IRBESARTAN ZENTIVA 150mg tablets medication leaflet

Irbesartan Zentiva 150 mg tablets.

Each tablet contains 150 mg of irbesartan.

Excipient with known effect: 30.75 mg of lactose monohydrate per tablet.

For the full list of excipients, see section 6.1.

Tablet.

White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2772engraved on the other side.

Irbesartan Zentiva is indicated in adults for the treatment of essential hypertension.

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

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food.

Irbesartan Zentiva at a dose of 150 mg once daily generally provides a better 24 hour blood pressurecontrol than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly inhaemodialysed patients and in the elderly over 75 years.

In patients insufficiently controlled with 150 mg once daily, the dose of Irbesartan Zentiva can beincreased to 300 mg, or other antihypertensive agents can be added (see sections pct. 4.3, pct. 4.4, 4.5 and 5.1).

In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additiveeffect with Irbesartan Zentiva (see section 4.5).

In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once dailyand titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.

The demonstration of renal benefit of Irbesartan Zentiva in hypertensive type 2 diabetic patients isbased on studies where irbesartan was used in addition to other antihypertensive agents, as needed, toreach target blood pressure (see sections pct. 4.3, pct. 4.4, 4.5 and 5.1).

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).

No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is noclinical experience in patients with severe hepatic impairment.

Older people

Although consideration should be given to initiating therapy with 75 mg in patients over 75 years ofage, dosage adjustment is not usually necessary for older people.

The safety and efficacy of Irbesartan Zentiva in children aged 0 to 18 has not been established.

Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on aposology can be made.

For oral use.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

The concomitant use of Irbesartan Zentiva with aliskiren-containing products is contraindicated inpatients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR)<60 ml/min/1.73m2) (see sections 4.5 and 5.1).

Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur inpatients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction,diarrhoea or vomiting. Such conditions should be corrected before the administration of Irbesartan

Zentiva.

Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiencywhen patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidneyare treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this isnot documented with Irbesartan Zentiva, a similar effect should be anticipated with angiotensin-IIreceptor antagonists.

Renal impairment and kidney transplantation: when Irbesartan Zentiva is used in patients withimpaired renal function, a periodic monitoring of potassium and creatinine serum levels isrecommended. There is no experience regarding the administration of Irbesartan Zentiva in patientswith a recent kidney transplantation.

Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal andcardiovascular events were not uniform across all subgroups, in an analysis carried out in the studywith patients with advanced renal disease. In particular, they appeared less favourable in women andnon-white subjects (see section 5.1).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that theconcomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk ofhypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dualblockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers oraliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy isconsidered absolutely necessary, this should only occur under specialist supervision and subject tofrequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors andangiotensin II receptor blockers should not be used concomitantly in patients with diabeticnephropathy.

Intestinal angioedema: intestinal angioedema has been reported in patients treated with angiotensin IIreceptor antagonists, including irbesartan (see section 4.8). These patients presented with abdominalpain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin IIreceptor antagonists. If intestinal angioedema is diagnosed, irbesartan should be discontinued andappropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system,hyperkalaemia may occur during the treatment with Irbesartan Zentiva, especially in the presence ofrenal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoringof serum potassium in patients at risk is recommended (see section 4.5).

Hypoglycaemia: Irbesartan Zentiva may induce hypoglycaemia, particularly in diabetic patients. Inpatients treated with insulin or antidiabetics an appropriate blood glucose monitoring should beconsidered; a dose adjustment of insulin or antidiabetics may be required when indicated (seesection 4.5).

Lithium: the combination of lithium and Irbesartan Zentiva is not recommended (see section 4.5).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators,special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructivehypertrophic cardiomyopathy.

Primary aldosteronism: patients with primary aldosteronism generally will not respond toantihypertensive medicinal products acting through inhibition of the renin-angiotensin system.

Therefore, the use of Irbesartan Zentiva is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity ofthe renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure orunderlying renal disease, including renal artery stenosis), treatment with angiotensin convertingenzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associatedwith acute hypotension, azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with anyantihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy orischaemic cardiovascular disease could result in a myocardial infarction or stroke.

As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensinantagonists are apparently less effective in lowering blood pressure in black people than in non-blacks,possibly because of higher prevalence of low-renin states in the black hypertensive population (seesection 5.1).

Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy.

Unless continued AIIRA therapy is considered essential, patients planning pregnancy should bechanged to alternative antihypertensive treatments which have an established safety profile for use inpregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately,and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Paediatric population: irbesartan has been studied in paediatric populations aged 6 to 16 years old butthe current data are insufficient to support an extension of the use in children until further data becomeavailable (see sections 4.8, 5.1 and 5.2).

Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicine.

Sodium: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Diuretics and other antihypertensive agents: other antihypertensive agents may increase thehypotensive effects of irbesartan; however Irbesartan Zentiva has been safely administered with otherantihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazidediuretics. Prior treatment with high dose diuretics may result in volume depletion and a risk ofhypotension when initiating therapy with Irbesartan Zentiva (see section 4.4).

Aliskiren-containing products or ACE-inhibitors: clinical trial data has shown that dual blockade ofthe 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 eventssuch as hypotension, hyperkalaemia and decreased renal function (including acute renal failure)compared to the use of a single RAAS-acting agent (see sections pct. 4.3, pct. 4.4 and 5.1).

Potassium supplements and potassium-sparing diuretics: based on experience with the use of othermedicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparingdiuretics, potassium supplements, salt substitutes containing potassium or other medicinal productsthat may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium andis, therefore, not recommended (see section 4.4).

Lithium: reversible increases in serum lithium concentrations and toxicity have been reported duringconcomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effectshave been very rarely reported with irbesartan so far. Therefore, this combination is not recommended(see section 4.4). If the combination proves necessary, careful monitoring of serum lithium levels isrecommended.

Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administeredsimultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors,acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effectmay occur.

As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to anincreased risk of worsening of renal function, including possible acute renal failure, and an increase inserum potassium, especially in patients with poor pre-existing renal function. The combination shouldbe administered with caution, especially in the elderly. Patients should be adequately hydrated andconsideration should be given to monitoring renal function after initiation of concomitant therapy, andperiodically thereafter.

Repaglinide: irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported thatirbesartan increased the Cmax and AUC of repaglinide (substrate of OATP1B1) by 1.8-fold and 1.3-fold, respectively, when administered 1 hour before repaglinide. In another study, no relevantpharmacokinetic interaction was reported, when the two drugs were co-administered. Therefore, doseadjustment of antidiabetic treatment such as repaglinide may be required (see section 4.4).

Additional information on irbesartan interactions: in clinical studies, the pharmacokinetic of irbesartanis not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesserextent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions wereobserved when irbesartan was coadministered with warfarin, a medicinal product metabolised by

CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartanhave not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration ofirbesartan.

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). Theuse of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitorsduring the first trimester of pregnancy has not been conclusive; however a small increase in riskcannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin 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 alternativeantihypertensive treatments which have an established safety profile for use in pregnancy. Whenpregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate,alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce humanfoetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonataltoxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

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

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

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

Irbesartan Zentiva is not recommended and alternative treatments with better established safetyprofiles 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 itsmetabolites in milk (for details see 5.3).

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

Based on its pharmacodynamic properties, irbesartan is unlikely to affect the ability to drive and usemachines. When driving vehicles or operating machines, it should be taken into account that dizzinessor weariness may occur during treatment.

In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events didnot differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to anyclinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than forplacebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in therecommended dose range), gender, age, race, or duration of treatment.

In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostaticdizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but inexcess of placebo.

The following table presents the adverse drug reactions that were reported in placebo-controlled trialsin which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to theadverse reactions that were additionally reported in > 2% of diabetic hypertensive patients withchronic renal insufficiency and overt proteinuria and in excess of placebo.

The frequency of adverse reactions listed below is defined using the following convention:very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effectsare presented in order of decreasing seriousness.

Adverse reactions additionally reported from post-marketing experience are also listed. These adversereactions are derived from spontaneous reports.

Not known: anaemia, thrombocytopenia

Not known: hypersensitivity reactions such as angioedema, rash, urticaria, anaphylactic reaction,anaphylactic shock

Not known: hyperkalaemia, hypoglycaemia

Common: dizziness, orthostatic dizziness*

Not known: vertigo, headache

Ear and labyrinth disorder

Not known: tinnitus

Uncommon: tachycardia

Common: orthostatic hypotension*

Uncommon: flushing

Uncommon: cough

Common: nausea/vomiting

Uncommon: diarrhoea, dyspepsia/heartburn

Rare: intestinal angioedema

Not known: dysgeusia

Uncommon: jaundice

Not known: hepatitis, abnormal liver function

Not known: leukocytoclastic vasculitis

Common: musculoskeletal pain*

Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinaselevels), muscle cramps

Not known: impaired renal function including cases of renal failure in patients at risk (seesection 4.4)

Uncommon: sexual dysfunction

Common: fatigue

Uncommon: chest pain

Very common: Hyperkalaemia* occurred more often in diabetic patients treated with irbesartan thanwith placebo. In diabetic hypertensive patients with microalbuminuria and normalrenal function, hyperkalaemia (≥ 5.5 mEq/L) occurred in 29.4% of the patients in theirbesartan 300 mg group and 22% of the patients in the placebo group. In diabetichypertensive patients with chronic renal insufficiency and overt proteinuria,hyperkalaemia (≥ 5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan groupand 26.3% of the patients in the placebo group.

Common: significant increases in plasma creatine kinase were commonly observed (1.7%) inirbesartan treated subjects. None of these increases were associated with identifiableclinical musculoskeletal events.

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

In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the followingadverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%),dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequentlaboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% ofchild recipients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The mostlikely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia mightalso occur from overdose. No specific information is available on the treatment of overdose with

Irbesartan Zentiva. The patient should be closely monitored, and the treatment should be symptomaticand supportive. Suggested measures include induction of emesis and/or gastric lavage. Activatedcharcoal may be useful in the treatment of overdose. Irbesartan is not removed by haemodialysis.

Pharmacotherapeutic group: Angiotensin-II antagonists, plain, ATC code: C09C A04.

Irbesartan is a potent, orally active, selective angiotensin-II receptor (type AT1) antagonist. It isexpected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the sourceor route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptorsresults in increases in plasma renin levels and angiotensin-II levels, and a decrease in plasmaaldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone atthe recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generatesangiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not requiremetabolic activation for its activity.

Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure isdose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of150-300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) byan average of 8-13/5-8 mm Hg (systolic/diastolic) greater than those associated with placebo.

Peak reduction of blood pressure is achieved within 3-6 hours after administration and the bloodpressure lowering effect is maintained for at least 24 hours. At 24 hours the reduction of bloodpressure was 60-70% of the corresponding peak diastolic and systolic responses at the recommendeddoses. Once daily dosing with 150 mg produced trough and mean 24 hour responses similar to twicedaily dosing on the same total dose.

The blood pressure lowering effect of Irbesartan Zentiva is evident within 1-2 weeks, with themaximal effect occurring by 4-6 weeks after start of therapy. The antihypertensive effects aremaintained during long term therapy. After withdrawal of therapy, blood pressure gradually returnstoward baseline. Rebound hypertension has not been observed.

The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patientsnot adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide(12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction attrough of 7-10/3-6 mm Hg (systolic/diastolic).

The efficacy of Irbesartan Zentiva is not influenced by age or gender. As is the case with othermedicinal products that affect the renin-angiotensin system, black hypertensive patients have notablyless response to irbesartan monotherapy. When irbesartan is administered concomitantly with a lowdose of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patientsapproaches that of white patients.

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

Reduction of blood pressure with 0.5 mg/kg (low), 1.5 mg/kg (medium) and 4.5 mg/kg (high) targettitrated doses of irbesartan was evaluated in 318 hypertensive or at risk (diabetic, family history ofhypertension) children and adolescents aged 6 to 16 years over a three week period. At the end of thethree weeks the mean reduction from baseline in the primary efficacy variable, trough seated systolicblood pressure (SeSBP) was 11.7 mmHg (low dose), 9.3 mmHg (medium dose), 13.2 mmHg (highdose). No significant difference was apparent between these doses. Adjusted mean change of troughseated diastolic blood pressure (SeDBP) was as follows: 3.8 mmHg (low dose), 3.2 mmHg (mediumdose), 5.6 mmHg (high dose). Over a subsequent two week period where patients were re-randomizedto either active medicinal product or placebo, patients on placebo had increases of 2.4 and 2.0 mmHgin SeSBP and SeDBP compared to +0.1 and -0.3 mmHg changes respectively in those on all doses ofirbesartan (see section 4.2).

Hypertension and type 2 diabetes with renal disease

The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progressionof renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a doubleblind, controlled, morbidity and mortality trial comparing Irbesartan Zentiva, amlodipine and placebo.

In 1,715 hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinineranging from 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of Irbesartan Zentiva on theprogression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mgto a maintenance dose of 300 mg Irbesartan Zentiva, from 2.5 mg to 10 mg amlodipine, or placebo astolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents(e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of≤ 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty percent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reducedthe relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renaldisease (ESRD) or all-cause mortality. Approximately 33% of patients in the irbesartan group reachedthe primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipinegroups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reductioncompared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint wereanalysed, no effect in all cause mortality was observed, while a positive trend in the reduction in

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

Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serumcreatinine, and albumin excretion rate were assessed for treatment effect. In the female and blacksubgroups which represented 32% and 26% of the overall study population respectively, a renalbenefit was not evident, although the confidence intervals do not exclude it. As for the secondaryendpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groupsin the overall population, although an increased incidence of non-fatal MI was seen for women and adecreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebo-based regimen. An increased incidence of non-fatal MI and stroke was seen in females in theirbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heartfailure was reduced in the overall population. However, no proper explanation for these findings inwomen has been identified.

The study of the “Effects of Irbesartan on Microalbuminuria in Hypertensive Patients with type 2

Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria inpatients with microalbuminuria. IRMA 2 was a placebo-controlled double blind morbidity study in590 patients with type 2 diabetes, microalbuminuria (30-300 mg/day) and normal renal function(serum creatinine ≤ 1.5 mg/dl in males and < 1.1 mg/dl in females). The study examined the long-termeffects (2 years) of Irbesartan Zentiva on the progression to clinical (overt) proteinuria (urinaryalbumin excretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% frombaseline). The predefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensiveagents (excluding ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calciumblockers) were added as needed to help achieve the blood pressure goal. While similar blood pressurewas achieved in all treatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in theplacebo (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. Anaccompanying improvement in the glomerular filtration rate (GFR) was not observed during the firstthree months of treatment. The slowing in the progression to clinical proteinuria was evident as earlyas three months and continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day)was more frequent in the Irbesartan Zentiva 300 mg group (34%) than in the placebo group (21%).

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and incombination 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 anangiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history ofcardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence ofend-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus anddiabetic nephropathy.

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

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

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints)was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitoror an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidneydisease, cardiovascular disease, or both. The study was terminated early because of an increased riskof adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in thealiskiren group than in the placebo group and adverse events and serious adverse events of interest(hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskirengroup than in the placebo group.

After oral administration, irbesartan is well absorbed: studies of absolute bioavailability gave values ofapproximately 60-80%. Concomitant food intake does not significantly influence the bioavailability ofirbesartan.

Plasma protein binding is approximately 96%, with negligible binding to cellular blood components.

The volume of distribution is 53-93 litres.

Following oral or intravenous administration of 14C irbesartan, 80-85% of the circulating plasmaradioactivity is attributable to unchanged irbesartan. Irbesartan is metabolised by the liver viaglucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide(approximately 6%). In vitro studies indicate that irbesartan is primarily oxidised by thecytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.

Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg.

A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximalrecommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrationsare attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157-176 and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours.

Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosingregimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-dailydosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in femalehypertensive patients. However, there was no difference in the half-life and accumulation ofirbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and Cmax valueswere also somewhat greater in older 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 inolder people.

Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IVadministration of 14C irbesartan, about 20% of the radioactivity is recovered in the urine, and theremainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administrationof single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg forfour weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults(twelve children over 12 years, nine children between 6 and 12 years). Results showed that Cmax, AUCand clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartandaily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once dailydosing.

In patients with renal impairment or those undergoing haemodialysis, the pharmacokinetic parametersof irbesartan are not significantly altered. Irbesartan is not removed by haemodialysis.

In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are notsignificantly altered.

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

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. Innon-clinical safety studies, high doses of irbesartan (≥ 250 mg/kg/day in rats and ≥ 100 mg/kg/day inmacaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit).

At very high doses (≥ 500 mg/kg/day) degenerative changes in the kidney (such as interstitialnephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea andcreatinine) were induced by irbesartan in the rat and the macaque and are considered secondary to thehypotensive effects of the medicinal product which led to decreased renal perfusion. Furthermore,irbesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells (in rats at ≥ 90 mg/kg/day, inmacaques at ≥ 10 mg/kg/day). All of these changes were considered to be caused by thepharmacological action of irbesartan. For therapeutic doses of irbesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not appear to have any relevance.

There was no evidence of mutagenicity, clastogenicity or carcinogenicity.

Fertility and reproductive performance were not affected in studies of male and female rats even atoral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), includingmortality at the highest dose. No significant effects on the number of corpora lutea, implants, or livefoetuses were observed. Irbesartan did not affect survival, development, or reproduction of offspring.

Studies in animals indicate that the radiolabelled irbesartan is detected in rat and rabbit foetuses.

Irbesartan is excreted in the milk of lactating rats.

Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation,hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits,abortion or early resorption were noted at doses causing significant maternal toxicity, includingmortality. No teratogenic effects were observed in the rat or rabbit.

Microcrystalline cellulose

Croscarmellose sodium

Lactose monohydrate

Magnesium stearate

Colloidal hydrated silica

Pregelatinised maize starch

Poloxamer 188

Not applicable.

3 years.

Do not store above 30°C.

Cartons of 14 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 28 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 56 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 98 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 56 x 1 tablet in PVC/PVDC/Aluminium perforated unit dose blisters.

Not all pack sizes may be marketed.

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

Zentiva k.s.

U kabelovny 130102 37 Prague 10

Czech Republic

EU/1/06/376/006-010

Date of first authorisation: 19 January 2007

Date of latest renewal: 20 January 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu