the seco d and third trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regardingproductthe 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

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity ( ecreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (r nal failure, hypotension, hyperkalaemia). (See section 5.3).

antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancyMedicinalis diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Should xposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check

of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Breast-feeding:

Because no information is available regarding the use of Sabervel during breast-feeding, Sabervel is

not recommended and alternative treatments with better established safety profiles during breast- feeding are preferable, especially while nursing a newborn or preterm infant.

It is unknown whether irbesartan or its metabolites are excreted in human milk.

Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its

metabolites in milk (for details see 5.3).

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.

4.8 Undesirable effects

In placebo-controlled trials in patients with hypertension, the overall incidenceauthorisedof adve se events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuati n due to any

clinical or laboratory adverse event was less frequent for irbesartan-treated pa ien s (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 nal function, orthostatic

dizziness and orthostatic hypotension were reported in 0.5% of the pati nts (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

 

 

longer

adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with

chronic renal insufficiency and overt proteinuria a d in excess of placebo.

 

no

 

The frequency of adverse reactions listed below is defined using the following convention:

very common (≥ 1/10); common (≥ 1/100to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare

product

 

 

(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects

are presented in order of decreasing seriousness.

 

Adverse reactions additionally eported from post–marketing experience are also listed. These adverse reactions are derived from s ontaneous reports.

Immune system disorders:

Not known:

hypersensitivity reactions such as angioedema, rash, urticaria

Metabolism and nutrition disorders:

Not known:

hyperkalaemia

Nervous system disorders:

Common:

dizziness, orthostatic dizziness*

NotMedicinalknown: vertigo, headache

Ear and labyrinth disorder:

Not known:

tinnitus

Cardiac disorders:

Uncommon: tachycardia

Vascular disorders:

Common:

orthostatic hypotension*

Respiratory, thoracic and mediastinal disorders:
Uncommon: cough
Gastrointestinal disorders:
Common: nausea/vomiting
Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia

Uncommon: flushing

Hepatobiliary disorders:

 

 

 

 

Uncommon:

jaundice

 

 

 

 

Not known:

hepatitis, abnormal liver function

 

 

 

Skin and subcutaneous tissue disorders:

 

 

 

 

Not known:

leukocytoclastic vasculitis

 

 

 

 

Musculoskeletal and connective tissue disorders:

 

 

 

Common:

musculoskeletal pain*

 

 

 

 

Not known:

arthralgia, myalgia (in some cases associated with increased plasma creatine kinase

 

levels), muscle cramps

 

 

 

authorised

Renal and urinary disorders:

 

 

 

 

 

 

 

Not known:

impaired renal function including

cases of renal failure in patients at risk (see

section 4.4)

 

 

 

longer

 

Reproductive system and breast disorders:

 

 

 

Uncommon:

sexual dysfunction

 

 

 

General disorders and administration site co ditio

s:

 

Common:

fatigue

no

 

 

Uncommon:

chest pain

 

 

 

 

 

 

Investigations:

 

 

 

 

 

Very common:

Hyperkalaemia* occurred more often in diabetic patients treated with

 

irbesartan than with placebo. In diabetic hypertensive patients with

 

microalbuminuria and normal renal function, hyperkalaemia (≥

 

5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg

 

group productand 22% of the patients in the placebo group. In diabetic

 

hypertensive patients with chronic renal insufficiency and overt

 

proteinuria, hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the

 

patients in the irbesartan group and 26.3% of the patients in the placebo

 

group.

 

 

 

 

Common:

significant increases in plasma creatine kinase were commonly observed

 

(1.7%) in irbesartan treated subjects. None of these increases were

 

associated with identifiable clinical musculoskeletal events.

 

In 1.7% of hypertensive patients with advanced diabetic renal disease

Medicinaltreated with irbesartan, a decrease in haemoglobin*, which was not

 

clinically significant, has been observed.

 

Paediatric population:

In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following

adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent

laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients.

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

5. PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin-II antagonists, plain.

ATC code: C09C A04.

Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin-II recept r (type AT1 ) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor,

regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the

angiotensin-II (AT1 ) receptors results in increases in plasma renin levels

 

nd ngiotensin-II levels, and

a decrease in plasma aldosterone concentration. Serum potassium levels

 

e not significantly affected

by irbesartan alone at the recommended doses. Irbesartan does not inhibit

authorised

 

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:

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Hypertension

no

 

 

Irbesartan lowers blood pressure with minimal cha ge in heart rate. The decrease in blood pressure is

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 c esp nding 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

dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lowerproductsupine or sea ed blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systoli /diastolic) greater than those associated with placebo.

daily dosing on the same total dose.

TheMedicinalblood pressure lowering effect of irbesartan is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long

term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertens on has not been observed.

The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not ad quately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide

(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic).

The efficacy of irbesartan is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients.

There is no clinically important effect on serum uric acid or urinary uric acid secretion.

Paediatric population

Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of

hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic

blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2).

Hypertension and type 2 diabetes with renal disease

The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression

authorised patients in the placebo group reached this target bloodlongerpressure whe eas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively.

of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a ouble

blind, controlled, morbidity and mortality trial comparing irbesartan, amlodipine and placebo. In 1,715

hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatin ne ranging

from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of irbesartan on the progress on of renal

disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg irbesartan, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.

Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g.,

diuretics, beta blockers, alpha blockers) to reach a predefined blood press re goal of ≤ 135/85 mmHg

or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of

Irbesartan significantly reduced the relative risk in the primary combin d 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 e dpoi t compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reducti n versus placebo (p = 0.024) and 23%

in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.

relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in allnocause mortality was observed, while a positive trend

Subgroups consisting of gender,productrace, age, dura ion 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 ca di vascular 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- Medicinalbased regimen. An incre sed incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart

failure was reduced in the overall population. However, no proper explanation for these findings in women has been dentified.

The stu y of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diab t s Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in

patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function

(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of irbesartan on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding

ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added

as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or

in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of

treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more

frequent in the irbesartan 300 mg group (34%) than in the placebo group (21%).

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D

was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, th se results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concom tantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and RenalDisease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor

or an angiotensin II receptor blocker in patients with type 2 diabetes mellit s

and chronic kidney

disease, cardiovascular disease, or both. The study was terminated early bec

se of an increased risk

of adverse outcomes. Cardiovascular death and stroke were both nume ic lly more frequent in the

aliskiren group than in the placebo group and adverse events and s

authorised

ious adverse events of interest

(hyperkalaemia, hypotension and renal dysfunction) were more fr

qu ntly reported in the aliskiren

group than in the placebo group.

longer

 

5.2Pharmacokinetic properties

irbesartan. Plasma protein binding is approximanoely 96%, with negligible binding to cellular blood components. The volume of distribution is 53 - 93 litres. Following oral or intravenous administration

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 exhibits line

product

r nd dose proportional pharmacokinetics over the dose range of 10 to 600 mg.

A less than proportio

l increase in oral absorption at doses beyond 600 mg (twice the maximal

Medicinal

of 14C irbesartan, 80-85% of the circ lating 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.

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 regim n. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily

dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of

irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values

were also somewhat greater in 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 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the

remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

Paediatric population

The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for

four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax,

AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.

Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by

haemodialysis.

Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered.

Studies have not been performed in patients with severe hepatic impairment.

5.3 Preclinical safety data

There was no evidence of abnormal systemic or target organ toxicity at clinicallyauthorisedrelevant 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, h emoglobin, haematocrit).

At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such asinterstitial nephritis, tubular distension, basophilic tubules, increasedlongerplasma conc ntrations 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 c nsidered to be caused by the

pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells dnoes n t appear to have any relevance.

There was no evidence ofproductmutagenicity, clas ogenicity or carcinogenicity.

Fertility and reproductive performance were not affected in studies of male and female rats even at

oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including

mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live

fetuses were observed. Irbesa tan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabeled irbesartan is detected in rat and rabbit fetuses.

Irbesartan is excreted in the milk of lactating rats.

AnimalMedicinalstudies with irbes rtan showed transient toxic effects (increased renalpelvic cavitation,

hydroureter or subcuta eous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Silica colloidal anhydrous

Hypromellose

Magnesium stearate.

Film-coating:

Hypromellose

Titanium dioxide (E171)

Macrogol 400

6.2Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

Cartons of 28, 56, 90 or 98 film-coated tablets in PVC/PVDC-aluminium/PVDC blisters. Not all pack sizes may be marketed.

authorised

6.6Special precautions for disposal

 

 

 

 

longer

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

7.

MARKETING AUTHORISATION HOLDER

Pharmathen S.A.

 

no

 

 

 

 

6, Dervenakion str.,

product

 

 

15351 Pallini

 

 

 

 

 

Attiki, Greece

 

 

 

Tel.: +30 210 66 65 067

 

 

 

8.

MARKETING AUTHORISATION NUMBERS

Medicinal

 

 

 

EU/1/12/765/001

 

 

 

EU/1/12/765/002

 

 

 

EU/1/12/765/007

 

 

 

EU/1/12/765/010

 

 

 

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first Authorization: 13 April 2012

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

1. NAME OF THE MEDICINAL PRODUCT

Sabervel 150 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 150 mg of irbesartan

Excipient with known effect:

40 mg of lactose monohydrate per film-coated tablet

For the full list of excipients, see section 6.1.

authorised

 

3.

PHARMACEUTICAL FORM

 

Film-coated tablet.

 

White, concave, round, film-coated tablet with 9 mm diameter.

 

4.

CLINICAL PARTICULARS

 

4.1 Therapeutic indications

and 5.1).

longer

Sabervel is indicated in adults for the treatment of essential hypertension.

It is also indicated for the treatment of renal disease in adu t patients with hypertension and type 2

diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 no product

4.2 Posology and method of administra ion

Posology

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Sabervel at a dose of 150 mg nce 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.

particular, the add t on of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Sabervel (see section 4.5).

InMedicinalpatients insufficie tly controlled with 150 mg once daily, the dose of Sabervel can be increased to 300 mg, or other a tihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In

In hyp rt nsive 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 Sabervel 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 sections 4.3, 4.4, 4.5 and 5.1).

Special Populations

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A 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 population:the safety and efficacy of Sabervel in children aged 0 to 18 has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Method of Administration

For oral use.

4.3 Contraindications

authorised

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).

The concomitant use of Sabervel with aliskiren-containing products is contraindica ed in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Renovascular hypertension: there is an increased risk oflongersevere hypotension and renal insufficiency when patients with bilateral renal artery stenosis r sten sis of the artery to a single functioning kidney

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 Sabervel.

are treated with medicinal products that affect the re in-angiotensin-aldosterone system. While this is

not documented with Sabervel, a similar effect should be anticipated with angiotensin-II receptor

antagonists.

no

product

 

Renal impairment and kidney transplantation: when Sabervel is used in patients with impaired renal function, a periodic monitoring f p tassium and creatinine serum levels is recommended. There is no experience regarding the administ ati n of Sabervel in patients with a recent kidney transplantation.

non-white subjects (see section 5.1).

Hypertensive patients with ty e 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascularMedicinalevents were not uniform across all subgroups, in an analysis carried out in the study with patients with dv nced renal disease. In particular, they appeared less favourable in women and

Dual blocka e of the renin-angiotensin-aldosterone system (RAAS)

There is evi ence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskir n increases the risk of hypotension, hyperkalaemia and decreased renal function (including

acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Sabervel, 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 Sabervel 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 Sabervel 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 associat d with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any ant hypertensive

Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be authorisedinitiated during pregnancy.

agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaem c cardiovascular disease could result in a myocardial infarction or stroke.

As observed for angiotensin converting enzyme inhibitors, irbesartan and the ot er angi tensin antagonists are apparently less effective in lowering blood pressure in black people an in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1).

Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in

pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,

and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

 

 

longer

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.

no

 

Paediatric population: irbesartanproducthas been studied in paediatric populations aged 6 to 16 years old but Diuretics and other ntihypertensive agents: other antihypertensive agents may increase the

the current data are insufficient to s pport an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

Medicinalhypotensive effects of irbesartan; however irbesartan has been safely administered with other antihypertens ve age ts, such as beta-blockers, long-acting calcium channel blockers, and thiazide

diuretics. Pr or treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Sabervel (see section 4.4).

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS)

through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal

function (including acute renalfailure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Potassium supplements and potassium-sp

aring 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, carefulmonitoring 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 hydrat d 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 pharmac kinetic 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 medicin l prod ct metabolised by

CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the ph

 

m cokinetic of irbesartan

have not been evaluated. The pharmacokinetic of digoxin was not alt

authorised

d by coadministration of

irbesartan.

longer

 

 

 

4.6 Fertility, pregnancy and lactation

Pregnancy:

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The

use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3

and 4.4).

 

no

 

 

 

product

 

Epidemiological evidence regar ing 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 the e 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

alternative therapy should be started.

AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensiveMedicinaltre tments which have an established safety profile for use in pregnancy. When pregnancy is diag osed, treatment with AIIRAs should be stopped immediately, and, if appropriate,

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity ( ecreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (r nal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Breast-feeding:

Because no information is available regarding the use of Sabervel during breast-feeding, Sabervel is not recommended and alternative treatments with better established safety profiles during breast-

feeding are preferable, especially while nursing a newborn or preterm infant.

It is unknown whether irbesartan or its metabolites are excreted in human milk.

Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3).

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.

4.8 Undesirable effects

In placebo-controlled trials in patients with hypertension, the overall incidenceauthorisedof adverse events did

not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discon inuation 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 rel ted to dose (in the recommended dose range), gender, age, race, or duration of treatment.

In diabetic hypertensive patients with microalbuminuria longerand normal r nal 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.no 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 a d in excess of placebo.

The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare

(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of dec easing seriousness.

Medicinal

Adverse reactions additiona ly reported from post–marketing experience are also listed. These adverse

reactions are derived from productspontaneous reports.

Immune system d sorders:

Not known:

hypersensitivity reactions such as angioedema, rash, urticaria

Metabolism and nutrition disorders:

Not known:

hyperkalaemia

Nervous system disorders:

Common:

dizziness, orthostatic dizziness*

Not known:

vertigo, headache

Ear and labyrinth disorder:

Not known:

tinnitus

Cardiac disorders:

Uncommon: tachycardia

Vascular disorders:

Common:

orthostatic hypotension*

Uncommon:

flushing

Respiratory, thoracic and mediastinal disorders:

Uncommon: cough

Gastrointestinal disorders:

Common:

nausea/vomiting

 

 

 

 

Uncommon:

diarrhoea, dyspepsia/heartburn

 

 

 

Not known:

dysgeusia

 

 

 

 

Hepatobiliary disorders:

 

 

 

authorised

Uncommon:

jaundice

 

 

 

 

 

 

 

Not known:

hepatitis, abnormal liver function

 

 

 

Skin and subcutaneous tissue disorders:

 

 

 

 

Not known:

leukocytoclastic vasculitis

 

 

 

 

Musculoskeletal and connective tissue disorders:

 

 

 

Common:

musculoskeletal pain*

 

 

 

 

Not known:

arthralgia, myalgia (in some cases associated with incre sed plasma creatine kinase

 

levels), muscle cramps

 

 

 

 

Renal and urinary disorders:

 

 

 

 

Not known:

impaired renal function including

cases of renal failure in patients at risk (see

section 4.4)

 

 

 

longer

 

Reproductive system and breast disorders:

no

 

Uncommon:

sexual dysfunction

 

 

 

 

General disorders and administration site co ditio

s:

 

 

Common:

mEq/L)productoccurred in 29.4% of the patients in the irbesartan 300 mg group

fatigue

 

 

 

 

Uncommon:

chest pain

 

 

 

 

Investigations:

 

 

 

 

 

Very common:

Hyperkalaemia* occurred more often in diabetic patients treated with

 

irbesartan than with placebo. In diabetic hypertensive patients with

Medicinal

 

 

 

 

 

microa buminuria and normal renal function, hyperkalaemia (≥ 5.5

 

d 22% of the patients in the placebo group. In diabetic hypertensive

 

patients with chronic renal insufficiency and overt proteinuria,

 

hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the

 

irbesartan group and 26.3% of the patients in the placebo group.

Common:

significant increases in plasma creatine kinase were commonly observed

 

(1.7%) in irbesartan treated subjects. None of these increases were

associated with identifiable clinical musculoskeletal events.

In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in haemoglobin*, which was not clinically significant, has been observed.

Paediatric population:

In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following

adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent

laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients.

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin-II antagonists, plain.

ATC code: C09C A04.

Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin-II recept r (type AT1 ) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor,

regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the

angiotensin-II (AT1 ) receptors results in increases in plasma renin levels

 

nd ngiotensin-II levels, and

a decrease in plasma aldosterone concentration. Serum potassium levels

 

e not significantly affected

by irbesartan alone at the recommended doses. Irbesartan does not inhibit

authorised

 

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:

longer

 

Hypertension

no

 

 

Irbesartan lowers blood pressure with minimal cha ge in heart rate. The decrease in blood pressure is

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 c esp nding 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

dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lowerproductsupine or sea ed blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systoli /diastolic) greater than those associated with placebo.

daily dosing on the same total dose.

TheMedicinalblood pressure lowering effect of irbesartan is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long

term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertens on has not been observed.

The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not ad quately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide

(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic).

The efficacy of irbesartan is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients.

There is no clinically important effect on serum uric acid or urinary uric acid secretion.

Paediatric population

Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of

hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic

blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2).

Hypertension and type 2 diabetes with renal disease

The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression

authorised patients in the placebo group reached this target bloodlongerpressure whe eas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively.

of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a ouble

blind, controlled, morbidity and mortality trial comparing irbesartan, amlodipine and placebo. In 1,715

hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatin ne ranging

from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of irbesartan on the progress on of renal

disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg irbesartan, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.

Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g.,

diuretics, beta blockers, alpha blockers) to reach a predefined blood press re goal of ≤ 135/85 mmHg

or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of

Irbesartan significantly reduced the relative risk in the primary combin d 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 e dpoi t compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reducti n versus placebo (p = 0.024) and 23%

in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.

relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in allnocause mortality was observed, while a positive trend

Subgroups consisting of gender,productrace, age, dura ion 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 ca di vascular 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- Medicinalbased regimen. An incre sed incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart

failure was reduced in the overall population. However, no proper explanation for these findings in women has been dentified.

The stu y of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diab t s Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in

patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function

(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of irbesartan on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding

ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added

as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or

in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of

treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more

frequent in the irbesartan 300 mg group (34%) than in the placebo group (21%).

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D

was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, th se results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concom tantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and RenalDisease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor

or an angiotensin II receptor blocker in patients with type 2 diabetes mellit s

and chronic kidney

disease, cardiovascular disease, or both. The study was terminated early bec

se of an increased risk

of adverse outcomes. Cardiovascular death and stroke were both nume ic lly more frequent in the

aliskiren group than in the placebo group and adverse events and s

authorised

ious adverse events of interest

(hyperkalaemia, hypotension and renal dysfunction) were more fr

qu ntly reported in the aliskiren

group than in the placebo group.

longer

 

5.2 Pharmacokinetic properties

irbesartan. Plasma protein binding is approximanoely 96%, with negligible binding to cellular blood components. The volume of distribution is 53 - 93 litres. Following oral or intravenous administration

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 exhibits line

product

r nd dose proportional pharmacokinetics over the dose range of 10 to 600 mg.

A less than proportio

l increase in oral absorption at doses beyond 600 mg (twice the maximal

Medicinal

of 14C irbesartan, 80-85% of the circ lating 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.

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 regim n. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily

dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of

irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values

were also somewhat greater in 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 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the

remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

Paediatric population

The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for

four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax,

AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.

Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by

haemodialysis.

Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered.

Studies have not been performed in patients with severe hepatic impairment.

5.3 Preclinical safety data

There was no evidence of abnormal systemic or target organ toxicity at clinicallyauthorisedrelevant 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, h emoglobin, haematocrit). At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increasedlongerplasma conc ntrations 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 renalperfusion. 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 c nsidered to be caused by the

pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells dnoes n t appear to have any relevance.

There was no evidence ofproductmutagenicity, clas ogenicity or carcinogenicity.

Fertility and reproductive performance were not affected in studies of male and female rats even at

oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including

mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live

fetuses were observed. Irbesa tan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabeled irbesartan is detected in rat and rabbit fetuses.

Irbesartan is excreted in the milk of lactating rats.

AnimalMedicinalstudies with irbes rtan showed transient toxic effects (increased renalpelvic cavitation,

hydroureter or subcuta eous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Silica colloidal anhydrous

Hypromellose

Magnesium stearate.

Film-coating:

Hypromellose

Titanium dioxide (E171)

Macrogol 400

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Cartons of 28, 56, 90 or 98 film-coated tablets in PVC/PVDC-aluminium/PVDC blisters. Not all pack sizes may be marketed.

authorised

6.6Special precautions for disposal

 

 

 

 

longer

Any unused product or waste materialshould be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

Pharmathen S.A.

 

no

 

 

 

 

6, Dervenakion str.,

product

 

 

15351 Pallini

 

 

 

 

 

Attiki, Greece

 

 

 

Tel.: +30 210 66 65 067

 

 

 

8.

MARKETING AUTHORISATION NUMBERS

DateMedicinalof first Authorization: 13 April 2012

 

 

EU/1/12/765/003

 

 

 

EU/1/12/765/004

 

 

 

EU/1/12/765/008

 

 

 

EU/1/12/765/011

 

 

 

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

1. NAME OF THE MEDICINAL PRODUCT

Sabervel 300 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 300 mg of irbesartan

Excipient with known effect:

80 mg of lactose monohydrate per film-coated tablet

For the full list of excipients, see section 6.1.

authorised

 

3.

PHARMACEUTICAL FORM

 

Film-coated tablet.

 

White, concave, round, film-coated tablet with 11 mm diameter.

 

4.

CLINICAL PARTICULARS

 

4.1 Therapeutic indications

and 5.1).

longer

Sabervel is indicated in adults for the treatment of essential hypertension.

It is also indicated for the treatment of renal disease in adu t patients with hypertension and type 2

diabetes mellitus as part of an antihypertensive medicinal product regimen (see sections 4.3, 4.4, 4.5 no product

4.2 Posology and method of administra ion

Posology

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Sabervel at a dose of 150 mg nce 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.

particular, the add t on of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Sabervel (see section 4.5).

InMedicinalpatients insufficie tly controlled with 150 mg once daily, the dose of Sabervel can be increased to 300 mg, or other a tihypertensive agents can be added (see sections 4.3, 4.4, 4.5 and 5.1). In

In hyp rt nsive 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 Sabervel 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 sections 4.3, 4.4, 4.5 and 5.1).

Special Populations

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A 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 population: the safety and efficacy of Sabervel in children aged 0 to 18 has not been established. Currently available data are described in section 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.
Method of Administration

For oral use.

4.3 Contraindications

authorised

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).

The concomitant use of Sabervel with aliskiren-containing products is contraindica ed in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Renovascular hypertension: there is an increased risk oflongersevere hypotension and renal insufficiency when patients with bilateral renal artery stenosis r sten sis of the artery to a single functioning kidney

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 Sabervel.

are treated with medicinal products that affect the re in-angiotensin-aldosterone system. While this is

not documented with Sabervel, a similar effect should be anticipated with angiotensin-II receptor

antagonists.

no

product

 

Renal impairment and kidney transplantation: when Sabervel is used in patients with impaired renal function, a periodic monitoring f p tassium and creatinine serum levels is recommended. There is no experience regarding the administ ati n of Sabervel in patients with a recent kidney transplantation.

non-white subjects (see section 5.1).

Hypertensive patients with ty e 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascularMedicinalevents were not uniform across all subgroups, in an analysis carried out in the study with patients with dv nced renal disease. In particular, they appeared less favourable in women and

Dual blocka e of the renin-angiotensin-aldosterone system (RAAS)

There is evi ence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskir n increases the risk of hypotension, hyperkalaemia and decreased renal function (including

acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Sabervel, 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 Sabervel 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 Sabervel 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 associat d with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any ant hypertensive

Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be authorisedinitiated during pregnancy.

agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaem c cardiovascular disease could result in a myocardial infarction or stroke.

As observed for angiotensin converting enzyme inhibitors, irbesartan and the ot er angi tensin antagonists are apparently less effective in lowering blood pressure in black people an in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see section 5.1).

Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in

pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,

and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

 

 

longer

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.

no

 

Paediatric population: irbesartanproducthas been studied in paediatric populations aged 6 to 16 years old but Diuretics and other ntihypertensive agents: other antihypertensive agents may increase the

the current data are insufficient to s pport an extension of the use in children until further data become available (see sections 4.8, 5.1 and 5.2).

4.5 Interaction with other medicinal products and other forms of interaction

Medicinalhypotensive effects of irbesartan; however irbesartan has been safely administered with other antihypertens ve age ts, such as beta-blockers, long-acting calcium channel blockers, and thiazide

diuretics. Pr or treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Sabervel (see section 4.4).

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS)

through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal

function (including acute renalfailure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Potassium supplements and potassium-sparing diuretics: based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing

diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and

is, therefore, not recommended (see section 4.4).

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during

Pregnancy:

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, carefulmonitoring 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 beauthorisedadequately hydrated and

consideration should be given to monitoring renal function after initiation of concomitant th rapy, and periodically thereafter.

Additional information on irbesartan interactions: in clinical studies, the pharmac kinetic 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 in eractions were observed when irbesartan was coadministered with warfarin, a medicinal prod ct metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the ph rm cokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not alte ed by coadministration of irbesartan.

4.6 Fertility, pregnancy and lactation

longer The use of AIIRAs is not recommended during nothe first trimester of pregnancy (see section 4.4). The

use of AIIRAs is contraindicated during the seco d and third trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regardingproductthe 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

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity ( ecreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (r nal failure, hypotension, hyperkalaemia). (See section 5.3).

antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancyMedicinalis diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Should xposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check

of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Breast-feeding:

Because no information is available regarding the use of Sabervel during breast-feeding, Sabervel is

not recommended and alternative treatments with better established safety profiles during breast- feeding are preferable, especially while nursing a newborn or preterm infant.

It is unknown whether irbesartan or its metabolites are excreted in human milk.

Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its

metabolites in milk (for details see 5.3).

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Based on its pharmacodynamic properties, irbesartan is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.

4.8 Undesirable effects

In placebo-controlled trials in patients with hypertension, the overall incidenceauthorisedof adve se events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuati n due to any

clinical or laboratory adverse event was less frequent for irbesartan-treated pa ien s (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 nal function, orthostatic

dizziness and orthostatic hypotension were reported in 0.5% of the pati nts (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

 

 

longer

adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with

chronic renal insufficiency and overt proteinuria a d in excess of placebo.

 

no

 

The frequency of adverse reactions listed below is defined using the following convention:

very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare

product

 

 

(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects

are presented in order of decreasing seriousness.

 

Adverse reactions additionally eported from post–marketing experience are also listed. These adverse reactions are derived from s ontaneous reports.

Immune system disorders:

Not known:

hypersensitivity reactions such as angioedema, rash, urticaria

Metabolism and nutrition disorders:

Not known:

hyperkalaemia

Nervous system disorders:

Common:

dizziness, orthostatic dizziness*

NotMedicinalknown: vertigo, headache

Ear and labyrinth disorder:

Not known:

tinnitus

Cardiac disorders:

Uncommon: tachycardia

Vascular disorders:

Common:

orthostatic hypotension*

Respiratory, thoracic and mediastinal disorders:
Uncommon: cough
Gastrointestinal disorders:
Common: nausea/vomiting
Uncommon: diarrhoea, dyspepsia/heartburn Not known: dysgeusia

Uncommon: flushing

Hepatobiliary disorders:

 

 

 

 

Uncommon:

jaundice

 

 

 

 

Not known:

hepatitis, abnormal liver function

 

 

 

Skin and subcutaneous tissue disorders:

 

 

 

 

Not known:

leukocytoclastic vasculitis

 

 

 

 

Musculoskeletal and connective tissue disorders:

 

 

 

Common:

musculoskeletal pain*

 

 

 

 

Not known:

arthralgia, myalgia (in some cases associated with increased plasma creatine kinase

 

levels), muscle cramps

 

 

 

authorised

Renal and urinary disorders:

 

 

 

 

 

 

 

Not known:

impaired renal function including

cases of renal failure in patients at risk (see

section 4.4)

 

 

 

longer

 

Reproductive system and breast disorders:

 

 

 

Uncommon:

sexual dysfunction

 

 

 

General disorders and administration site co ditio

s:

 

Common:

fatigue

no

 

 

Uncommon:

chest pain

 

 

 

 

 

 

Investigations:

 

 

 

 

 

Very common:

Hyperkalaemia* occurred more often in diabetic patients treated with

 

irbesartan than with placebo. In diabetic hypertensive patients with

 

microalbuminuria and normal renal function, hyperkalaemia (≥ 5.5

 

mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group

 

nd 22%productof the patients in the placebo group. In diabetic hypertensive

 

p tients with chronic renal insufficiency and overt proteinuria,

 

hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the

 

irbesartan group and 26.3% of the patients in the placebo group.

Common:

significant increases in plasma creatine kinase were commonly observed

 

(1.7%) in irbesartan treated subjects. None of these increases were

 

associated with identifiable clinical musculoskeletal events.

 

In 1.7% of hypertensive patients with advanced diabetic renal disease

 

treated with irbesartan, a decrease in haemoglobin*, which was not

Medicinal

 

 

 

 

 

clinically significant, has been observed.

 

Paediatric population:

In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following

adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent

laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients.

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin-II antagonists, plain.

ATC code: C09C A04.

Mechanism of action: Irbesartan is a potent, orally active, selective angiotensin-II recept r (type AT1 ) antagonist. It is expected to block all actions of angiotensin-II mediated by the AT1 receptor,

regardless of the source or route of synthesis of angiotensin-II. The selective antagonism of the

Irbesartan lowers blood pressure with minimal cha ge in heart rate. The decrease in blood pressure is

angiotensin-II (AT1 ) receptors results in increases in plasma renin levels

 

nd ngiotensin-II levels, and

a decrease in plasma aldosterone concentration. Serum potassium levels

 

e not significantly affected

by irbesartan alone at the recommended doses. Irbesartan does not inhibit

authorised

 

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:

longer

 

Hypertension

no

 

 

 

 

 

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 c esp nding 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

dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150-300 mg once daily lowerproductsupine or sea ed blood pressures at trough (i.e. 24 hours after dosing) by an average of 8-13/5-8 mm Hg (systoli /diastolic) greater than those associated with placebo.

daily dosing on the same total dose.

TheMedicinalblood pressure lowering effect of irbesartan is evident within 1-2 weeks, with the maximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during long

term therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertens on has not been observed.

The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not ad quately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide

(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic).

The efficacy of irbesartan is not influenced by age or gender. As is the case with other medicinal products that affect the renin-angiotensin system, black hypertensive patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with a low dose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients.

There is no clinically important effect on serum uric acid or urinary uric acid secretion.

Paediatric population

Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) target titrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history of

hypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of the three weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolic

blood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (high dose). No significant difference was apparent between these doses. Adjusted mean change of trough seated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (medium dose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomized to either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHg in SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses of irbesartan (see section 4.2).

Hypertension and type 2 diabetes with renal disease

The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression

authorised patients in the placebo group reached this target bloodlongerpressure whe eas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively.

of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a ouble

blind, controlled, morbidity and mortality trial comparing irbesartan, amlodipine and placebo. In 1,715

hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatin ne ranging

from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of irbesartan on the progress on of renal

disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg irbesartan, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.

Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g.,

diuretics, beta blockers, alpha blockers) to reach a predefined blood press re goal of ≤ 135/85 mmHg

or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of

Irbesartan significantly reduced the relative risk in the primary combin d 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 e dpoi t compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reducti n versus placebo (p = 0.024) and 23%

in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.

relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in allnocause mortality was observed, while a positive trend

Subgroups consisting of gender,productrace, age, dura ion 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 ca di vascular 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- Medicinalbased regimen. An incre sed incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart

failure was reduced in the overall population. However, no proper explanation for these findings in women has been dentified.

The stu y of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2 Diab t s Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria in

patients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in 590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function

(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-term effects (2 years) of irbesartan on the progression to clinical (overt) proteinuria (urinary albumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding

ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were added

as needed to help achieve the blood pressure goal. While similar blood pressure was achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) or

in the irbesartan 150 mg group (9.7%) reached the endpoint of overt proteinuria, demonstrating a 70% relative risk reduction versus placebo (p = 0.0004) for the higher dose. An accompanying improvement in the glomerular filtration rate (GFR) was not observed during the first three months of

treatment. The slowing in the progression to clinical proteinuria was evident as early as three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was more

frequent in the irbesartan 300 mg group (34%) than in the placebo group (21%).

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D

was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, th se results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concom tantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and RenalDisease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor

or an angiotensin II receptor blocker in patients with type 2 diabetes mellit s

and chronic kidney

disease, cardiovascular disease, or both. The study was terminated early bec

se of an increased risk

of adverse outcomes. Cardiovascular death and stroke were both nume ic lly more frequent in the

aliskiren group than in the placebo group and adverse events and s

authorised

ious adverse events of interest

(hyperkalaemia, hypotension and renal dysfunction) were more fr

qu ntly reported in the aliskiren

group than in the placebo group.

longer

 

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 approxima ely 96%, with negligible binding to cellular blood

components. The volume of distribution is 53

no

- 93 litres. Following oral or intravenous administration

of 14C irbesartan, 80-85% of the circ lating 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 line

product

r nd dose proportional pharmacokinetics over the dose range of 10 to 600 mg.

A less than proportio

l increase in oral absorption at doses beyond 600 mg (twice the maximal

Medicinal

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 regim n. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female

hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax values

were also somewhat greater in 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 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

Paediatric population

The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for

four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax,

AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.

Renal impairment: in patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by

haemodialysis.

Hepatic impairment: in patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered.

Studies have not been performed in patients with severe hepatic impairment.

5.3 Preclinical safety data

There was no evidence of abnormal systemic or target organ toxicity at clinicallyauthorisedrelevant 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, h emoglobin, haematocrit).

At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increasedlongerplasma conc ntrations 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 c nsidered to be caused by the

pharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juxtaglomerular cells dnoes n t appear to have any relevance.

There was no evidence ofproductmutagenicity, clas ogenicity or carcinogenicity.

Fertility and reproductive performance were not affected in studies of male and female rats even at

oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including

mortality at the highest dose. No significant effects on the number of corpora lutea, implants, or live

fetuses were observed. Irbesa tan did not affect survival, development, or reproduction of offspring. Studies in animals indicate that the radiolabeled irbesartan is detected in rat and rabbit fetuses.

Irbesartan is excreted in the milk of lactating rats.

AnimalMedicinalstudies with irbes rtan showed transient toxic effects (increased renalpelvic cavitation,

hydroureter or subcuta eous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including mortality. No teratogenic effects were observed in the rat or rabbit.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Silica colloidal anhydrous

Hypromellose

Magnesium stearate.

Film-coating:

Hypromellose

Titanium dioxide (E171)

Macrogol 400

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Cartons of 28, 56, 90 or 98 film-coated tablets in PVC/PVDC-aluminium/PVDC blisters. Not all pack sizes may be marketed.

authorised

6.6Special precautions for disposal

 

 

 

 

longer

Any unused product or waste materialshould be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

Pharmathen S.A.

 

no

 

 

 

 

6, Dervenakion str.,

product

 

 

15351 Pallini

 

 

 

 

 

Attiki, Greece

 

 

 

Tel.: +30 210 66 65 067

 

 

 

8.

MARKETING AUTHORISATION NUMBERS

Medicinal

 

 

 

EU/1/12/765/005

 

 

 

EU/1/12/765/006

 

 

 

EU/1/12/765/009

 

 

 

EU/1/12/765/012

 

 

 

9.

DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first Authorization: 13 April 2012

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

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