 Treatment of essential hypertension in adults.
 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).
 Treatment of hypertension in children and adolescents aged 6 to <18 years.

Posology in hypertension
The recommended initial dose and usual maintenance dose of candesartan 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.
Candesartan 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 candesartan.
Elderly population
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).
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).
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. Candesartan 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, up-titration of candesartan and concomitant therapy may be more frequently needed for blood
pressure control in black patients than 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). Candesartan 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).
Candesartan has not been studied in children with glomerular filtration rate less than 30 ml/min/1.73 m2 (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.
• Candesartan is contraindicated in children aged below 1 year (see section 4.3).
Posology in heart failure
The usual recommended initial dose of candesartan is 4 mg once daily. Up-titration to the target dose of 32 mg
once daily (maximum dose) or to 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. Candesartan can be administered with other
heart failure treatment, including ACE-inhibitors, beta-blockers, diuretics and digitalis or a combination of these
medicinal products. Candesartan 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 and candesartan 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,
renal impairment or mild to moderate hepatic impairment.
Paediatric population
The safety and efficacy of candesartan 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
CANDAN should be taken once daily with or without food.
The bioavailability of candesartan is not affected by food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Second and third trimester 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 Candesartan Cilexetil with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

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 sections 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 candesartan.
When candesartan is used in hypertensive patients with renal impairment, periodic monitoring of serum
potassium and creatinine levels are recommended. There is limited experience in patients with very severe or
end-stage renal impairment (Clcreatinine <15 ml/min). In these patients candesartan 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 candesartan,
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
Candesartan has not been studied in children with a glomerular filtration rate less than 30 ml/min/1.73 m2 (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 candesartan is used in combination with an ACE-inhibitor.
Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and candesartan are 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, candesartan
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 limited clinical evidence regarding candesartan use in patients who have undergone renal transplant.

Hypotension
Hypotension may occur during treatment with candesartan 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 hypovolaemia 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 candesartan is not
recommended in this population.
Hyperkalaemia
Concomitant use of candesartan 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 candesartan, hyperkalaemia may occur. Periodic monitoring of serum
potassium is recommended. The combination of an ACE-inhibitor, a potassium-sparing diuretic (e.g.
spironolactone) and candesartan is not recommended and should be considered only after careful evaluation of
the potential benefits and risks.
General
In patients whose vascular tone and renal function depend predominantly on the activity of the reninangiotensinaldosterone
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 decreases 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.

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).
CANDAN contains lactose monohydrate
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose
malabsorption should not take this medicine.

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 medicines 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.

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 foetotoxicity
(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 are recommended.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and
4.4).
Breast-feeding
Because no information is available regarding the use of candesartan during breast-feeding, candesartan is not
recommended and alternative treatments with better established safety profiles during breast-feeding are
preferable, especially while nursing a newborn or preterm infant.

 

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
candesartan.

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.

Laboratory findings
In general, there were no clinically important influences of candesartan 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 candesartan. 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 adolescents, particularly in:
• Headache, dizziness and upper respiratory tract 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 uncommon (≥ 1/1,000 to < 1/100) in children
and very rare (< 1/10,000) in adults.
• Sinus arrhythmia, nasopharyngitis, pyrexia is “common” (i.e. ≥ 1/100 to < 1/10) and oropharyngeal pain is “very
common” (i.e. ≥ 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 candesartan 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
candesartan 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 reninangiotensin-
aldosterone system, in particular an ACE-inhibitor and/or spironolactone.

 

 

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.

Pharmacotherapeutic group: Angiotensin II antagonists, plain, ATC code: C09CA06.
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 disorders. It also has a role in the
pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as
vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth,
are mediated via the type 1 (AT1) receptor.
Pharmacodynamic effects
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance,
candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin
II receptor antagonist, selective for AT1 receptors, with tight binding to and slow dissociation from the receptor.
It has no agonist activity.
Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There
is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing
candesartan with ACE-inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil.
Candesartan does not bind to or block other hormone receptors or ion channels known to be important in
cardiovascular regulation. The antagonism of the angiotensin II (AT1) receptors 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-lasting reduction in arterial blood pressure. The
antihypertensive action is due to decreased systemic peripheral resistance, without reflex increase in heart rate.
There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of
treatment.
After administration of a single dose of candesartan cilexetil, onset of antihypertensive effect generally occurs
within 2 hours. With continuous treatment, most of the reduction in blood pressure with any dose is generally

attained within four weeks and is sustained during long-term treatment. According to a meta-analysis, the average
additional effect of a dose increase from 16 mg to 32 mg once daily was small. Taking into account the interindividual
variability, a more than average effect can be expected in some patients. Candesartan cilexetil once
daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between
maximum and trough effects during the dosing interval. The antihypertensive effect and tolerability of
candesartan and losartan were compared in two randomised, double-blind studies in a total of 1,268 patients
with mild to moderate hypertension. The trough blood pressure reduction (systolic/diastolic) was 13.1 /10.5
mmHg with candesartan cilexetil 32 mg once daily and 10.0 /8.7 mmHg with losartan potassium 100 mg once
daily (difference in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001).
When candesartan cilexetil is used together with hydrochlorothiazide, the reduction in blood pressure is additive.
An increased antihypertensive effect is also seen when candesartan cilexetil is combined with amlodipine or
felodipine.
Medicinal products that block the renin-angiotensin-aldosterone system have less pronounced antihypertensive
effect in black patients (usually a low-renin population) than in non-black patients. This is also the case for
candesartan. In an open label clinical experience trial in 5,156 patients with diastolic hypertension, the blood
pressure reduction during candesartan treatment was significantly less in black than non-black patients
(14.4/10.3 mmHg vs. 19.0/12.7 mmHg, p<0.0001/p<0.0001).
Candesartan increases renal blood flow and either has no effect on or increases glomerular filtration rate while
renal vascular resistance and filtration fraction are reduced. In a 3-month clinical study in hypertensive patients
with type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced
urinary albumin excretion (albumin/creatinine ratio, mean 30%, 95% confidence interval 15-42%). There is
currently no data on the effect of candesartan on the progression to diabetic nephropathy.
The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg), once daily, on cardiovascular morbidity and
mortality was evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70-89 years; 21% aged 80
or above) with mild to moderate hypertension followed for a mean of 3.7 years (Study on COgnition and Prognosis
in the Elderly). Patients received candesartan cilexetil or placebo with other antihypertensive treatment added as
needed. The 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, non-fatal stroke and non-fatal myocardial
infarction). There were 26.7 events per 1000 patient-years in the candesartan group versus 30.0 events per 1000
patient-years in the control group (relative risk 0.89, 95% CI 0.75 to 1.06, p=0.19).

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with
Ramipril Global Endpoint Trial) and VA NEPHRON-0 (The Veterans Affairs Nephropathy in Diabetes)) have
examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or
type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in
patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality,
while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy
was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE
inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers 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
designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II
receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or
both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death

events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more
frequently reported in the aliskiren group than in the placebo group.
Paediatric population - hypertension
The antihypertensive effects of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6
to <17 years in two randomised, double-blind multicentre, 4-week dose ranging studies.
In children aged 1 to <6 years, 93 patients, 74% of whom had renal disease, were randomised to receive an oral
dose of candesartan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily. The primary method of analysis
was slope of the 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 across the three doses of candesartan cilexetil.
However, since there was no placebo group, the true magnitude of blood pressure effect remains uncertain which
makes a conclusive assessment of benefit-risk balance difficult 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 who weighed < 50 kg, the doses of candesartan
cilexetil were 2, 8, or 16 mg once daily. In children who weighed > 50 kg, the candesartan cilexetil doses were 4,
16 or 32 mg once daily. Candesartan at pooled doses reduced SiSBP by 10.2 mmHg (P< 0.0001) and SiDBP
(P=0.0029) by 6.6 mmHg, from the base line. 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 the baseline. Despite the large placebo effect, all
individual candesartan doses (and all doses pooled) were significantly superior to placebo. Maximum response
in reduction of blood pressure in children below and above 50 kg was reached at 8 mg and 16 mg doses,
respectively and the effect plateaued after that point.
Of those enrolled, 47% were black patients and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years. In
children aged 6 to < 17 years there was a trend for a lesser effect on blood pressure in black patients compared
to non-black patients.
Heart failure
Treatment with candesartan cilexetil reduces mortality, reduces hospitalisation due to heart failure, and improves
symptoms in patients with left ventricular systolic dysfunction as shown in the Candesartan in Heart failure –
Assessment of Reduction in Mortality and morbidity (CHARM) programme. This placebo controlled, double-blind
study programme in chronic heart failure (CHF) patients with NYHA functional class II to IV consisted of three
separate studies: CHARM-Alternative (n=2,028) in patients with LVEF ≤ 40% not treated with an ACE-inhibitor
because of intolerance (mainly due to cough, 72%), CHARMAdded (n=2,548) in patients with LVEF ≤ 40% and
treated with an ACE-inhibitor, and CHARM Preserved (n=3,023) in patients with LVEF > 40%. Patients on optimal
CHF therapy at baseline were randomised to placebo or candesartan cilexetil (titrated from 4 mg or 8 mg once
daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a median of 37.7
months. After 6 months of treatment 63% of the patients still taking candesartan cilexetil (89%) were at the target
dose of 32 mg.

In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was
significantly reduced with candesartan in comparison with placebo, hazard ratio (HR) 0.77 (95% CI 0.67-0.89,
p<0.001). This corresponds to a relative risk reduction of 23%. Of candesartan patients 33.0% (95%CI: 30.1 to
36.0) and of placebo patients 40.0% (95%CI: 37.0 to 43.1) experienced this endpoint, absolute difference 7.0%
(95%CI: 11.2 to 2.8). Fourteen patients needed to be treated for the duration of the study to prevent one patient
from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint
of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.80 (95%
CI 0.70-0.92, p=0.001). Of candesartan patients 36.6% (95%CI: 33.7 to 39.7) and of placebo patients 42.7%
(95%CI: 39.6 to 45.8) experienced this endpoint, absolute difference 6.0% (95%CI: 10.3 to 1.8). Both the mortality
and morbidity (CHF hospitalisation) components of these composite endpoints contributed to the favourable
effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class
(p=0.008).

In CHARM-Added, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was
significantly reduced with candesartan in comparison with placebo, HR 0.85 (95% CI 0.75-0.96, p=0.011). This
corresponds to a relative risk reduction of 15%. Of candesartan patients 37.9% (95%CI: 35.2 to 40.6) and of
placebo patients 42.3% (95%CI: 39.6 to 45.1) experienced this endpoint, absolute difference 4.4% (95%CI: 8.2
to 0.6). Twenty-three patients needed to be treated for the duration of the study to prevent one patient from dying
of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause
mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.87 (95% CI 0.78-
0.98, p=0.021). Of candesartan patients 42.2% (95%CI: 39.5 to 45.0) and of placebo patients 46.1% (95%CI:
43.4 to 48.9) experienced this endpoint, absolute difference 3.9% (95%CI: 7.8 to 0.1). Both the mortality and
morbidity components of these composite endpoints contributed to the favourable effects of candesartan.
Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.020).
In CHARM-Preserved, no statistically significant reduction was achieved in the composite endpoint of
cardiovascular mortality or first CHF hospitalisation, HR 0.89 (95% CI 0.77-1.03, p=0.118).
All-cause mortality was not statistically significant when examined separately in each of the three CHARM
studies. However, all-cause mortality was also assessed in pooled populations, CHARM-Alternative and
CHARM-Added, HR 0.88 (95% CI 0.79-0.98, p=0.018) and all three studies, HR 0.91 (95% CI 0.83-1.00,
p=0.055).
The beneficial effects of candesartan were consistent irrespective of age, gender and concomitant medication.
Candesartan was effective also in patients taking both beta-blockers and ACE-inhibitors at the same time, and
the benefit was obtained whether or not patients were taking ACE-inhibitors at the target dose recommended by
treatment guidelines.
In patients with CHF and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF
≤40%), candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases
plasma renin activity and angiotensin II concentration and decreases aldosterone levels.

 

Absorption and distribution
Following oral administration, candesartan cilexetil is converted to 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 formulation compared with the same oral solution is approximately 34% with
very little variability. The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum
concentration (Cmax) is reached 3-4 hours following tablet intake. The candesartan serum concentrations
increase linearly with increasing doses in the therapeutic dose range. No gender related differences in the
pharmacokinetics of candesartan has been observed. The area under the serum concentration versus time curve
(AUC) of candesartan is not significantly affected by food.
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of
candesartan is 0.1 l/kg.
The bioavailability of candesartan is not affected by food.
Biotransformation and elimination
Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic
metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in
vitro data, no interaction would be expected to occur in vivowith drugs whose metabolism is dependent on
cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. The
terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.

Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg.
The renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an
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 the elderly (over 65 years) Cmax and AUC of candesartan are increased by approximately 50% and 80%,
respectively in comparison to young subjects. However, the blood pressure response and the incidence of
adverse events are similar after a given dose of candesartan in young and elderly patients (see section 4.2). In
patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing
by approximately 50% and 70%, respectively, but t½ was not altered, 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 of candesartan was approximately doubled in patients with severe renal
impairment. The AUC of candesartan in patients undergoing haemodialysis was similar to that in patients with
severe renal impairment.
In two studies, both including patients with mild to moderate hepatic impairment, there was an increase in the
mean AUC of candesartan of approximately 20% in one study and 80% in the other study (see section 4.2).
There is no experience in patients with severe hepatic impairment.
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 dose of 0.2 mg/kg, oral
suspension. There was no correlation between Cmax and AUC with age or weight. No clearance data has been
collected; therefore, the possibility of a correlation between clearance and weight/age in this population is
unknown.
In children aged 6 to <17 years, 22 children received a single dose of 16 mg tablet. There was no correlation
between Cmax and AUC with age. However, weight seems to significantly correlate with Cmax (p=0.012) and
AUC (p=0.011). No clearance data has been collected, therefore the possibility of a correlation between
clearance and weight/age in this population is unknown.
Children >6 years of age had exposure similar to adults given the same dose.
The pharmacokinetics of candesartan cilexetil have not been investigated in paediatric patients <1 year of age.

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In preclinical
safety studies candesartan had effects on the kidneys and on red cell parameters at high doses in mice, rats,
dogs and monkeys. Candesartan caused a reduction of 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, which could be
secondary to the hypotensive effect leading to alterations of renal perfusion. Furthermore, candesartan induced
hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered to be caused by the
pharmacological action of candesartan. For therapeutic doses of candesartan in humans, the
hyperplasia/hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
In preclinical studies in normotensive neonatal and juvenile rats, candesartan caused a reduction in body weight
and heart weight. As in adult animals, these effects are considered to result from the pharmacological action of
candesartan. At the lowest dose of 10 mg/kg exposure to candesartan was between 12 and 78 times the levels
found in children aged 1 to <6 who received candesartan cilexetil at a dose of 0.2 mg/kg and 7 to 54 times those

found in children aged 6 to <17 who received candesartan cilexetil at a dose of 16 mg. As a no observed effect
level was not identified in these studies, the safety margin for the effects on heart weight and the clinical relevance
of the finding is unknown.
Foetotoxicity has been observed in late pregnancy (see section 4.6).
Data from in vitro and in vivo mutagenicity testing indicates that candesartan will not exert mutagenic or
clastogenic activities under conditions of clinical use. There was no evidence of carcinogenicity.
The renin-angiotensin-aldosterone system plays a critical role in kidney development in utero. Reninangiotensinaldosterone
system blockade has been shown to lead to abnormal kidney development in very young mice.
Administering drugs that act directly on the renin-angiotensin-aldosterone system can alter normal renal
development. Therefore, children aged less than 1 year should not receive candesartan cilexetil (see section
4.3).

Lactose Monohydrate, Maize Starch, Red iron oxide, Hydroxypropyl Cellulose, Polyethylene Glycol,
Carboxymethyl Cellulose Calcium and Magnesium Stearate

Not applicable.

2 years

Store below 30°C.

PVC/PVDC/ Alu blister.
Pack sizes:28 tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.