Irbecard 75 mg, 150 mg and 300 mg FC tablets.

IRBECARD is indicated for the treatment of essential hypertension. It may be used either alone or in combination with other antihypertensive medicines. IRBECARD is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (> 300 mg/day) in patients with type 2 diabetes and hypertension.

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. In patients insufficiently controlled with 150 mg once daily, the dose of IRBECARD may be increased to 300 mg, or other antihypertensive medicines may be added. In patients with hypertension and type 2 diabetic renal disease, 300 mg of IRBECARD once daily is the preferred maintenance dose.

Special populations

Elderly patients and patients with renal or hepatic impairment
No dosage reduction is generally necessary in the elderly or in patients with impaired renal function or impaired hepatic function (mild to moderate degree).

Patients with intravascular volume depletion
See section 4.4: u2018 Intravascular volume depletionu2019.

Paediatric population
Safety and efficacy in paediatric patients have not been established.

Method of administration
For oral use.

IRBECARD is contraindicated in patients who have the following:

• hypersensitivity to irbesartan or to any of the ingredients of IRBECARD.
• a history of angioedema related to previous therapy with angiotensin receptor blockers (ARBs) or angiotensin converting enzyme inhibitors (ACEIs): these patients must never again be given these medicines.
• hereditary or idiopathic angioedema.
• hypertrophic obstructive cardiomyopathy (HOCM).
• severe renal function impairment (creatinine clearance less than 30 mL/min).
• moderate to severe renal impairment, and concomitantly using fluoroquinolones.
• bilateral renal artery stenosis.
• renal artery stenosis in patients with single kidney, or a transplanted kidney.
• aortic stenosis.
• concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene, amiloride.
• porphyria.
• lithium therapy: concomitant administration with IRBECARD may lead to toxic blood concentrations of lithium (see sections 4.4 and 4.5).
• pregnancy and lactation (see sections 4.4 and 4.6).
• the concomitant use of IRBECARD with aliskiren-containing products (see sections 4.4 and 4.5).

Should a woman become pregnant while receiving IRBECARD, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).

Intravascular volume depletion
IRBECARD has been associated with hypotension in hypertensive patients without other co-morbid conditions. 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 IRBECARD or a lower starting dose (IRBECARD 75 mg) should be considered (See section 4.2).

Renal impairment and kidney transplantation
When IRBECARD is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended (see section 4.5). As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. There is no experience regarding the administration of IRBECARD in patients with a recent kidney transplantation.

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 medicines that affect the renin-angiotensin-aldosterone system. While this is not documented with IRBECARD, a similar effect should be anticipated with angiotensin II receptor antagonists. The use of IRBECARD in patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney is contraindicated (see section 4.3).

Fluoroquinolones and ARBs
Concomitant use of fluoroquinolones and ARBs such as IRBECARD may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ARBs such as IRBECARD whether used separately and/or concomitantly.

Lithium
The combination of lithium and IRBECARD is contraindicated (see sections 4.3 and 4.5).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
Special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy (see section 4.3).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors or angiotensin II receptor blockers such as IRBECARD is therefore not recommended (see section 4.5). ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. IRBECARD should not be used concomitantly with aliskiren (see section 4.3).

Hyperkalaemia
Hyperkalaemia may occur during the treatment with IRBECARD, 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).

Primary aldosteronism
Patients with primary aldosteronism generally will not respond to antihypertensive medicines acting through inhibition of the renin-angiotensin system. Therefore, the use of IRBECARD 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, uraemia, oliguria, or acute renal failure (see section 4.5). Excessive blood pressure decreases in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

Lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption, should not take IRBECARD.

Fluoroquinolones
Concomitant use of ARBs as in IRBECARD and fluoroquinolones may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Potassium supplements and potassium-sparing diuretics
Based on experience with the use of other medicines that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicines 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). The use of potassium-sparing diuretics with IRBECARD is contraindicated (see section 4.3).

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 reported with IRBECARD so far. Therefore, this combination is contraindicated (see section 4.3).

Non-steroidal anti-inflammatory drugs
When angiotensin II antagonists are administered simultaneously with nonsteroidal anti-inflammatory drugs (NSAIDs) (i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. 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. These effects may be reversible. The combination should be administered with caution, especially in the elderly, volume-depleted (including those on diuretic therapy) or with compromised renal function. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Diuretics and other antihypertensive medicines
Other antihypertensive medicines may increase the hypotensive effects of irbesartan; however IRBECARD has been safely administered with other antihypertensive medicines, 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 IRBECARD (see section 4.4).

Dual blockade of the RAAS with ARBs and 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 associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting medicine (see section 4.4).

Additional information on IRBECARD interactions
The pharmacokinetics of IRBECARD is not affected by nifedipine or hydrochlorothiazide. IRBECARD is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significantly pharmacokinetic or pharmacodynamic interactions are observed when IRBECARD is co-administered with warfarin, a medicine metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetics of IRBECARD have not been evaluated. The pharmacokinetics of digoxin or simvastatin are not altered by co-administration of IRBECARD.

Women of childbearing potential
Women of childbearing age should ensure effective contraception.

Pregnancy
Safety in pregnancy has not been established (see sections 4.3 and 4.4). When pregnancy is planned or confirmed, IRBECARD should be discontinued. Medicines affecting the renin-angiotensin system, such as IRBECARD, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered in pregnant women. Patients planning pregnancy should be changed to alternative antihypertensive treatments, which have an established safety profile for use in pregnancy.

Breastfeeding
Safety in lactation has not been established. It is unknown whether irbesartan or its metabolites are excreted in human milk. Available pharmacodynamics/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk.

Fertility
IRBECARD had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity.

IRBECARD may cause dizziness and fatigue which may affect the ability to drive and use machines. Caution is advised before driving or operating machinery until the effects of IRBECARD are known.

The following adverse reactions have been reported during clinical trials in patients with hypertension:

Nervous system disorders
Frequent : dizziness, headache

Cardiac disorders
Less frequent : tachycardia

Vascular disorders
Less frequent : flushing

Respiratory, thoracic and mediastinal disorders
Less frequent : cough

Gastrointestinal disorders
Frequent : nausea, vomiting
Less frequent : diarrhoea, dyspepsia/heartburn

Hepatobiliary disorders
Less frequent : jaundice

Reproductive system and breast disorders
Less frequent : sexual dysfunction

General disorders and administration site conditions
Frequent : fatigue
Less frequent: chest pain

Investigations
No clinically significant changes in laboratory test parameters occurred in controlled clinical studies of hypertension. No special monitoring of laboratory parameters is necessary for patients with essential hypertension receiving therapy with IRBECARD.

Other
Frequency unknown: Oedema

The following adverse reactions have been reported during clinical trials in patients with hypertension and type 2 diabetic renal disease:

Nervous system disorders
Frequent : dizziness, orthostatic dizziness

Vascular disorders
Frequent: orthostatic hypotension

Musculoskeletal and connective tissue disorders
Frequent: musculoskeletal pain

Investigations
Frequent : hyperkalaemia, increased plasma creatine kinase, decrease in haemoglobin

1 None of these increases were associated with identifiable clinical musculoskeletal events.

2 In hypertensive patients with advanced diabetic renal disease treated with irbesartan. The decrease in haemoglobin was not clinically significant.

The following adverse reactions have been reported during post-marketing experience:

Blood and lymphatic system disorders
Frequency unknown: thrombocytopenia

Immune system disorders
Frequency unknown: hypersensitivity reactions (such as angioedema, rash, urticaria, anaphylactic reaction, anaphylactic shock)

Metabolism and nutrition disorders
Frequency unknown: hyperkalaemia

Nervous system disorders
Frequency unknown: vertigo, headache

Ear and labyrinth disorders
Frequency unknown: tinnitus

Gastrointestinal disorders
Frequency unknown: dysguesia

Hepatobiliary disorders
Frequency unknown: abnormal liver function, jaundice, hepatitis

Skin and subcutaneous tissue disorders
Frequency unknown: leukocytoclastic vasculitis

Musculoskeletal and connective tissue disorders
Frequency unknown: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps

Renal and urinary disorders
Frequency unknown: Impaired renal function including cases of renal failure of patients at risk (see section 4.4)

General disorders and administration site conditions
Frequency unknown: asthenia

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after authorisation of IRBECARD is important. It allows continued monitoring of the benefit/risk balance of IRBECARD. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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 expected to be hypotension and tachycardia; bradycardia might also occur from overdose. No specific information is available on the treatment of overdosage with IRBECARD. The patient should be closely monitored and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis. Activated charcoal may be useful in the treatment of overdose. IRBECARD is not removed by haemodialysis.