Treatment of essential hypertension. Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive drug regimen.

Angiotensin-ll receptor blocker

Irbesartan is an angiotensin II receptor antagonist. It blocks the vasoconstricting and aldosterone-secreting effects of angiotensin II by binding to AT1 receptors.

Adult: The usual recommended initial and maintenance dose is Irbesartan 150 mg once daily, with or without food. Irbesartan 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 Irbesartan 75 mg could be considered, particularly in haemodialysed patients and in the elderly over 75 years. In patients insufficiently controlled with Irbesartan 150 mg once daily, the dose of Irbesartan can be increased to Irbesartan 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 Irbesartan. In hypertensive type 2 diabetic patients, therapy should be initiated at Irbesartan 150 mg once daily and titrated up to Irbesartan 300 mg once daily as the preferred maintenance dose for treatment of renal disease. The demonstration of renal benefit of Irbesartan 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.

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

Paediatric: Irbesartan is not recommended for use in children and adolescents due to insufficient data on safety and efficacy.

Diuretics and other antihypertensive agents: prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with Irbesartan.

Potassium supplements and potassium-sparing diuretics: based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassiumsparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs 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. 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 drug 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.

Concomitant use with aliskiren in patients with diabetes and renal impairment (GFR <60 ml/min). Pregnancy.

Diarrhoea, fatigue, dyspepsia or heartburn, dizziness, orthostatic hypotension, nausea, vomiting, musculoskeletal pain, thrombocytopaenia, hyperkalaemia, elevated serum creatinine.

Pregnancy: Irbesartan is contraindicated in the second and third trimesters of pregnancy. In the second and third trimesters, substances that act directly on the renin-angiotensin-system can cause foetal or neonatal renal failure, foetal skull hypoplasia and even foetal death. As precautionary measure, irbesartan should preferably not be used during first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy. If pregnancy is diagnosed, irbesartan should be discontinued as soon as possible, skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.

Lactation: Irbesartan is contraindicated during lactation. It is not known whether irbesartan is excreted in human milk. Irbesartan is excreted in the milk of lactating rats. Precautions: 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.

Patients with unilateral or bilateral renal artery stenosis, depletion of intravascular volume, aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. Renal impairment. Lactation.

Renal impairment: no dosage adjustment is necessary in patients with impaired renal function. A lower starting dose of Irbesartan 75 mg should be considered for patients undergoing haemodialysis. Intravascular volume depletion: volume and/or sodium depletion should be corrected prior to administration of Irbesartan.

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.

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 drugs that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Irbesartan, 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.

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 drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Irbesartan is not recommended.

General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensinaldosterone 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 anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

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

Store in a cool and dry place, protected from light.