Angiotensin II antagonists (angiotensin II receptor antagonists)

Irbesartan

Aprovel 75 mg film-coated tablets. Aprovel 150 mg film-coated tablets. Aprovel 300 mg film-coated tablets

Film-coated tablet. Aprovel 75 mg White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2871 engraved on the other side. Aprovel 150 mg White to off-white, biconvex, and oval-shaped with a heart debossed on one side and the number 2872 engraved on the other side. Aprovel 300 mg White to off-white biconvex, and oval-shaped with a heart debossed on one side and the number 2873 engraved on the other side.

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

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

In patients insufficiently controlled with 150 mg once daily, the dose of Aprovel can be increased to 300 mg, or other anti-hypertensive agents can be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with Aprovel.

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

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

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.

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

Not recommended.

Over 75 years, consider starting dose of 75 mg once daily then titrate according to response.

Hypersensitivity to the active substance, or to any of the excipients

Second and third trimester of pregnancy

Lactation

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

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

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

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

Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended.

Lithium: the combination of lithium and Aprovel is not recommended.

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

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

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensinII receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any anti-hypertensive 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.

Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive 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.

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.

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

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.

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. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

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

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

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

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

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

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

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

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

Investigations:

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

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

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

Cardiac disorders:

Uncommon: tachycardia

Nervous system disorders:

Common: dizziness, orthostatic dizziness*

Respiratory, thoracic and mediastinal disorders:

Uncommon: cough

Gastrointestinal disorders:

Common: nausea/vomiting

Uncommon: diarrhoea, dyspepsia/heartburn

Musculoskeletal and connective tissue disorders:

Common: musculoskeletal pain*

Vascular disorders:

Common: orthostatic hypotension*

Uncommon: flushing

General disorders and administration site conditions:

Common: fatigue

Uncommon: chest pain

Reproductive system and breast disorders:

Uncommon: sexual dysfunction

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

Nervous system disorders:

Headache

Ear and labyrinth disorders:

Tinnitus

Gastrointestinal disorders:

Dysgeusia

Renal and urinary disorders:

Impaired renal function including cases of renal failure in patients at risk

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-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients.

Bristol-Myers Squibb/Sanofi- Synthelabo

(POM)