Candesartan cilexetil 2 mg tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Candesartan cilexetil 2 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

2 mg: Each tablet contains 2 mg of candesartan cilexetil.

Excipients with known effect:

Each 2 mg tablet contains 95.40 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Candesartan 2 mg: Round tablets of approx. 7mm diameter, white colour with a "2" in one of the faces.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Candesartan cilexetil is indicated for the

• Treatment of primary 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 ACE inhibitors are not tolerated, or as adjunctive 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

Dosage for hypertension

The recommended starting dose and usual maintenance dose is 8 mg of candesartan cilexetil once daily. Most of the antihypertensive effect is achieved within 4 weeks. In some patients whose blood pressure cannot be controlled satisfactorily, the dose may be increased to 16 mg once daily and up to a maximum of 32 mg once daily. Treatment should be adjusted depending on response to blood pressure.

Candesartan cilexetil may also be co-administered with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1). Adding hydrochlorthiazide to different doses of candesartan cilexetil has shown an additive antihypertensive effect.

Older patients

It is not necessary to adjust the starting dose in older patients.

Patients with reduced intravascular volume

A starting dose of 4 mg may be considered in patients at risk of hypotension, such as patients with possible reduced intravascular volume (see section 4.4).

Reduced kidney function

The starting dose is 4 mg for patients with impaired renal function, including patients on haemodialysis. Dose should be adjusted according to response. There is limited experience in patients with very severe or end-stage renal disease (creatinine clearance (Clcreatinine) <15 ml/minute) (see section 4.4).

Reduced liver function

A starting dose of 4 mg once daily is recommended for patients with mild to moderate hepatic impairment. Dose may be adjusted according to response. candesartan cilexetil is contraindicated in patients with severely impaired hepatic function and/or cholestasis (see sections 4.3 and 5.2).

Black patients

The antihypertensive effect of candesartan is lower in black patients than in non-black patients. As a consequence, there may be a greater need for optimisation of candesartan cilexetil and other concomitant therapy to achieve blood pressure control in black patients than in non-black patients (see section 5.1).

Paediatric population

Children and young people aged 6 to <18 years

The recommended starting dose is 4 mg once daily.

• Patients weighing < 50 kg: For patients whose blood pressure is inadequately controlled, the dose may be increased to a maximum of 8 mg once daily.
• Patients weighing ≥ 50 kg: For patients whose blood pressure is inadequately controlled, the dose may be increased to 8 mg once daily and then to 16 mg once daily, if necessary (see section 5.1).

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

The majority of the antihypertensive effect is achieved within 4 weeks.

In children with possible reduced intravascular volume (e.g. patients treated with diuretics, especially patients with impaired renal function), candesartan cilexetil treatment should be initiated under close monitoring and a lower starting dose than the general starting dose mentioned above should be considered (see section 4.4).

Candesartan cilexetil has not been studied in children with a glomerular filtration rate below 30 ml/min/1,73m2 (see section 4.4).

Black paediatric patients

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

Children aged under 1 year to <6 years

• Safety and efficacy in children aged 1 to <6 years have not been studied. The available data are described in section 5.1, but no dosage recommendations can be made.
• candesartan cilexetil is contraindicated in children under 1 year of age (see section 4.3).

Dosage in heart failure

Usual recommended starting dose of candesartan cilexetil is 4 mg once daily. Titration to the target dose of 32 mg once daily (maximum dose) or to the maximum 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 include assessment of renal function, including monitoring of serum creatinine and serum potassium. Candesartan cilexetil may be used in combination with other treatments for heart failure, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicines. Candesartan cilexetil may be used with an ACE inhibitor in patients with symptomatic heart failure despite optimal standard therapy when mineralocorticoid receptor antagonists are not tolerated. Combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and candesartan cilexetil is not recommended and should only be considered after careful consideration of the benefits and risks (see sections 4.4, 4.8 and 5.1).

Special patient groups

It is not necessary to adjust the starting dose in elderly patients or in patients with reduced intravascular volume, renal insufficiency or mild to moderate hepatic insufficiency.

Paediatric population

The safety and efficacy of candesartan cilexetil in the treatment of heart failure in children from birth to 18 years of age have not been established. No data are available.

Method of administration

Oral use.

Candesartan cilexetil should be taken once daily with or without simultaneous food intake.

Bioavailability of candesartan is not affected by food intake.

4.3 Contraindications

Hypersensitivity to candesartan cixetil or to one or more of the excipients listed in section 6.1.

Second and third trimester of pregnancy (see points 4.4 and 4.6).

Severely impaired hepatic function and/or cholestasis.

Children under 1 year of age (see section 5.3).

Concomitant use of candesartan cilexetil and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or impaired renal function (GFR < 60 ml/min/1,73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Dual inhibition of the renin-angiotensin-aldosterone system (RAAS) There is evidence that concomitant use of ACE inhibitors and angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and impaired renal function (including acute renal failure). Dual inhibition of RAAS by combination of ACE inhibitors with angiotensin II receptor antagonists or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual inhibitor therapy is considered absolutely necessary, this should only be done under the supervision of a specialist physician and with close monitoring of the patient's renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Reduced kidney function

As with other drugs that inhibit the renin-angiotensin-aldosterone system, changes in renal function may be expected in predisposed patients treated with candesartan cilexetil

When candesartan cilexetil is used in hypertensive patients with impaired renal function, it is recommended to monitor serum potassium and serum creatinine levels regularly. There is limited experience in patients with very severe or end-stage renal disease (Clcreatinine < 15 mL/minute). In these patients candesartan cilexetil should be titrated cautiously with careful monitoring of blood pressure.

Evaluation of patients with heart failure should include regular assessment of renal function, particularly in elderly patients aged 75 years or over and in patients with impaired renal function. During dose titration of candesartan cilexetil regular monitoring of serum creatinine and serum potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine > 265 mol/l (> 3 mg/dl).

Paediatric population, including paediatric patients with renal impairment candesartan cilexetil has not been studied in children with a glomerular filtration rate of less than 30 ml/min/1.73m2 (see section 4.2).

Concomitant treatment with ACE inhibitors in heart failure

The risk of side effects, especially hypotension, hyperkalaemia and impaired renal function (including acute renal failure) may be increased when candesartan cilexetil is used in combination with an ACE inhibitor (see section 4.8).Triple combination with an ACE inhibitor, a mineralocorticoid receptor antagonist and candesartan should also not be used. Such combinations should only be used under the supervision of a specialist physician and with close monitoring of the patient's renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Hemodialysis

During dialysis, blood pressure may be particularly sensitive to AT1 receptor blockade due to reduced plasma volume and activation of the renin-angiotensin-aldosterone system. candesartan cilexetil should therefore be titrated cautiously with careful monitoring of blood pressure in patients on haemodialysis.

Renal artery stenosis

Other drugs that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may cause elevated serum urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to one kidney.

Kidney transplantation

There is limited clinical experience with the use of candesartan cilexetil in renal transplant patients.

Hypotension

Hypotension may occur in patients with heart failure receiving candesartan cilexetil Similarly, hypotension may occur in hypertensive patients with reduced intravascular volume, such as patients treated with high doses of diuretics. Caution should be exercised at the start of treatment and attempt should be made to correct for hypovolaemia.

In children with possible reduced intravascular volume (e.g. patients treated with diuretics, especially patients with impaired renal function), candesartan cilexetil treatment should be initiated under close monitoring and a lower starting dose should be considered (see section 4.2).

Anaesthesia and surgery

In patients treated with angiotension II antagonists, hypotension may occur during anaesthesia and surgery due to blockade of the renin-angiotension system. Very rarely, hypotension may be so severe as to require the use of intravenous fluids and/or vasopressor therapy.

Stenosis of aortic and mitral valves (obstructive hypertrophic cardiomyopathy) As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant stenosis of the aortic or mitral valves or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism usually do not respond to antihypertensive drugs that act via inhibition of the renin-angiotensin-aldosterone system. candesartan cilexetil is therefore not recommended for these patients.

Hyperkalaemia

Concomitant use of candesartan cilexetil and potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicines that may increase potassium levels (for example, heparin, CoTrimoxazole, also known as trimethoprim/sulfamethoxazole) may result in an increase in serum potassium in hypertensive patients. Monitoring of serum potassium should be performed when appropriate.

Hyperkalaemia may occur in patients with heart failure treated with candesartan cilexetil, Regular monitoring of serum potassium is recommended. Combination of an ACE inhibitor, a potassium-sparing diuretic (for example spironolactone) and candesartan cilexetil is not recommended and should only be considered after careful evaluation of the possible benefits and risks.

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including candesartan (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 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 are predominantly dependent on the renin-angiotensin-aldosterone system (for example, patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products affecting this system has been associated with acute hypotension, azotemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded for AIIRAs. As with other antihypertensive drugs, a severe reduction in blood pressure in patients with ischaemic heart disease or cerebrovascular ischaemic disorder may result in myocardial infarction or stroke.

The antihypertensive effect of candesartan may be potentiated by drugs with blood pressure-lowering effects, whether prescribed as antihypertensives or for other indications.

Candesartan cilexetil contains lactose and should not be used in patients with hereditary galactose intolerance, a specific form of lactase deficiency or glucose/galactose malabsorption.

Pregnancy

Treatment with AIIRAs should not be started during pregnancy. Unless continued AIIRA therapy is considered absolutely necessary, patients planning to become pregnant should be switched to alternative antihypertensive therapy with an established safety profile for use during pregnancy. Once pregnancy is established, treatment with AIIRAs should be discontinued immediately and other treatment initiated if deemed appropriate (see sections 4.3 and 4.6).

In post-menarche patients, the likelihood of pregnancy should be evaluated regularly. Appropriate information should be provided and/or precautions taken to avoid 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

The chemical compounds 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 demonstrated.

Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other medicines (for example, heparin) may increase potassium levels. Serum potassium should be monitored when appropriate (see section 4.4).

Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors. A similar effect may occur with AIIRAs. Use of candesartan concomitantly with lithium is not recommended. If concomitant therapy is necessary, careful monitoring of serum lithium levels is recommended.

When AIIRAs are used concomitantly with non-steroidal anti-inflammatory drugs (e.g. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), the antihypertensive effect may be weakened.

As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may result in an increased risk of worsening renal function, including possible acute renal failure and an increase in serum potassium, particularly in patients with already impaired renal function. The combination should be administered with caution, especially in the elderly. Patients should be well hydrated and monitoring of renal function should be considered after initiation of concomitant therapy and periodically thereafter.

Data from clinical studies have shown that dual inhibition of the renin-angiotensin-aldosterone system (RAAS) by combination therapy with ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalaemia and impaired renal function (including acute renal failure) compared to the use of a single RAAS-acting drug (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 in the first trimester (see section 4.4) and is contraindicated in the second and third trimesters (see sections 4.3 and 4.4).

Epidemiological studies on the risk of teratogenicity associated with ACE inhibitor therapy in the first trimester of pregnancy are inconclusive, but a slightly increased risk cannot be excluded. Although there are no controlled epidemiological data on the risk of AIIRAs, there may be similar risks for this group of drugs. Unless continued treatment with AIIRAs is considered absolutely necessary, patients planning to become pregnant should switch to an alternative antihypertensive treatment with an established safety profile for use during pregnancy. Once pregnancy is established, AIIRA treatment should be discontinued immediately and other treatment should be initiated if appropriate.

AIIRA treatment in the second and third trimester is known to cause human fetotoxicity (impaired renal function, oligohydramnios, delayed ossification of the skull) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

In case of exposure to AIIRAs in the second or third trimester of pregnancy, ultrasound scanning of renal function and skull is recommended.

Children whose mothers have taken AIIRAs should be closely monitored for hypotension (see sections 4.3 and 4.4).

Breast-feeding

As there is no information on the use of candesartan cilexetil during lactation, candesartan cilexetil is not recommended. Other treatments with better established safety profiles during lactation are recommended, especially in breastfeeding newborn or premature infants.

4.7 Effects on ability to drive and use machines

No studies have been conducted on the effect of candesartan on the ability to drive and operate machinery. However, it should be taken into account that dizziness and fatigue may occur during treatment.

4.8 Undesirable effects

Treatment of hypertension

In controlled clinical studies, side effects were mild and transient. The overall frequency of adverse events showed no correlation with dose or age. Discontinuation of treatment due to adverse events was similar for candesartan cilexetil (3.1%) and placebo (3.2%).

In a pooled analysis of the results from clinical trials in hypertensive patients, adverse reactions to candesartan cilexetil were defined on the basis of a frequency that was at least 1% higher for candesartan cilexetil than for placebo. According to this definition, the most frequently reported adverse reactions were dizziness, headache and respiratory tract infection.

The table below shows adverse reactions from clinical trials and post-marketing experience.

The frequencies used in the tables in section 4.8 are: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000) and very rare (<1/10,000), and not known (cannot be estimated form the available data).

Laboratory findings

In general, candesartan cilexetil had no influence of clinical significance on routinely measured laboratory values. As with other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin were seen. Routine monitoring of laboratory parameters is not usually necessary in patients treated with candesartan cilexetil. However, regular monitoring of serum potassium and serum creatinine is recommended in patients with impaired renal function.

Pediatric population

The safety of candesartan cilexetil was monitored in 255 hypertensive children and adolescents aged 6 to <18 years during a 4-week clinical efficacy study and a 1-year unblinded study (see section 5.1). Within almost all of the different system organ classes, the frequency of adverse events in children is within the common/non-common range. While the nature and severity of adverse reactions are comparable to that seen in adults (see table above), the frequency of all adverse reactions is higher in children and adolescents, particularly in:

• Headache, dizziness, and upper respiratory infection are "very common"

  (i.e. ≥1/10) in children and "common" (≥1/100 to <1/10) in adults.

• Cough is "very common" (i.e. >1/10) in children and "very rare"

  (<1/10,000) in adults.

• Rash is "common" (i.e. ≥1/100 to <1/10) in children and "very rare"

  (<1/10,000) in adults.

• Hyperkalaemia, hyponatraemia and abnormal liver function are "not common" (≥1/1,000 to <1/100) in children and "very rare" (<1/10,000) in adults.

• Sinus arrhythmia, nasopharyngitis and pyhralgia are "common" (i.e.

  >1/100 to <1/10) and oropharyngeal pain is "very common" (i.e. ≥1/10) in children but not reported in adults. However, these are transient and common childhood diseases.

The overall safety profile of candesartan cilexetil in paediatric patients is not significantly different from the safety profile in adults.

Treatment of heart failure

The adverse event profile of candesartan cilexetil in adult patients with heart failure was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical trial programme, comparing candesartan cilexetil up to 32 mg (n=3,803) with placebo (n=3,796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment due to adverse events. The most frequently reported adverse events were hyperkalaemia, hypotension and renal impairment.

These adverse reactions were more frequent in patients over 70 years of age, in diabetics and in patients receiving other medicinal products affecting the renin-angiotensin-aldosterone system, in particular an ACE inhibitor and/or spironolactone.

The table below shows adverse reactions from clinical trials and post-marketing experience.

Laboratory results

Hyperkalaemia and impaired renal function are common in patients treated with candesartan cilexetil for the indication of heart failure. Regular monitoring of serum creatinine and serum 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 website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Based on pharmacological considerations, the main symptoms of overdose are likely to be hypotension and dizziness. In individual reports of overdose (with up to 672 mg of candesartan cilexetil) in adults, patients recovered without complications.

Treatment

If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed in the supine position with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of, for example, isotonic sodium chloride infusion fluid. Sympathomimetic drugs may be given if the above measures are not sufficient.

Candesartan is not removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonist., ATC code: C 09 CA 06

Mechanism of action

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular diseases. It also has a role in the pathogenesis of target organ hypertrophy and damage. The main physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water balance and stimulation of cell growth, are mediated via the type I- (AT_1-) receptor.

Pharmacodynamic effect

Candesartan-cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, candesartan, via ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA, selective for AT₁- receptors, with strong binding to and slow dissociation from the receptor. It is without agonist activity.

Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and breaks down bradykinin. There is no effect on ACE and no enhancement of bradykinin or substance P. In controlled clinical studies comparing candesartan with ACE inhibitors, the frequency of cough was lower in patients receiving candesartan-cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to play an important role in cardiovascular regulation. Angiotensin II- (AT₁-) receptor antagonism results in dose-related increases in plasma renin levels, angiotensin I- and angiotensin II- levels and a decrease in plasma aldosterone concentration.

Clinical efficacy and safety

Hypertension

In hypertension, candesartan causes a dose-dependent, long-term reduction in arterial blood pressure. The antihypertensive effect is due to a decrease in systemic peripheral resistance without a reflex increase in heart rate. There is no evidence of severe or profound hypotension after the first dose or rebound effect after discontinuation of treatment.

After administration of a single dose of candesartan cilexetil, the antihypertensive effect usually occurs within 2 hours. With continued treatment, most of the blood pressure reduction, regardless of dose, is generally achieved within 4 weeks and maintained during long-term therapy. According to a meta-analysis, the average additive effect of increasing the dose from 16 mg to 32 mg once daily is small. Taking into account inter-individual variation, in some patients an effect greater than the average effect can be expected. Candesartan cilexetil once daily provides effective and smooth blood pressure reduction over 24 hours with little variation between the peak effect and the trough effect over the dose range. The antihypertensive efficacy and tolerability of candesartan and losartan were compared in two randomised, double-blind trials in a total of 1,268 patients with mild to moderate hypertension. Trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with 32 mg candesartan cilexetil once daily and 10.0/8.7 mmHg with 100 mg losartan potassium once daily (difference in blood pressure reduction was 3.1/1.8 mmHg, p<0.0001/p<0.0001).

When candesartan cilexetil is given concomitantly with hydrochlorthiazide, the blood pressure reduction is additive. An increased antihypertensive effect may also be seen when candesartan cilexetil is co-administered with amlodipine or felodipine.

Drugs that inhibit the renin-angiotensin-aldosterone system have a less pronounced antihypertensive effect in black patients (a typical low-renin population) than in non-black patients. This is also true for candesartan. In an open-label clinical trial of 5,156 patients with diastolic hypertension, blood pressure reduction with candesartan treatment was significantly lower in black than in non-black patients (14.4/10.3 mmHg versus 19.0/12.7 mmHg; p<0.0001/p<0.0001).

Candesartan increases renal blood flow and either does not affect or increases glomerular filtration rate, while decreasing renal carbohydrate and filtration fraction. In a 3-month clinical study of hypertensive patients with type 2 diabetes and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio, mean: 30% with 95% confidence interval: 15 42%). No data are currently available on the effect of candesartan on progression to diabetic nephropathy.

The effect of candesartan cilexetil 8 16 mg (mean dose 12 mg) once daily on cardiovascular morbidity and mortality was studied in a randomised clinical trial of 4,937 elderly patients (age 70 89 years; 21% 80 years or older) with mild to moderate hypertension followed for an average of 3.7 years (SCOPE: Study on Cognition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo along with other antihypertensive treatment, which was added as needed. Blood pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group and from 167/90 to 149/82 mmHg in the control group. There was no statistically significant difference in the primary endpoint, major cardiovascular events (cardiovascular mortality, nonfatal stroke and nonfatal myocardial infarction). There were 26.7 events per 1,000 patient-years in the candesartan group versus 30.0 events per 1,000 patient-years in the control group (relative risk: 0.89; 95% confidence interval: 0.75 1.06; p=0.19).

The combination of an ACE inhibitor and an angiotensin II receptor antagonist has been studied in two large randomised controlled trials (ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)).

ONTARGET was a study of patients who had a history of cardiovascular or cerebrovascular disease, or who had type 2 diabetes mellitus with evidence of organ involvement.

VA NEPHRON-D was a study of patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies showed no significantly better effect on renal and/or cardiovascular endpoints and mortality compared to monotherapy, while an increased risk of hyperkalaemia, acute renal failure and/or hypotension was observed. Given the common pharmacodynamic properties, these results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists.

ACE inhibitors and angiotensin II receptor antagonists should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study to investigate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease or both. This study was terminated early due to an increased risk of adverse events. Both cardiovascular death and apoplexy were numerically more frequent in the aliskiren group than in the placebo group, and adverse events and relevant serious adverse events (such as hyperkalaemia, hypotension and renal impairment) were reported more frequently in the aliskiren group than in the placebo group.

Paediatric population - hypertension

Candesartan's antihypertensive effects were evaluated in hypertensive children aged 1 to <6 years and 6 to <17 years in two randomised, double-blind 4-week multicentre dosing studies.

In children aged 1 to <6 years, 93 patients, 74% of whom had renal disease, were randomised to receive an oral candesartan cilexetil suspension dose of 0.05, 0.20 or 0.40 mg/kg once daily. The primary method of analysis was the slope coefficient of change in systolic blood pressure (SBP) as a function of dose. SBP and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline over the three doses of candesartan cilexetil. However, as there was no placebo group, the magnitude of the blood pressure effect is uncertain, making it difficult to unambiguously assess benefit and risk in this age group.

In children aged 6 to <17 years, 240 patients were randomised to receive either placebo or low, medium or high doses of candesartan cilexetil in a ratio of 1:2:2:2. For children weighing <50 kg, candesartan cilexetil doses were 2, 8, or 16 mg once daily. For children weighing > 50 kg, the candesartan cilexetil doses were 4, 16, or 32 mg once daily. Overall, candesartan doses reduced SiSBP by 10.2 mmHg (P<0.0001) and SiDBP (P=0.0029) by 6.6 mmHg from baseline. In the placebo group, there was also a reduction of 3.7 mmHg in SiSBP (P=0.0074) and 1.80 mmHg for SiDBP (P=0.0992) from baseline. Despite the large placebo effect, all individual candesartan doses (and all total doses) were significantly superior to placebo. The maximum dose response for blood pressure reduction in children below and above 50 kg was achieved at doses of 8 mg and 16 mg, respectively, and the effect flattened out after that point.

Of the study participants, 47% were black patients and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years. In children aged 6 to < 17 years, the blood pressure effect tended to be smaller in black patients compared with non-black patients.

Heart failure

Treatment with candesartan cilexetil reduces mortality, reduces hospitalisations for heart failure and improves symptoms in patients with impaired left ventricular systolic function as shown in the CHARM (Candesartan in Heart Failure - Assessment of Reduction in Mortality and morbidity) programme.

CHARM was a placebo-controlled, double-blind study program in patients with chronic heart failure (CHF), NYHA functional class II to IV, and consisted of three separate studies: CHARM-Alternative (n=2,028) with patients with LVEF ≤ 40% who were not on ACE inhibitor therapy due to intolerance (mainly due to cough, 72%), CHARM-Added (n=2. 548) with patients with LVEF ≤ 40% and treated with an ACE inhibitor and CHARM-Preserved (n=3,023) with patients with LVEF > 40%. Patients in optimal CHF treatment at baseline were randomized to placebo or candesartan cilexetil (titrated from 4 mg or 8 mg once daily to 32 mg once daily or to the maximum tolerated dose, mean dose was 24 mg) and followed for a mean period of 37.7 months. After 6 months of treatment, 63% of patients still receiving candesartan cilexetil (89%) had reached the target dose of 32 mg.

In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first hospitalisation for chronic heart failure was significantly reduced with candesartan compared to placebo, hazard ratio (HR) 0.77 (95% confidence interval: 0.67-0.89; p<0.001). This corresponds to a relative risk reduction of 23%. 33.0% of candesartan patients (95% confidence interval: 30.1 36.0) and 40% of placebo patients (95% confidence interval: 37.0 43.1) experienced this endpoint, absolute difference, 7.0% (95% confidence interval: 11.2 2.8). It is necessary to treat 14 patients for the duration of the study to prevent one patient from dying of a cardiovascular event or from being hospitalized for treatment of heart failure. The combined endpoint, all-cause mortality or first hospitalisation for chronic heart failure, was also significantly reduced with candesartan, HR 0.80 (95% confidence interval: 0.70 0.92; p=0.001). 36.6% of candesartan patients (95% confidence interval: 33.7 39.7) and 42.7% of placebo patients (95% confidence interval: 39.6 45.8) experienced this endpoint, absolute difference 6.0% (95% confidence interval: 10.3 1.8). Both the mortality and morbidity (hospitalisation due to chronic heart failure) components of these combined endpoints contributed to the positive effect of candesartan. Treatment with candesartan cilexetil resulted in an improved NYHA functional class (p=0.008).

In CHARM-Added, the combined endpoint of cardiovascular mortality or first hospitalisation for chronic heart failure was significantly reduced with candesartan compared to placebo, HR 0.85 (95% confidence interval: 0.75-0.96; p=0.011). This corresponds to a relative risk reduction of 15%. 37.9% of candesartan patients (95% confidence interval: 35.2 40.6) and 42.3% of placebo patients (95% confidence interval: 39.6 45.1) experienced this endpoint, absolute difference 4.4% (95% confidence interval: 8.2 0.6). It is necessary to treat 23 patients for the duration of the study to prevent one patient from dying of a cardiovascular event or from being hospitalized for treatment of heart failure. The combined endpoint, all-cause mortality or first hospitalisation for chronic heart failure, was also significantly reduced with candesartan, HR 0.87 (95% confidence interval: 0.78 0.98; p=0.021). 42.2% of candesartan patients (95% confidence interval: 39.5 45.0) and 46.1% of placebo patients (95% confidence interval: 43.4 48.9) experienced this endpoint, absolute difference 3.9% (95% confidence interval: 7.8 0.1). Both mortality and morbidity components of these composite endpoints contributed to the positive effect of candesartan. Treatment with candesartan cilexetil resulted in an improved NYHA functional class (p=0.020).

In CHARM-Preserved, there was no statistically significant reduction in the combined endpoint of cardiovascular mortality or first hospitalisation for heart failure, HR 0.89 (95% confidence interval 0.77 - 1.03, p=0.118).

All-cause mortality was not statistically significant when analysed separately in each of the three CHARM studies. However, all-cause mortality was also calculated in the pooled data, CHARM-Alternate and CHARM-Aggregate, HR 0.88 (95% confidence interval 0.79 0.98, p = 0.018) and in all three studies, HR 0.91 (95% confidence interval 0.83 1.00, p = 0.055).

The beneficial effects of candesartan were the same regardless of age, sex or concomitant use of other drugs. Candesartan was also effective in patients taking both beta-blockers and ACE inhibitors simultaneously, and the benefit was present whether or not patients received the target doses of ACE inhibitors recommended in treatment guidelines.

In patients with chronic heart failure and impaired left ventricular systolic function (LVEF ≤ 40%), candesartan decreases systemic vascular resistance and pulmonary artery infiltration pressure, increases plasma renin activity and angiotension II concentration, and decreases aldosterone levels.

5.2 Pharmacokinetic properties

Absorption and distribution

After oral administration, candesartan cilexetil is converted into the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet compared to the oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14 %. The mean maximum serum concentration (C_max) is reached within 3-4 hours after tablet ingestion. The serum concentration of candesartan increases linearly with increasing doses within the therapeutic dose range. No sex-related difference in candesartan pharmacokinetics has been observed. The area under the curve showing the serum concentration over time (AUC) of candesartan is not significantly affected by food intake.

Candesartan is strongly bound to plasma proteins (> 99%). The apparent volume of distribution of candesartan is 0,1 1/kg.

Bioavailability of candesartan is not affected by food intake.

Metabolism and elimination Candesartan is eliminated predominantly unconverted via the urine and bile and is only slightly converted via hepatic metabolism (CYP2C9). Available interaction studies suggest no effect on CYP2C9 and CYP3A4. Based on in vitro data, no interaction is expected to occur in vivo with medicinal products whose metabolism depends on the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal t½ for candesartan is approximately 9 hours. There is no accumulation after repeated doses.

The total plasma clearance of candesartan is approximately 0.37 mL/min/kg with a renal clearance of approximately 0.19 mL/min/kg. Renal elimination of candesartan occurs via glomerular filtration as well as via active tubular secretion. Following a single oral dose of ¹⁴C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite.

Pharmacokinetics in special populations

In elderly subjects (> 65 years), the C_max and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to younger subjects. Nevertheless, the reduction in blood pressure and the frequency of adverse events after a given dose of candesartan cilexetil are similar in younger and older patients (see section 4.2).

In patients with mild to moderate renal impairment, the C_max and AUC of candesartan increased after repeated dosing by approximately 50% and 70%, respectively, but t½ was unchanged compared to patients with normal renal function. The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t½ for candesartan was approximately doubled in patients with severely impaired renal function. The AUC of candesartan in patients on haemodialysis was similar to that seen in patients with severe renal impairment.

In two studies, both in patients with mild to moderate hepatic impairment, there was an increase in mean AUC for candesartan of approximately 20% in one study and 80% in the other (see section 4.2). There is no experience in patients with severely impaired hepatic function.

Paediatric population

The pharmacokinetic properties of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6 to <17 years in two single-dose PK studies.

In children aged 1 to <6 years, 10 children weighing 10 to <25 kg received a single oral suspension dose of 0.2 mg/kg. There was no correlation between C_max and AUC with respect to age or weight. No clearance data were collected and therefore the likelihood of a relationship between clearance and weight/age in this population is unknown.

In children aged 6 to <17 years, 22 children received a 16 mg tablet as a single dose. Half the subjects were below, and half were above 12 years if age. There was no correlation between C_max and AUC with age. However, weight appears to have a significant relationship with C_max (p=0.012) and AUC (p=0.011). No clearance data were collected and therefore the likelihood of a relationship between clearance and weight/age in this population is unknown.

Children aged >6 years had an exposure comparable to that of adults receiving the same dose.

The pharmacokinetics of candesartan cilexetil have not been studied in paediatric patients aged <1 year.

5.3 Preclinical safety data

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In high dose preclinical safety studies, candesartan affected the kidneys and red blood cells in mice, rats, dogs and monkeys. Candesartan caused a reduction in red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan and could be secondary to the hypotensive effect causing changes in renal blood flow. Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes are thought to be induced by the pharmacological effects of candesartan. It does not appear that

hyperplasia/hypertrophy of the juxtaglomerular cells has any relevance in humans at therapeutic doses of candesartan.

In preclinical studies with normotensive neonatal and juvenile rats, candesartan caused a reduction in body weight and heart weight. As in adult animals, these effects are thought to be due to the pharmacological action of candesartan. At the lowest dose of 10 mg/kg, exposure to candesartan was between 12 and 78 times higher than the levels found in children aged 1 to <6 given candesartan cilexetil at a dose of 0.2 mg/kg and 7 to 54 times higher than the levels found in children aged 6 to <17 given a dose of 16 mg candesartan cilexetil. As no no observed effect level was identified in these studies, the margin of safety for the effect on heart weight and the clinical relevance of this finding are unknown.

Fetotoxicity has been observed in the late part of pregnancy (see section 4.6).

Data from in vitro and in vivo mutagenicity studies suggest that candersartan will not exert mutagenic or clastogenic activity in clinical use.

There was no evidence of carcinogenicity.

The renin angiotensin aldosterone system plays an important role in renal development in utero. Renin angiotensin aldosterone system blockade has been shown to cause abnormal kidney development in very young mice. Administration of drugs that act directly on the renin angiotensin aldosterone system may alter normal kidney development. Therefore, children under 1 year of age should not receive candesartan cilexetil (see section 4.3).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Maize starch

Hydroxypropylcellulose

Carmellose calcium

Polyethylene glycol 8000 (Macrogol)

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

There are no specific storage temperature requirements for this medicinal product.

6.5 Nature and contents of container

Tablets are available in:

2 mg pack-sizes:

Blister composed by PVC and Aluminium: 10, 14, 20, 28, 30, 42, 50, 56, 84, 90, 98, 100 tablets

HDPE Bottle: 140 tablets

Not all pack sizes are necessarily marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Laboratorios Liconsa, S.A.

C/Dulcinea S/N, 28805

Alcalá de Henares,

Madrid - Spain

8 MARKETING AUTHORISATION NUMBER(S)

PL 23218/0275

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

11/09/2024

10 DATE OF REVISION OF THE TEXT

08/06/2026