Atacand Tablets

ATACAND is indicated for mild to moderate hypertension. ATACAND can be used as monotherapy or in combination with other antihypertensive agents such as thiazide diuretics and dihydropyridine calcium antagonists, for enhanced efficacy. Heart failure Treatment with ATACAND reduces mortality, reduces hospitalisation due to heart failure, and improves symptoms in patients with left ventricular systolic dysfunction (LVEF u2264 40 %).

Dosage in hypertension The recommended initial dose of ATACAND is 8 mg once daily. The usual maintenance dose is 8 mg to 16 mg once daily. The maximal antihypertensive effect is attained within 4 weeks of initiation of treatment. Some patients may receive an additional benefit by increasing the dose to 32 mg once daily. Use in elderly No initial dosage adjustment is necessary for elderly patients with normal renal and hepatic function.

Use in impaired renal function No initial dosage adjustment is necessary in patients with mild to moderate renal impairment (i.e. creatinine clearance u2265 30 mL/min/1,73mu00b2 BSA). In patients with more severe renal impairment (i.e. creatinine clearance < 15 u2013 30 mL/min/1,73 mu00b2 BSA), the clinical experience is limited, and a lower initial dose of 4 mg should be used. Use in impaired hepatic function No initial dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no experience available in patients with severe hepatic impairment and/or cholestasis (see section 4.3).

Concomitant therapy ATACAND can be used as monotherapy or in combination with other antihypertensive medicines, such as thiazide diuretics and dihydropyridine calcium antagonists, e.g. amlodipine, for enhanced efficacy. Use in black patients The antihypertensive effect of ATACAND is less in black than non-black (Caucasian, Asian and other) patients. Consequently, up-titration of ATACAND and concomitant therapy (such as thiazide diuretics) may be more frequently needed for blood pressure control in black than non-black patients.

Dosage in heart failure The usual recommended initial dose of ATACAND is 4 mg once daily. Up-titration to the target dose of 32 mg once daily or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks (see section 4.4). Special patient populations No initial dose adjustment is necessary for elderly patients or in patients with renal or mild to moderate hepatic impairment.

Concomitant therapy ATACAND can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicines (see section 5.1). Paediatric population The safety and efficacy of ATACAND have not been established in children. Method of administration For oral use. ATACAND should be taken once daily with or without food.

• Hypersensitivity to candesartan cilexetil or to any of the excipients listed in section 6.1.
• Severe renal function impairment (creatinine clearance < 30 mL/min) (see section 4.4).
• Second and third trimester of pregnancy and lactation (see sections 4.4 and 4.6).
• Severely impaired hepatic function and/or cholestasis.
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic valve stenosis.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBu2019s). These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic Obstructive Cardiomyopathy (HOCM).
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Porphyria.
• Lithium therapy: concomitant administration with ATACAND may lead to toxic blood concentrations of lithium (see section 4.5).
• Children aged below 1 year (see section 5.3)
• The concomitant use with aliskiren - containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1,73mu00b2) (see sections 4.4 and 4.5).
• Concomitant use of fluoroquinolones with ACE inhibitors/Renin - Angiotensin blockers is contraindicated in patients with moderate to severe renal impairment.

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

Dual blockade of the renin - angiotensin - aldosterone system (RAAS) There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers (ARBs) or aliskiren may increase the risk of hypotension, hyperkalaemia and decreases renal function (including renal failure). Dual blockade of RAAS through combined use of ATACAND and aliskiren is therefore contraindicated (see section 4.3). ATACAND should not be used concomitantly with aliskiren (see section 4.3). ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Intestinal angioedema Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including candesartan, the active ingredient of Atacand (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists.

If intestinal angioedema is diagnosed, candesartan, the active ingredient of Atacand, should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Renal impairment Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury (AKI), 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 ACE inhibitors/renin-angiotensin receptor blockers. When ATACAND is used in hypertensive patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered. There is very limited experience in patients with very severe or end-stage renal impairment (creatinine clearance < 15 mL/min/1,73 mu00b2 BSA). In these patients, ATACAND should be carefully titrated with thorough monitoring of blood pressure.

Evaluation of patients with heart failure should include periodic assessments of renal function, especially in elderly patients 75 years or older, and patients with impaired renal function. During dose titration of ATACAND, monitoring of serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine > 265 u03bc mol/L (> 3 mg/dL).

Concomitant therapy with an ACE inhibitor in heart failure The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when ATACAND is used in combination with an ACE-inhibitor. Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and ATACAND is also not recommended. Use of these combinations should be under specialist supervision 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 with diabetic nephropathy.

Haemodialysis During dialysis the blood pressure may be particularly sensitive to AT1-receptor blockade as a result of reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore, ATACAND should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.

Kidney transplantation There is no experience regarding the administration of ATACAND in patients with recent kidney transplantation.

Hypotension Hypotension may occur during treatment with ATACAND in heart failure patients. As described for other agents acting on the renin-angiotensin-aldosterone system, it may also occur in hypertensive patients with intravascular volume depletion. Caution should be observed when initiating therapy and correction of hypovolaemia should be attempted.

Anaesthesia and surgery Hypotension may occur during anaesthesia and surgery in patients treated with ATACAND due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

Primary hyperaldosteronism Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicines acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of ATACAND is not recommended.

Hyperkalaemia In heart failure patients treated with ATACAND, hyperkalaemia may occur. During treatment with ATACAND in patients with heart failure, periodic monitoring of serum potassium is recommended, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone.

Renal impairment As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with ATACAND. There is very limited experience in patients with very severe or end-stage renal impairment (i.e. creatinine clearance < 15 mL/min/1,73 mu00b2 BSA). Evaluation of patients with heart failure should include periodic assessments of renal function. During dose titration of ATACAND, monitoring of serum creatinine and potassium is 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 medicines that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. Excessive blood pressure decreases in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke. The antihypertensive effect of ATACAND may be enhanced by other medicines with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications.

Paediatric population Use in paediatric patients including patients with renal impairment ATACAND has not been studied in children with a glomerular filtration rate less than 30 mL/min/1,73mu00b2 (see section 4.2).

For children with possible intravascular volume depletion (e.g. patients treated with diuretics, particularly those with impaired renal function), ATACAND treatment should be initiated under close medical supervision and a lower starting dose should be considered (see section 4.2).

In post-menarche patients the possibility of pregnancy should be evaluated on a regular basis. Appropriate information should be given and/or action taken to prevent the risk of exposure during pregnancy (see sections 4.3 and 4.6).

ATACAND contains lactose monohydrate Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take ATACAND.

Dual blockade of the RAAS with ARBs, ACE inhibitors, or aliskiren 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 (see sections 4.3 & 4.4). Concomitant use of fluoroquinolones and ACE inhibitors/renin-angiotensin receptor blockers may precipitate acute kidney injury (AKI) (see sections 4.3 & 4.4). Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicines (e.g. heparin) may increase potassium levels. Monitoring of potassium should be undertaken as appropriate (see sections 4.3 & 4.4).

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists (AIIRAs). Use of candesartan with lithium is not recommended (see section 4.3). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

When AIIRAs are administered simultaneously with non-steroidal 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. As with ACE inhibitors, concomitant use of AIIRAs 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.

Pregnancy The use of ATACAND is not recommended during the first trimester of pregnancy (see section 4.4). The use of ATACAND is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). When used in pregnancy during the second and third trimesters, medicines that act directly on the renin-angiotensin system can cause foetal and neonatal injury and death. These medicines pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios as well as hypotension, oliguria and anuria in newborns, have been reported after administration in the second and third trimester. Cases of defective skull ossification have been observed. Premature and low birth mass can occur. Should exposure to AIIRAs have occurred from the second trimester of pregnancy, an ultrasound check of renal function and the skull is recommended.

Should a woman become pregnant while receiving ATACAND, the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should institute alternative medication. Safety in pregnancy and lactation has not been established (see section 4.3). When pregnancy is planned or confirmed, ATACAND should be discontinued. Medicines affecting the renin-angiotensin system, such as ATACAND, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. Women of childbearing age should ensure effective contraception. ATACAND is contraindicated in pregnancy (see section 4.3). Infants whose mother have taken AIIRAs should be closely observed for hypotension (see section 4.3 and 4.4).

Breastfeeding Candesartan is excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, breastfeeding should be discontinued if the use of ATACAND is considered essential (see section 4.3).

The effect of ATACAND on the ability to drive and use machines has not been studied. When driving vehicles or operating machines, it should be taken into account that dizziness or weariness may occur during treatment.

Treatment of hypertension In controlled clinical studies, adverse reactions were mild and transient. The overall incidence of adverse events showed no association with dose, age or gender. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil (3,1 %) and placebo (3,2 %). In a pooled analysis of clinical trial data, the following common (> 1/100) adverse reactions with candesartan cilexetil were reported based on an incidence of adverse events with candesartan cilexetil at least 1 % higher than the incidence seen with placebo. By this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache and respiratory infection.

The table below presents adverse reactions from clinical trials and post-marketing experience. The frequencies used in the tables throughout this section are: - Very common (u2265 1/10) - Common ( u2265 1/100 to < 1/10) - Uncommon (u2265 1/1 000 to <1/100) - Rare (u2265 1/10 000 to < 1/1 000) - Very rare (<1/10 000) - Not known (cannot be estimated from the available data).

System Organ Class Frequency Undesirable Effect Infections and infestations Common Respiratory infection Blood and lymphatic system disorders Very rare Leukopenia, neutropenia and agranulocytosis Metabolism and nutrition disorders Very rare Hyperkalaemia, hyponatraemia Nervous system disorders Common Dizziness/vertigo, headache Respiratory, thoracic and mediastinal disorders Very rare Cough Gastrointestinal disorders Very rare Nausea, intestinal angioedema Not known Diarrhoea Hepato-biliary disorders Very rare Increased liver enzymes, abnormal hepatic function or hepatitis Skin and subcutaneous tissue disorders Very rare Angioedema, rash, urticaria, pruritus Musculoskeletal and connective tissue disorders Very rare Back pain, arthralgia, myalgia Renal and urinary disorders Very rare Renal impairment, including renal failure in susceptible patients (see section 4.4) Laboratory findings Small decreases in haemoglobin have been seen. Significant increases in creatinine, urea or potassium and decrease in sodium have been observed. In patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered.

Paediatric population The safety of candesartan cilexetil was monitored in 255 hypertensive children and adolescents, aged 6 to < 18 years old, during a 4-week clinical efficacy study and a 1-year open label study (see section 5.1). In nearly all different system organ classes, the frequency of adverse events in children are within common/uncommon range. Whilst the nature and severity of the adverse events are similar to those in adults (see the table above), the frequency of all adverse events are higher in children and adolescent, particularly in: - Headache, dizziness and upper respiratory tract infection, are u201cvery commonu201d (i.e. u2265 1/10) in children and common ( u2265 1/100 to 1/10) in children and very rare (<1/10 000) in adults. - Rash is u201ccommonu201d (i.e. u2265 1/100 to < 1/10) in children and u201cvery rareu201d (<1/10 000) in adults. - Hyperkalaemia, hyponatraemia and abnormal liver function are uncommon (u2265 1/1 000 to < 1/100) in children and very rare (< 1/10 000) in adults. - Sinus arrhythmia, nasopharyngitis, pyrexia is u201ccommonu201d (i.e. u2265 1/100 to < 1/10) and oropharyngeal pain is u201cvery commonu201d (i.e. u2265 1/10) in children, but none are reported in adults. However, these are temporary and widespread childhood illnesses.

The overall safety profile for ATACAND in paediatric patients does not differ significantly from the safety profile in adults.

Treatment of heart failure The adverse experience profile of ATACAND in heart failure patients was consistent with the pharmacology of the medicine and the health status of the patients. In the CHARM clinical programme, comparing ATACAND in doses up to 32 mg (n = 3,803) to placebo (n = 3,796), 21,0 % of the candesartan cilexetil group and 16,1 % of the placebo group discontinued treatment because of adverse events. The most commonly reported adverse reactions were hyperkalaemia, hypotension and renal impairment. These events were more common in patients over 70 years of age, diabetics, or subjects who received other medicines which affect the renin-angiotensin-aldosterone system, in particular an ACE inhibitor and/or spironolactone.

The table below presents adverse reactions from clinical trials and post-marketing experience. System Organ Class Frequency Undesirable Effect Blood and lymphatic system disorders: Very rare Leukopenia, neutropenia and agranulocytosis Metabolism and nutrition disorders Common Hyperkalaemia Very rare Hyponatraemia Nervous system disorders Very rare Dizziness, headache Vascular disorders Common Hypotension Gastrointestinal disorders Very rare Nausea Hepato-biliary disorders Very rare Increased liver enzymes, abnormal hepatic function or hepatitis Skin and subcutaneous tissue disorders Very rare Angioedema, rash, urticaria, pruritus Musculoskeletal and connective tissue disorders Very rare Back pain, arthralgia, myalgia Renal and urinary disorders Common Renal impairment, including renal failure in susceptible patients (see section 4.4) Laboratory findings Hyperkalaemia and renal impairment are common in patients treated with ATACAND for the indication of heart failure. Increases in creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium is recommended (see section 4.4).

Symptoms Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In single case reports of overdose (up to 672 mg candesartan cilexetil) patient recovery was uneventful.

Management If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of, for example, isotonic saline solution. Sympathomimetic medicines may be administered if the above-mentioned measures are not sufficient. Candesartan is not removed by haemodialysis.