4.1. Therapeutic indications

Amias is indicated for the:

• Treatment of essential hypertension in adults.

• Treatment of hypertension in children and adolescents aged 6 to <18 years.

• Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) when Angiotensin Converting Enzyme (ACE) inhibitors are not tolerated or as add-on therapy to ACE inhibitors in patients with symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated (see sections 4.2, 4.4, 4.5, and 5.1).

4.2. Posology and method of administration

Posology in Hypertension

The recommended initial dose and usual maintenance dose of Amias is 8 mg once daily. Most of the antihypertensive effect is attained within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 16 mg once daily and to a maximum of 32 mg once daily. Therapy should be adjusted according to blood pressure response.

Amias may also be administered with other antihypertensive agents – (see sections 4.3, 4.4, 4.5 and 5.1). Addition of hydrochlorothiazide has been shown to have an additive antihypertensive effect with various doses of Amias.

Older people

No initial dose adjustment is necessary in elderly patients.

Patients with intravascular volume depletion

An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion (see section 4.4).

Patients with renal impairment

The starting dose is 4 mg in patients with renal impairment, including patients on haemodialysis. The dose should be titrated according to response. There is limited experience in patients with very severe or end-stage renal impairment (Clcreatinine < 15 ml/min) (see section 4.4).

Patients with hepatic impairment

An initial dose of 4 mg once daily is recommended in patients with mild to moderate hepatic impairment. The dose may be adjusted according to response. Amias is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections 4.3 and 5.2).

Black patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients. Consequently, uptitration of Amias and concomitant therapy may be more frequently needed for blood pressure control in black patients than in non-black patients (see section 5.1).

Paediatric Population

Children and adolescents aged 6 to <18 years:

The recommended starting dose is 4 mg once daily.

• For patients weighing < 50 kg: In patients whose blood pressure is not adequately controlled, the dose can be increased to a maximum of 8 mg once daily.

• For patients weighing ≥ 50 kg: In patients whose blood pressure is not adequately controlled, the dose can be increased to 8 mg once daily and then to 16 mg once daily if needed (see section 5.1).

Doses above 32 mg have not been studied in paediatric patients.

Most of the antihypertensive effect is attained within 4 weeks.

For children with possible intravascular volume depletion (e.g., patients treated with diuretics, particularly those with impaired renal function), Amias treatment should be initiated under close medical supervision and a lower starting dose than the general starting dose above should be considered (see section 4.4).

Amias has not been studied in children with glomerular filtration rate less than 30 ml/min/1.73m2 (see section 4.4).

Black paediatric patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients (see section 5.1).

Children aged below 1 year to <6 years

The safety and efficacy in children aged 1 to <6 years of age has not been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Amias is contraindicated in children aged below 1 year (see section 4.3).

Posology in Heart Failure

The usual recommended initial dose of Amias is 4 mg once daily. Up-titration to the target dose of 32 mg once daily (maximum dose) or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks (see section 4.4). Evaluation of patients with heart failure should always comprise assessment of renal function including monitoring of serum creatinine and potassium. Amias can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicinal products. Amias may be co-administered with an ACE-inhibitor in patients with symptomatic heart failure despite optimal standard heart failure therapy when mineralocorticoid receptor antagonists are not tolerated. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and Amias is not recommended and should be considered only after careful evaluation of the potential benefits and risks (see sections 4.4, 4.8 and 5.1).

Special patient populations

No initial dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion or renal impairment or mild to moderate hepatic impairment.

Paediatric Population

The safety and efficacy of Amias in children aged between birth and 18 years have not been established in the treatment of heart failure. No data are available.

Method of administration

Oral use.

Amias should be taken once daily with or without food.

The bioavailability of candesartan is not affected by food.

4.3. Contraindications

Hypersensitivity to candesartan cilexetil or to any of the excipients listed in section 6.1.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Severe hepatic impairment and/or cholestasis.

Children aged below 1 year (see section 5.3).

The concomitant use of Amias with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR< 60ml/min/1.73m2) (see sections 4.5 and 5.1).

4.4. Special warnings and precautions for use

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, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Section 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur 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.

Renal impairment

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with Amias.

When Amias is used in hypertensive patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. There is limited experience in patients with very severe or end-stage renal impairment (Clcreatinine < 15 ml/min). In these patients Amias 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 Amias, monitoring of serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine > 265 µmol/l (> 3 mg/dl).

Use in paediatric patients including patients with renal impairment

Amias has not been studied in children with a glomerular filtration rate less than 30 ml/min/1.73m2 (see section 4.2).

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 Amias is used in combination with an ACE inhibitor (see section 4.8). Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and candesartan cilexetil 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, Amias should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.

Renal artery stenosis

Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Kidney transplantation

There is no experience regarding the administration of Amias in patients with a recent kidney transplantation.

Hypotension

Hypotension may occur during treatment with Amias in heart failure patients. It may also occur in hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted.

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

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists 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.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of Amias is not recommended in this population.

Hyperkalaemia

Concomitant use of Amias with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients. Monitoring of potassium should be undertaken as appropriate.

In heart failure patients treated with Amias, hyperkalaemia may occur. Periodic monitoring of serum potassium is recommended. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and Amias is not recommended and should be considered only after careful evaluation of the potential benefits and risks.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including candesartan cilexetil (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 cilexetil should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

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 other medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with AIIRAs. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications.

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

Pregnancy

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).

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).

4.5. Interaction with other medicinal products and other forms of interaction

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products have been identified.

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium should be undertaken as appropriate (see section 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 AIIRAs. Use of candesartan with lithium is not recommended. 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.

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 agent (see sections 4.3, 4.4 and 5.1).

Paediatric population

Interaction studies have only been performed in adults

4.6. Fertility, 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 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 retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check 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).

Breastfeeding

Because no information is available regarding the use of Amias during breastfeeding, Amias 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 use machines

No studies on the effects of candesartan on the ability to drive and use machines have been performed. However, it should be taken into account that occasionally dizziness or weariness may occur during treatment with Amias.

4.8. Undesirable effects

Treatment of Hypertension

In controlled clinical studies adverse reactions were mild and transient. The overall incidence of adverse events showed no association with dose or age. 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 of hypertensive patients, adverse reactions with candesartan cilexetil were defined 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 section 4.8 are: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and 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

Intestinal angioedema, nausea

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

In general, there were no clinically important influences of Amias on routine laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. No routine monitoring of laboratory variables is usually necessary for patients receiving Amias. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

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 “very common” (ie, ≥1/10) in children and common (≥ 1/100 to < 1/10) in adults.

• Cough is “very common” (ie, > 1/10) in children and very rare (<1/10,000) in adults.

• Rash is “common” (ie, ≥1/100 to <1/10) in children and “very rare” (<1/10,000) in adults.

• Hyperkalaemia, hyponatraemia and abnormal liver function are uncommon (≥ 1/1,000 to < 1/100) in children and very rare (< 1/10,000) in adults.

• Sinus arrhythmia, Nasopharyngitis, pyrexia are “common” (ie, ≥1/100 to <1/10) and oropharyngeal pain is “very common” (ie, ≥1/10) in children; but none are reported in adults. However these are temporary and widespread childhood illnesses.

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

Treatment of Heart Failure

The adverse experience profile of Amias in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical programme, comparing Amias 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 medicinal products 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

Respiratory, thoracic and mediastinal disorders

Very rare

Cough

Gastrointestinal disorders

Very rare

Intestinal angioedema, nausea

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

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 Amias for the indication of heart failure. Periodic monitoring of serum creatinine and potassium is recommended (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms

Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672 mg candesartan cilexetil) in an adult, 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 medicinal products may be administered if the above-mentioned measures are not sufficient.

Candesartan is not removed by haemodialysis.