Irbesartan BMS - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 75 mg of irbesartan.

Excipient: 15.37 mg of lactose monohydrate per tablet.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

White to off-white, biconvex, and oval-shaped engraved on the other side.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Treatment of essential hypertension.

Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see section 5.1).

4.2 Posology and method of administration

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Irbesartan BMS at a dose of 150 mg odaily generally provides a better 24 hour blood pressure control than 75 mg. However, initiatio therapy with 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years.

with 150 mg once daily, the dose of Irbesartan BMS can be antihypertensive agents can be added. In particular, the addition of a rothiazide has been shown to have an additive effect with Irbesartan BMS

In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily

o 300 mg once daily as the preferred maintenance dose for treatment of renal disease.

The demonstration of renal benefit of Irbesartan BMS in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure (see section 5.1).

Renal impairment : no dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing haemodialysis (see section 4.4).

Hepatic impairment : no dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.

Elderly patients : although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.

Paediatric patients : irbesartan is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see sections 4.8, 5.1 and 5.2).

4.3 Contraindications

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).

4.4 Special warnings and precautions for use

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

Renovascular hypertension : there is an increased risk of severe hypotension and renal i when patients with bilateral renal artery stenosis or stenosis of the artery to a single are treated with medicinal products that affect the renin-angiotensin-aldosterone sys not documented with Irbesartan BMS, a similar effect should be anticipated with angiotensin-II receptor antagonists.

Renal impairment and kidney transplantation : when Irbesartan BMS is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Irbesartan BMS in patients with a recent kidney transplantation.

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

Hyperkalaemia : as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Irbesartan BMS, 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).

ium and Irbesartan BMS is not recommended (see section 4.5).

nosis, obstructive hypertrophic cardiomyopathy : as with other vasodilators, icated in patients suffering from aortic or mitral stenosis, or obstructive yopathy.

Primary aldosteronism : patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Irbesartan BMS is not recommended.

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

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

Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Lactose : this medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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

4.5 Interaction with other medicinal products and other forms of interaction

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

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

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

Non-steroidal anti-inflammatory drugs : when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Additional information on irbesartan interactions : in clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothi­azide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetic of irbesartan have not been evaluated. The pharmacokinetic of digoxin was not altered by coadministration of irbesartan.

4.6 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).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human

fetotoxicity (decreased renal function, oligohydramnios, skull ossification ret toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3). Should exposure to AIIRAs have occurred from the second trimester o of renal function and skull is recommended.

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

Lactation:

Because no information is available regarding the use of Irbesartan BMS during breast-feeding, Irbesartan BMS is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

• 4.7 Effects on ability to drive and

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

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

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

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

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

very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Vascular disorders:

General disorde.

Common:

Uncommon:

Reproductive system and breast disorders:

Uncommon: sexual dysfunction

The following additional adverse reactions have been reported during post-marketing experience; they are derived from spontaneous reports and therefore, the frequency of these adverse reactions is not known:

Nervous system disorders: Headache

Ear and labyrinth disorders: Tinnitus

Gastrointestinal disorders:

Dysgeusia

Renal and urinary disorders:

Impaired renal function including cases of renal failure in patients at risk (see section 4.4)

Skin and subcutaneous tissue disorders:

Leukocytoclastic vasculitis

Musculoskeletal and connective tissue disorders:

Arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps

Metabolism and nutrition disorders: Hyperkalaemia

Immune system disorders:

Hypersensitivity reactions such as angioedema, rash, urticaria

Hepato-biliary disorders:

Hepatitis, abnormal liver function

Paediatric patients : in a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following related adverse events occurred in the 3– double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). 26-week open-label period of this trial the most frequent laboratory abnormalities observed wer tinine 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 expeo be hypotension and tachycardia; bradycardia might also occur from overdose. No specific ation is available on the treatment of overdose with Irbesartan BMS. 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 teatment of overdose. Irbesartan is not removed by haemodialysis.

Mechanism of action : Irbesartan is a potent, orally active, selective angiotensin-II receptor (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 and angiotensin-II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase-II), an enzyme which generates angiotensin-II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.

Clinical efficacy :

Hypertension

Irbesartan lowers blood pressure with minimal change in heart rate. The decrease in blood pressure is dose-related for once a day doses with a tendency towards plateau at doses above 300 mg. Doses of 150–300 mg once daily lower supine or seated blood pressures at trough (i.e. 24 hours after dosing) by an average of 8–13/5–8 mm Hg (systolic/dias­tolic) greater than those associated with placebo.

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

The blood pressure lowering effect of Irbesartan BMS 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 towar Rebound hypertension has not been observed.

The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at

trough of 7–10/3–6 mm Hg (systolic/dias­tolic).

The efficacy of Irbesartan BMS is not influenced by age or gender. As is

products that affect the renin-angiotensin system, black hypertensive response to irbesartan monotherapy. When irbesartan is administered of hydrochlorothiazide (e.g. 12.5 mg daily), the antihypertensive resp that of white patients.

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

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

Hypertension and type 2 diabetes with renal disease

The “Irbesartan Diabetic Nephropathy Trial (IDNT)” shows that irbesartan decreases the progression of renal disease in patients with chronic renal insufficiency and overt proteinuria. IDNT was a double

d, morbidity and mortality trial comparing Irbesartan BMS, amlodipine and placebo. In 1,715 hypertensive patients with type 2 diabetes, proteinuria > 900 mg/day and serum creatinine ranging from 1.0–3.0 mg/dl, the long-term effects (mean 2.6 years) of Irbesartan BMS on the progression of renal disease and all-cause mortality were examined. Patients were titrated from 75 mg to a maintenance dose of 300 mg Irbesartan BMS, from 2.5 mg to 10 mg amlodipine, or placebo as tolerated. Patients in all treatment groups typically received between 2 and 4 antihypertensive agents (e.g., diuretics, beta blockers, alpha blockers) to reach a predefined blood pressure goal of < 135/85 mmHg or a 10 mmHg reduction in systolic pressure if baseline was > 160 mmHg. Sixty per cent (60%) of patients in the placebo group reached this target blood pressure whereas this figure was 76% and 78% in the irbesartan and amlodipine groups respectively. Irbesartan significantly reduced the relative risk in the primary combined endpoint of doubling serum creatinine, end-stage renal disease (ESRD) or all-cause mortality. Approximately 33% of patients in the irbesartan group reached the primary renal composite endpoint compared to 39% and 41% in the placebo and amlodipine groups [20% relative risk reduction versus placebo (p = 0.024) and 23% relative risk reduction compared to amlodipine (p = 0.006)]. When the individual components of the primary endpoint were analysed, no effect in all cause mortality was observed, while a positive trend in the reduction in ESRD and a significant reduction in doubling of serum creatinine were observed.

Subgroups consisting of gender, race, age, duration of diabetes, baseline blood pressure, serum creatinine, and albumin excretion rate were assessed for treatment effect. In the female and black subgroups which represented 32% and 26% of the overall study population respectively, a renal

benefit was not evident, although the confidence intervals do not exclude it. As for the secondary endpoint of fatal and non-fatal cardiovascular events, there was no difference among the three groups in the overall population, although an increased incidence of non-fatal MI was seen for women and a decreased incidence of non-fatal MI was seen in males in the irbesartan group versus the placebobased regimen. An increased incidence of non-fatal MI and stroke was seen in females in the irbesartan-based regimen versus the amlodipine-based regimen, while hospitalization due to heart failure was reduced in the overall population. However, no proper explanation for these findings in women has been identified.

5.2 Pharmacokinetic propertie

Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg. A less than proportional increase in oral absorption at doses beyond 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5–2 hours after oral administration. The total body and renal clearance are 157–176 and 3–3.5 ml/min, respectively. The terminal elimination half-life of irbesartan is 11–15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (< 20%) is observed in plasma upon repeated once-daily dosing. In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and 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         C irbesartan, about 20% of the radioactivity is recovered in the urine, and the remainder in the faeces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.

The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that 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 haemodialysi pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not haemodialysis.

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

Studies have not been performed in patients with severe hepatic impai

5.3 Preclinical safety data

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In non-clinical safety studies, high doses of irbesartan (> 250 mg/kg/day in rats and > 100 mg/kg/day in macaques) caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). At very high doses (> 500 mg/kg/day) degenerative changes in the kidney (such as interstitial nephritis, tubular distension, basophilic tubules, increased plasma concentrations of urea and

d the macaque and are considered secondary to the led to decreased renal perfusion. Furthermore,

irbesartan induced hyperplasia/hypertr     of the juxtaglomerular cells (in rats at > 90 mg/kg/day, in

macaques at > 10 mg/kg/day). All oe changes were considered to be caused by the pharmacological action of irbesarta. For therapeutic doses of irbesartan in humans, the hyperplasia/ hypertrophy of the renal juomerular cells does not appear to have any relevance.

agenicity, clastogenicity or carcinogenicity.

Animal studies with irbesartan showed transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous oedema) in rat foetuses, which were resolved after birth. In rabbits, abortion or early resorption were noted at doses causing significant maternal toxicity, including

ratogenic effects were observed in the rat or rabbit.

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Cartons of 14 tablets: 1 blister card of 14 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 28 tablets: 2 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 56 tablets: 4 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 98 tablets: 7 blister cards of 14 tablets in PVC/PVDC/Aluminium blisters.

Cartons of 56 × 1 tablet; 7 blister cards of 8 × 1 tablet each in PVC/PVDC/Alu dose blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed

7. MARKETING AUTHORISATION HO

8.  MARKETING AU

RST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 January 2007 Date of latest renewal:

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency (EMEA)