IFIRMASTA 300mg tablets medication leaflet

Ifirmasta 75 mg film-coated tablets

Ifirmasta 150 mg film-coated tablets

Ifirmasta 300 mg film-coated tablets

Ifirmasta 75 mg film-coated tablets

Each film-coated tablet contains 75 mg irbesartan (as hydrochloride).

Ifirmasta 150 mg film-coated tablets

Each film-coated tablet contains 150 mg irbesartan (as hydrochloride).

Ifirmasta 300 mg film-coated tablets

Each film-coated tablet contains 300 mg irbesartan (as hydrochloride).

Ifirmasta 75 mg film-coated tablets

Each film-coated tablet contains 4 mg castor oil.

Ifirmasta 150 mg film-coated tablets

Each film-coated tablet contains 8 mg castor oil.

Ifirmasta 300 mg film-coated tablets

Each film-coated tablet contains 16 mg castor oil.

For the full list of excipients, see section 6.1.

Film-coated tablet.

White, oval tablets.

Ifirmasta 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.

Ifirmasta at a dose of 150 mg once daily generally provides a better 24 hour blood pressure controlthan 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 Ifirmasta can be increased to300 mg, or other antihypertensive agents can be added (see sections pct. 4.3, pct. 4.4, 4.5 and 5.1). Inparticular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additiveeffect with Ifirmasta (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 Ifirmasta in hypertensive type 2 diabetic patients is based onstudies where irbesartan was used in addition to other antihypertensive agents, as needed, to reachtarget blood pressure (see sections pct. 4.3, pct. 4.4, 4.5 and 5.1).

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

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

The safety and efficacy of Ifirmasta in children aged 0 to 18 has not been established. Currentlyavailable data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can bemade.

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 Ifirmasta with aliskiren-containing products is contraindicated in patients withdiabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/orsodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Suchconditions should be corrected before the administration of Ifirmasta.

Renovascular hypertension

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateralrenal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinalproducts that affect the renin-angiotensin-aldosterone system. While this is not documented with

Ifirmasta, a similar effect should be anticipated with angiotensin-II receptor antagonists.

When Ifirmasta is used in patients with impaired renal function, a periodic monitoring of potassiumand creatinine serum levels is recommended. There is no experience regarding the administration of

Ifirmasta in patients with a recent kidney transplantation.

Hypertensive patients with type 2 diabetes and renal disease

The effects of irbesartan both on renal and cardiovascular events were not uniform across allsubgroups, in an analysis carried out in the study with patients with advanced renal disease. Inparticular, they appeared less favourable in women and non-white subjects (see section 5.1).

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers oraliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (includingacute 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 specialistsupervision 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 withdiabetic nephropathy.

Hyperkalemia

As with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalemiamay occur during the treatment with Ifirmasta, especially in the presence of renal impairment, overtproteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium inpatients at risk is recommended (see section 4.5).

Irbesartan may induce hypoglycaemia, particularly in diabetic patients. In patients treated with insulinor antidiabetics an appropriate blood glucose monitoring should be considered; a dose adjustment ofinslulin or antidiabetics may be required when indicated (see section 4.5).

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists,including irbesartan (see section 4.8). These patients presented with abdominal pain, nausea, vomitingand diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. Ifintestinal angioedema is diagnosed, irbesartan should be discontinued and appropriate monitoringshould be initiated until complete resolution of symptoms has occurred.

The combination of lithium and Ifirmasta is not recommended (see section 4.5).

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitralstenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal productsacting through inhibition of the renin-angiotensin system. Therefore, the use of Ifirmasta is notrecommended.

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 renaldisease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors orangiotensin-II receptor antagonists that affect this system has been associated with acute hypotension,azotaemia, oliguria, or rarely acute renal failure (see section 4.5). As with any antihypertensive agent,excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovasculardisease 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).

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unlesscontinued AIIRA therapy is considered essential, patients planning pregnancy should be changed toalternative antihypertensive treatments which have an established safety profile for use in pregnancy.

When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, ifappropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data areinsufficient to support an extension of the use in children until further data become available (seesections 4.8, 5.1 and 5.2).

Diuretics and other antihypertensive agents:

Other antihypertensive agents may increase the hypotensive effects of irbesartan; however Ifirmastahas been safely administered with other antihypertensive agents, such as beta-blockers, long-actingcalcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result involume depletion and a risk of hypotension when initiating therapy with Ifirmasta (see section 4.4).

Aliskiren-containing products or ACE-inhibitors:

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 associatedwith a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renalfunction (including acute renal failure) compared to the use of a single RAAS-acting agent (seesections pct. 4.3, pct. 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 containingpotassium or other medicinal products that may increase serum potassium levels (e.g. heparin) maylead to increases in serum potassium and is, therefore, not recommended (see section 4.4).

Rreversible 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 medicinal products:

When angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory medicinal products (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) andnon-selective NSAIDs), attenuation of the antihypertensive effect may 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 that irbesartanincreased 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 irbesartan is not affected by hydrochlorothiazide. Irbesartanis mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significantpharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministeredwith warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such asrifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic ofdigoxin was not altered by coadministration of irbesartan.

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 Ifirmasta during breast-feeding, Ifirmasta isnot 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 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 medicinal product reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*)refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patientswith chronic renal insufficiency and overt proteinuria and in excess of placebo.

The frequency of adverse reactions listed below is defined using the following convention:very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable 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: anemia, 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 overdosage are expected to be hypotension and tachycardia; bradycardiamight also occur from overdose. No specific information is available on the treatment of overdosagewith Ifirmasta. The patient should be closely monitored, and the treatment should be symptomatic andsupportive. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoalmay be useful in the treatment of overdosage. Irbesartan is not removed by haemodialysis.

Pharmacotherapeutic group: angiotensin II antagonist, plain, ATC code: C09CA04.

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 require metabolic 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 twice dailydosing on the same total dose.

The blood pressure lowering effect of irbesartan is evident within 1-2 weeks, with the maximal effectoccurring by 4-6 weeks after start of therapy. The antihypertensive effects are maintained during longterm therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Reboundhypertension 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 is not influenced by age or gender. As is the case with other medicinalproducts that affect the renin-angiotensin system, black hypertensive patients have notably lessresponse to irbesartan monotherapy. When irbesartan is administered concomitantly with a low doseof hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive response in black patients approachesthat 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, amlodipine and placebo. In 1,715hypertensive patients with type 2 diabetes, proteinuria ≥ 900 mg/day and serum creatinine rangingfrom 1.0-3.0 mg/dl, the long-term effects (mean 2.6 years) of irbesartan on the progression of renaldisease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenancedose of 300 mg irbesartan, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated.

Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g.,diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of ≤ 135/85 mmHgor a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) ofpatients in the placebo group reached this target blood pressure whereas this figure was 76% and 78%in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative riskin the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) orallcause mortality. Approximately 33% of patients in the irbesartan group reached the primary renalcomposite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relativerisk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p =0.006)]. When the individual components of the primary endpoint were analysed, no effect in all causemortality was observed, while a positive trend in the reduction in ESRD and a significant reduction indoubling 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 the irbesartan-based regimenversus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in theoverall population. However, no proper explanation for these findings in women has been identified.

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

Diabetes Mellitus (IRMA 2)” shows that irbesartan 300 mg delays progression to overt proteinuria 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 on the progression to clinical (overt) proteinuria (urinary albuminexcretion rate (UAER) > 300 mg/day, and an increase in UAER of at least 30% from baseline). Thepredefined blood pressure goal was ≤ 135/85 mmHg. Additional antihypertensive agents (excluding

ACE inhibitors, angiotensin II receptor antagonists and dihydropyridine calcium blockers) were addedas needed to help achieve the blood pressure goal. While similar blood pressure was achieved in alltreatment groups, fewer subjects in the irbesartan 300 mg group (5.2%) than in the placebo (14.9%) orin 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 accompanyingimprovement in the glomerular filtration rate (GFR) was not observed during the first three months oftreatment. The slowing in the progression to clinical proteinuria was evident as early as three monthsand continued over the 2 year period. Regression to normoalbuminuria (< 30 mg/day) was morefrequent in the irbesartan 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 of cardiovascular or cerebrovasculardisease, 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 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 the cytochrome

P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect.

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

A less than proportional increase in oral absorption at doses beyond 600 mg (twice the 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 157-176and 3-3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11-15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen.

Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. Ina study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensivepatients. However, there was no difference in the half-life and accumulation of irbesartan. No dosageadjustment is necessary in female patients. Irbesartan AUC and Cmax values were also somewhatgreater in older subjects (≥ 65 years) than those of young subjects (18-40 years). However the terminalhalflife was not significantly altered. No dosage adjustment is necessary in older people.

Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or 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,

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

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.

Mannitol

Hydroxypropylcellulose

Low-substituted Hydroxypropyl Cellulose (LH-21)

Low-substituted Hydroxypropyl Cellulose (LH-11)

Talc

Macrogol 6000

Castor oil, hydrogenated

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3000

Talc

Not applicable.

5 years

Do not store above 30°C. Store in the original package in order to protect from moisture.

Blister (PVC/PE/PVDC/Alu): 14, 28, 30, 56, 84, 90 or 98 film-coated tablets in box are available.

Blister (PVC/PE/PVDC/Alu): 56 x 1 film-coated tablets in perforated unit dose blisters in box.

Not all pack sizes may be marketed.

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

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Ifirmasta 75 mg film-coated tablets14 tablets: EU/1/08/480/00128 tablets: EU/1/08/480/00230 tablets: EU/1/08/480/01956 tablets: EU/1/08/480/00356 x 1 tablets: EU/1/08/480/00484 tablets: EU/1/08/480/00590 tablets: EU/1/08/480/02098 tablets: EU/1/08/480/006

Ifirmasta 150 mg film-coated tablets14 tablets: EU/1/08/480/00728 tablets: EU/1/08/480/00830 tablets: EU/1/08/480/02156 tablets: EU/1/08/480/00956 x 1 tablets: EU/1/08/480/01084 tablets: EU/1/08/480/01190 tablets: EU/1/08/480/02298 tablets: EU/1/08/480/012

Ifirmasta 300 mg film-coated tablets14 tablets: EU/1/08/480/01328 tablets: EU/1/08/480/01430 tablets: EU/1/08/480/02356 tablets: EU/1/08/480/01556 x 1 tablets: EU/1/08/480/01684 tablets: EU/1/08/480/01790 tablets: EU/1/08/480/02498 tablets: EU/1/08/480/018

Date of first authorisation: 1 December 2008

Date of latest renewal: 26 August 2013

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

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