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CANDESARTAN RANBAXY 8 MG TABLETS

Active substance(s): CANDESARTAN CILEXETIL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
CANDESARTAN RANBAXY 8 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
CANDESARTAN RANBAXY 8 mg:
Each tablet contains 8 mg candesartan cilexetil.
Excipients with known effect:
[Candesartan 8 mg]: Each tablet contains 75.8 mg of lactose monhydrate
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
CANDESARTAN RANBAXY 8 mg:
Pink capsule shaped tablet with ‘C’ & ‘10’ debossed on either side of
breakline on one side and breakline on other side.
The tablet can be divided into equal halves.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

CANDESARTAN RANBAXY is indicated for the:


Treatment of essential hypertension in adults.




4.2

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%) as add-on therapy to
Angiotensin Converting Enzyme (ACE) inhibitors or when ACE inhibitors are
not tolerated (see section 5.1).
Posology and method of administration

For dosages, which cannot be achieved with CANDESARTAN BASICS tablets other
strengths of candesartan cilexetil containing medicinal products are available.

Posology in Hypertension

The recommended initial dose and usual maintenance dose of CANDESARTAN
RANBAXY 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 RANBAXY may also be administered with other antihypertensive
agents. Addition of hydrochlorothiazide has been shown to have an additive
antihypertensive effect with various doses of CANDESARTAN RANBAXY.

Elderly population

No initial dosage 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 BASICS 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 RANBAXY 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 some 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 some 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
RANBAXY 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 RANBAXY 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
nonblack patients.
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 RANBAXY is contraindicated in children aged below 1
year (see section 4.3).

Posology in Heart Failure

The usual recommended initial dose of CANDESARTAN BASICS 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 RANBAXY can be administered with other heart failure treatment,
including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of
these medicinal products. The combination of an ACE inhibitor, a potassium-sparing
diuretic (e.g. spironolactone) and CANDESARTAN RANBAXY 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 RANBAXY 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

For Oral use.
CANDESARTAN RANBAXY should be taken once daily with or without food.
The bioavailability of candesartan is not affected by food.
4.3

Contraindications





4.4

Hypersensitivity to candesartan cilexetil or to any of the excipients as listed in
section 6.1.
Second and third trimesters of pregnancy (see section 4.4 and 4.6)
Severe hepatic impairment and/or cholestasis.
Children aged below 1 year (see section 5.3)
Special warnings and precautions for use

Renal impairment
As with other agents inhibiting the rennin-angiotensin-aldesterone system, changes in
renal function may be anticipated in susceptible patients treated with
CANDESARTAN RANBAXY.
When CANDESARTAN RANBAXY 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
RANBAXY 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 BASICS, monitoring of serum creatinine
and potassium is recommended. Clinical trials in heart failure did not include patients with
serum creatinine >265 mol/l (>3 mg/dl).

μ

Concomitant therapy with an ACE inhibitor in heart failure
The risk of adverse reactions, especially renal function impairment and hyperkalaemia, may
increase when candesartan is used in combination with an ACE inhibitor (see section 4.8).
Patients with such treatment should be monitored regularly and carefully.

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 RANBAXY 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 RANBAXY
in patients with a recent kidney transplantation.
Hypotension
Hypotension may occur during treatment with CANDESARTAN RANBAXY 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.
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 RANBAXY
is not recommended in this population.
Hyperkalaemia
Concomitant use of CANDESARTAN RANBAXY 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 RANBAXY, 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 RANBAXY is not recommended and should be considered
only after careful evaluation of the potential benefits and risks.
Use in paediatric patients, including patients with renal impairment
CANDESARTAN RANBAXY has not been studied in children with a glomerular
filtration rate less than 30 ml/min/1.73m (see section 4.2).
2

For children with possible intravascular volume depletion (e.g. patients treated with
diuretics, particularly those with impaired renal function), CANDESARTAN
RANBAXY treatment should be initiated under close medical supervision and a lower
starting dose should be considered (see section 4.2).
In post-menarche patients the possibility of pregnancy should be evaluated on a
regular basis. Appropriate information should be given and/or action taken to prevent
the risk of exposure during pregnancy (see sections 4.3 and 4.6)
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.
Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicinal product. (See section 6.1)
Pregnancy
AIIRAs should not be initiated during pregnancy. Unless continued AIIRAs therapy
is considered essential, patients planning pregnancy should be changed to alternative
anti-hypertensive 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).
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) that 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 (>3g/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.
Paediatric population
Interaction studies have only been performed in adults.
4.6

Fertility, pregnancy and lactation

Pregnancy

The use of Angiotensin II Receptor Inhibitors 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 also
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 also sections 4.3 and 4.4).

Lactation

Because no information is available regarding the use of CANDESARTAN
RANBAXY during breast feeding, CANDESARTAN RANBAXY 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 RANBAXY.

4.8

Undesirable effects

Treatment of Hypertension

In controlled clinical studies adverse reactions were mild and transient. The overall
incidence of adverse events showed no association with dose or age. Withdrawals
from treatment due to adverse events were similar with candesartan cilexetil (3.1%)
and placebo (3.2%).

In a pooled analysis of clinical trial data of hypertensive patients, adverse reactions
with candesartan cilexetil were defined based on an incidence of adverse events with
candesartan cilexetil at least 1 % higher than the incidence seen with placebo. By this
definition, the most commonly reported adverse reactions were dizziness/vertigo,
headache and respiratory infection.
The table below presents adverse reactions from clinical trials and post-marketing
experience.
The frequencies used in the tables throughout section 4.8 are: Very common (≥ 1/10),
Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < 1/100), Rare (≥ 1/10,000 to
< 1/1,000), Very rare (< 1/10,000).
System Organ Class
Infections and infestations
Blood and lymphatic
system disorders
Metabolism and nutrition
disorders
Nervous system disorders
Gastrointestianl disorders
Hepato-biliary disorders
Skin and subcutaneous
tissue disorders
Musculoskeletal and
connective tissue disorders
Renal and urinary
disorders

Frequency
Common
Very rare
Very rare
Common
Very rare
Very rare
Very rare
Very rare
Very rare

Undesirable Effect
Respiratory infection
Leukopenia, neutropenia and
agranulocytosis
Hyperkalaemia, hyponatraemia
Dizziness/vertigo, headache
Nausea
Increased liver enzymes, abnormal
hepatic function or hepatitis
Angioedema, rash, urticaria,
pruritus
Back pain, arthralgia, myalgia
Renal impairment, including renal
failure in susceptible patients (see
section 4.4)

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

Treatment of Heart Failure

The adverse experience profile of candesartan in 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
Blood
and
lymphatic Very rare
system disorders
Metabolism and nutrition
Common
disorders
Very rare
Nervous system disorders
Very rare
Vascular disorders
Common
Gastrointestianl disorders
Very rare
Hepato-biliary disorders
Very rare
Skin and subcutaneous
Very rare
tissue disorders
Musculoskeletal and
Very rare
connective tissue disorders
Renal and urinary disorders Common

Undesirable Effect
Leukopenia, neutropenia and
agranulocytosis
Hyperkalaemia
Hyponatraemia
Dizziness, headache
Hypotension
Nausea
Increased liver enzymes, abnormal
hepatic function or hepatitis
Angioedema, rash, urticaria,
pruritus
Back pain, arthralgia, myalgia
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 BASICS for the indication of heart failure. Periodic monitoring of
serum creatinine and potassium is recommended (see section 4.4).
Paediatric population
The safety of candesartan cilexetil was monitored in 255 hypertensive children and
adolescents, aged 6 to <18 years old, during a 4 week clinical efficacy study and a 1
year open label study (see section 5.1). In nearly all different system organ classes, the
frequency of adverse events in children are within common/uncommon range. Whilst
the nature and severity of the adverse events are similar to those in adults (see the
table above), the frequency of all adverse events are higher in children and adolescent,
particularly in:
• Headache, dizziness and upper respiratory tract infection, are “very common” (ie,
≥1/10) in children and common (≥ 1/100 to < 1/10) in adults.
• Cough is “very common” (ie, > 1/10) in children and very rare (<1/10,000) in
adults.
• Rash is “common” (ie, ≥1/100 to <1/10) in children and “very rare” (<1/10,000) in
adults.
• 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.
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), 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: C09 CA 06
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.

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.

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%
confidence level interval 15-42%). There are 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 149/82mmHg
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).
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
randomized 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 8mg 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%), CHARM-Added
(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 all-cause 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 hospitalization, 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 betablockers 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 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
t1/2 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 t1/2 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 weighting 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.
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).
Foetotoxicity has been observed in late pregnancy (see section 4.6).

Data from in vitro and in vivo mutagenicity testing indicate that candesartan will not
exert mutagenic or clastogenic activities under conditions of clinical use.
There was no evidence of carcinogenicity.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
CANDESARTAN RANBAXY 8 mg:
Carmellose calcium, Hyprolose, Iron oxide red (E172), Lactose monohydrate,
Magnesium stearate, Maize starch, Macrogol 6000

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

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

6.5

Nature and contents of container
PVC/PE/PVDC/Aluminium blister
Pack sizes 7,14,15, 20, 28,30,50, 56,90, 98,100 tablets

Not all pack sizes may be marketed.

6.6

Special precautions for disposal
ANY UNUSED PRODUCT OR WASTE SHOULD BE DISPOSED OF IN
ACCORDANCE WITH LOCAL REQUIREMENTS.

7

MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Limited
Building 4, Chiswick Park, W4 5YE London
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 14894/0538

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/03/2010

10

DATE OF REVISION OF THE TEXT
31/03/2014

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

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