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CANDESARTAN 32 MG TABLETS

Active substance(s): CANDESARTAN CILEXETIL

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Candesartan 32 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 32 mg candesartan cilexetil.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
Candesartan 32 mg Tablets are red, round tablets with a break line on one side.
The tablet can be divided into equal doses.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Candesartan Cilexetil is indicated for the:


Treatment of essential hypertension in adults.



The 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 add-on therapy to ACE-inhibitors in patients with symptomatic
heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists
are not tolerated (see section 4.3, 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 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).
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. 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, uptitration of Candesartan 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),
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/1.73m2 (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.
• 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 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 (e.g. spironolactone) 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 or 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.
Candesartan 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.
The concomitant use of Candesartan 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).

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 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
cilexetil.
When candesartan cilexetil 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 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/1.73m2 (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 Candesartan is used
in combination with an ACE inhibitor. . Triple combination of an ACE inhibitor, a
mineralocorticoid receptor antagonist and candesartan 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 reninangiotensin-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 no experience regarding the administration of Candesartan in patients with a
recent kidney transplantation.

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 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 reninangiotensin-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 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.

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-aldosteronesystem (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
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 Candesartan during
breastfeeding, 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.

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 Candesartan.

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) and very rare (< 1/10,000).
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

Very rare

Hyperkalaemia, hyponatraemia

nutrition disorders
Nervous system
disorders

Common

Dizziness/vertigo, headache

Respiratory, thoracic
and mediastinal
disorders

Very rare

Cough

Gastrointestinal
disorders

Very rare

Nausea

Hepato-biliary
disorders

Very rare

Increased liver enzymes,
abnormal hepatic function or
hepatitis

Skin and subcutaneous
tissue disorders

Very rare

Angioedema, rash, urticaria,
pruritus

Musculoskeletal and
connective tissue
disorders

Very rare

Back pain, arthralgia, myalgia

Renal and urinary
disorders

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 candesartan cilexetil on
routine laboratory variables. As for other inhibitors of the renin-angiotensinaldosterone system, small decreases in haemoglobin have been seen. No routine
monitoring of laboratory variables is usually necessary for patients receiving
candesartan cilexetil. 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 adverse events
are similar to those in adults (see 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” (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
• Hyperkalemia, 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 candesartan cilexetil 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 cilexetil 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.
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

Nausea

Hepato-biliary disorders

Very rare

Increased liver enzymes,
abnormal hepatic function or
hepatitis

Skin and subcutaneous
tissue disorders

Very rare

Angioedema, rash, urticaria,
pruritus

Musculoskeletal and
connective tissue
disorders

Very rare

Back pain, arthralgia, myalgia

Renal and urinary
disorders

Common

Renal impairment, including
renal failure in susceptible
patients (see section 4.4)

Laboratory findings

Hyperkalaemia and renal impairment are common in patients treated with candesartan
cilexetil 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II antagonists, plain, ATC code: C09CA06
Mechanism of action
Angiotensin II is the primary vasoactive hormone of the renin-angiotensinaldosterone 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 AIIRA, 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 inter-individual 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%CI
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 were 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-D
(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 endorgan 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 and stroke were both numerically more frequent in
the aliskiren group than in the placebo group and adverse 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, doubleblind 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 nonblack 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 to 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 to 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 to 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 allcause mortality or first CHF hospitalisation was also significantly reduced with
candesartan, HR 0.87 (95%CI: 0.78 to 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 to 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 to 0.98, p=0.018) and all three studies, HR 0.91 (95%CI: 0.83 to 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.

5.2

Pharmacokinetic properties
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 have 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 vivo with drugs whose metabolism is dependent upon
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 cilexetil 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.

5.3

Preclinical safety data
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.
Fetotoxicity 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. Renin-angiotensin-aldosterone 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 (see section 4.3).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Mannitol
Maize starch
Copovidone
Glycerol
Magnesium stearate
Red iron oxide (E172)
Microcrystalline cellulose

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
30 months.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
OPA/Al/PVC-Aluminium blister.
Blister packs of 28 tablets.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited,
Units 3 & 4, Quidhampton Business Units,
Polhampton Lane, Overton,
Hants RG25 3ED
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0277

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
16/12/2015

10

DATE OF REVISION OF THE TEXT
16/12/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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