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CANDESARTAN AND HYDROCHLOROTHIAZIDE 32MG/12.5MG TABLETS

Active substance(s): CANDESARTAN CILEXETIL / HYDROCHLOROTHIAZIDE / CANDESARTAN CILEXETIL / HYDROCHLOROTHIAZIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Candesartan and Hydrochlorothiazide 32mg/12.5mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 32 mg candesartan cilexetil and 12.5 mg
hydrochlorothiazide.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
Candesartan and Hydrochlorothiazide Tablets are yellow, oval, biconvex
(~12x 6 mm) tablets, with a break line on one side.
The tablet can be divided into equal doses.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Candesartan and Hydrochlorothiazide Tablets are indicated for the:
• Treatment of essential hypertension in adult patients whose blood
pressure is not optimally controlled with candesartan cilexetil or
hydrochlorothiazide monotherapy.

4.2

Posology and method of administration
Posology

The recommended dose of Candesartan and Hydrochlorothiazide Tablets is
one tablet once daily.
Dose titration with the individual components (candesartan cilexetil and
hydrochlorothiazide) is recommended. When clinically appropriate a direct
change from monotherapy to Candesartan and Hydrochlorothiazide Tablets

may be considered. Dose titration of candesartan cilexetil is recommended
when switching from hydrochlorothiazide monotherapy. Candesartan and
Hydrochlorothiazide Tablets may be administered in patients whose blood
pressure is not optimally controlled with candesartan cilexetil or
hydrochlorothiazide monotherapy or Candesartan and Hydrochlorothiazide
Tablets at lower doses (.
Most of the antihypertensive effect is usually attained within 4 weeks of
initiation of treatment.
Special populations
Elderly population
No dose adjustment is necessary in elderly patients.
Patients with intravascular volume depletion
Dose titration of candesartan cilexetil is recommended in patients at risk for
hypotension, such as patients with possible volume depletion (an initial dose
of candesartan cilexetil of 4 mg may be considered in these patients).
Patients with renal impairment
Loop diuretics are preferred to thiazides in this population. Dose titration of
candesartan cilexetil is recommended in patients with mild to moderate renal
impairment (creatinine clearance 30≥ml/min/1.73 m2 Body Surface Area
(BSA)) before treatment with Candesartan and Hydrochlorothiazide Tablets
(the recommended starting dose of candesartan cilexetil is 4 mg in these
patients)
Candesartan and Hydrochlorothiazide Tablets are contraindicated in patients
with severe renal impairment (creatinine clearance < 30ml/min/1.73 m2 BSA)
(see section 4.3).
Patients with hepatic impairment
Dose titration of candesartan cilexetil is recommended in patients with mild to
moderate hepatic impairment. before treatment with Candesartan and
Hydrochlorothiazide Tablets (the recommended starting dose of candesartan
cilexetil is 4 mg in these patients). Candesartan and Hydrochlorothiazide
Tablets is contraindicated in patients with severe hepatic impairment and/or
cholestasis (see section4.3).
Paediatric population
The safety and efficacy of Candesartan and Hydrochlorothiazide Tablets in
children aged between birth and 18 years have not been established. No data
are available.
Method of administration
Oral use.
Candesartan and Hydrochlorothiazide Tablets can be taken with or without
food.
The bioavailability of candesartan is not affected by food.

There is no clinically significant interaction between hydrochlorothiazide and
food.

4.3

Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in
section 6.1 or to sulfonamide derived active substances. Hydrochlorothiazide
is a sulfonamide derived active substance.
Second and third trimesters of pregnancy (see sections4.4 and 4.6)
Severe renal impairment (creatinine clearance<30 ml/min/1.73m2 BSA).
Severe hepatic impairment and/or cholestasis.
Refractory hypokalaemia and hypercalcaemia.
Gout.
The concomitant use of Candesartan and Hydrochlorothiazide Tablets 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/kidney transplantation
Loop diuretics are preferred to thiazides in this population. When Candesartan
and Hydrochlorothiazide Tablets is used in patients with impaired renal
function, a periodic monitoring of potassium, creatinine and uric acid levels is
recommended.
There is no experience regarding the administration of Candesartan and
Hydrochlorothiazide Tablets in patients with recent kidney transplantation.
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.

Intravascular volume depletion
In patients with intravascular volume and/or sodium depletion symptomatic
hypotension may occur, as described for other agents acting on the reninangiotensin-aldosterone system. Therefore, the use of Candesartan and
Hydrochlorothiazide Tablets is not recommended until this condition has been
corrected.
Anaesthesia and surgery
Hypotension may occur during anaesthesia and surgery in patients treated with
AIIRAs 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.
Hepatic impairment
Thiazides should be used with caution in patients with impaired hepatic
function or progressive liver disease, since minor alterations of fluid and
electrolyte balance may precipitate hepatic coma. There is no clinical
experience with Candesartan and Hydrochlorothiazide Tablets in patients with
hepatic impairment.
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 generally will not respond to
antihypertensive agents acting through inhibition of the renin-angiotensinaldosterone system. Therefore the use of Candesartan and Hydrochlorothiazide
Tablets is not recommended in this population.
Electrolyte imbalance
Periodic determination of serum electrolytes should be performed at
appropriate intervals. Thiazides, including hydrochlorothiazide, can cause
fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia,
hypomagnesaemia and hypochloraemic alkalosis).
Thiazide diuretics may decrease the urinary calcium excretion and may cause
intermittent and slightly increased serum calcium concentrations. Marked
hypercalcaemia may be a sign of hidden hyperparathyroidism. Thiazides
should be discontinued before carrying out tests for parathyroid function.
Hydrochlorothiazide dose-dependently increases urinary potassium excretion
which may result in hypokalaemia. This effect of hydrochlorothiazide seems
to be less evident when combined with candesartan cilexetil. The risk for
hypokalaemia may be increased in patients with cirrhosis of the liver, in
patients experiencing brisk diuresis, in patients with an inadequate oral intake
of electrolytes and in patients receiving concomitant therapy with
corticosteroids or adrenocorticotropic hormone (ACTH).

Treatment with candesartan cilexetil may cause hyperkalaemia, especially in
the presence of heart failure and/or renal impairment. Concomitant use of
Candesartan and Hydrochlorothiazide Tablets and ACE inhibitors, aliskiren,
potassium-sparing diuretics, potassium supplements or salt substitutes or other
medicinal products that may increase serum potassium levels (e.g. heparin
sodium) may lead to increases in serum potassium. Monitoring of potassium
should be undertaken as appropriate.
Thiazides have been shown to increase the urinary excretion of magnesium,
which may result in hypomagnesaemia.
Metabolic and endocrine effects
Treatment with a thiazide diuretic may impair glucose tolerance. Dose
adjustment of antidiabetic medicinal products, including insulin, may be
required. Latent diabetes mellitus may become manifest during thiazide
therapy. Increases in cholesterol and triglyceride levels have been associated
with thiazide diuretic therapy. At the doses contained in Candesartan and
Hydrochlorothiazide Tablets, only minimal effects were observed. Thiazide
diuretics increase serum uric acid concentration and may precipitate gout in
susceptible patients.
Photosensitivity
Cases of photosensitivity reactions have been reported during use of thiazide
diuretics (see section 4.8). If a photosensitivity reaction occurs, it is
recommended to stop treatment. If re-administration of treatment is essential,
it is recommended to protect areas exposed to the sun or to artificial UVA
radiation.
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 medicinal products that affect this system
including AIIRAs, has been associated with acute hypotension, azotaemia,
oliguria or, rarely, acute renal failure. As with any antihypertensive agent,
excessive blood pressure decrease in patients with ischaemic heart disease or
atherosclerotic cerebrovascular disease could result in a myocardial infarction
or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with
or without a history of allergy or bronchial asthma, but are more likely in
patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported
with the use of thiazide diuretics.
The antihypertensive effect of Candesartan and Hydrochlorothiazide Tablets
may be enhanced by other antihypertensives.
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).

4.5

Interaction with other medicinal products and other forms of interaction
Compounds which have been investigated in clinical pharmacokinetic studies
include warfarin, digoxin, oral contraceptives (i.e.
ethinylestradiol/levonorgestrel), glibenclamide and nifedipine. No
pharmacokinetic interactions of clinical significance were identified in these
studies.
The potassium depleting effect of hydrochlorothiazide could be expected to be
potentiated by other medicinal products associated with potassium loss and
hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin,
carbenoxolone, penicillin G sodium, salicylic acid derivates, steroids, ACTH).
Concomitant use of Candesartan and Hydrochlorothiazide Tablets and
potassium-sparing diuretics, potassium supplements or salt substitutes or other
medicinal products that may increase serum potassium levels (e.g. heparin
sodium) may lead to increases in serum potassium. Monitoring of potassium
should be undertaken as appropriate (see section 4.4).
Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the
potential cardiotoxic effects of digitalis glycosides and antiarrhythmics.
Periodic monitoring of serum potassium is recommended when Candesartan
and Hydrochlorothiazide Tablets are administered with such medicinal
products, and with the following medicinal products that could induce torsades
de pointes:
• Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine,
disopyramide)


Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)



Some antipsychotics (e.g. thioridazine, chlorpromazine,
levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride,
amisulpride, tiapride, pimozide, haloperidol, droperiodol)



Others (e.g. bepridil, cisapride, diphemanil, erythromycin iv,
halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacine,
terfenadine, vincamine iv)

Reversible increases in serum lithium concentrations and toxicity have been
reported during concomitant administration of lithium with Angiotensin
Converting Enzyme (ACE) inhibitors or hydrochlorothiazide. A similar effect
has also been reported with AIIRAs. Use of candesartan and
hydrochlorothiazide 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.
The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is
blunted by NSAIDs.
The absorption of hydrochlorothiazide is reduced by colestipol or
cholestyramine.
The effect of nondepolarising skeletal muscle relaxants (e.g. tubocurarine)
may be potentiated by hydrochlorothiazide.
Thiazide diuretics may increase serum calcium levels due to decreased
excretion. If calcium supplements or Vitamin D must be prescribed, serum
calcium levels should be monitored and the dose adjusted accordingly.
The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced
by thiazides.
Anticholinergic agents (e.g. atropine, biperiden) may increase the
bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility
and stomach emptying rate.
Thiazide may increase the risk of adverse effects caused by amantadine.
Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g.
cyclophosphamide, methotrexate) and potentiate their myelosuppressive
effects.
Postural hypotension may become aggravated by simultaneous intake of
alcohol, barbiturates or anaesthetics.
Treatment with a thiazide diuretic may impair glucose tolerance. Dose
adjustment of antidiabetic medicinal products, including insulin, may be
required. Metformin should be used with caution because of the risk of lactic
acidosis induced by possible functional renal failure linked to
hydrochlorothiazide.
Hydrochlorothiazide may cause the arterial response to pressor amines (e.g.
adrenaline) to decrease but not enough to exclude a pressor effect.
Hydrochlorothiazide may increase the risk of acute renal insufficiency
especially with high doses of iodinated contrast media.
Concomitant treatment with cyclosporine may increase the risk of
hyperuricaemia and gout-type complications.
Concomitant treatment with baclofen, amifostin, tricyclic antidepressants or
neuroleptics may lead to enhancement of the antihypertensive effect and may
induce hypotension.
Clinical trial data has shown that dual blockade of the renin-angiotensinaldosterone-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).

4.6

Fertility, pregnancy and lactation
Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs):
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).
Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy,
especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological
mechanism of action of hydrochlorothiazide its use during the second and
third trimesters may compromise foeto-placental perfusion and may cause
foetal and neonatal effects like icterus, disturbance of electrolyte balance and
thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational
hypertension or preeclampsia due to the risk of decreased plasma volume and
placental hypoperfusion, without a beneficial effect on the course of the
disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant
women except in rare situations where no other treatment could be used.
Breast-feeding
Angiotensin II Receptor Antagonists (AIIRAs):
Because no information is available regarding the use of Candesartan and
Hydrochlorothiazide Tablets during breastfeeding, Candesartan and
Hydrochlorothiazide Tablets are not recommended and alternative treatments
with better established safety profiles during breast-feeding are preferable,
especially while nursing a newborn or preterm infant.
Hydrochlorothiazide:
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in
high doses causing intense diuresis can inhibit the milk production. The use of
Candesartan and Hydrochlorothiazide Tablets during breast-feeding is not
recommended.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. When driving vehicles or operating machines, it should be taken
into account that occasionally dizziness or weariness may occur during
treatment with Candesartan and Hydrochlorothiazide Tablets.

4.8

Undesirable effects
In controlled clinical studies with candesartan cilexetil/hydrochlorothiazide
adverse reactions were mild and transient. Withdrawals from treatment due to
adverse events were similar with candesartan cilexetil/hydrochlorothiazide
(2.3-3.3%) and placebo (2.7-4.3%).
In clinical trials with candesartan cilexetil/hydrochlorothiazide, adverse
reactions were limited to those that were reported previously with candesartan
cilexetil and/or hydrochlorothiazide.
The table below presents adverse reactions with candesartan cilexetil from
clinical trials and post marketing experience. 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.
The frequencies used in the tables throughout section4.8 are: very common (≥
1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥
1/10,000 to < 1/1,000), very rare (<1/10,000) and not known (cannot be
estimated from the available data).
System Organ Class
Infections and infestations
Blood and lymphatic system
disorders
Metabolism and nutrition
disorders
Nervous system disorders
Respiratory,
thoracic
and
mediastinal disorders
Gastrointestinal disorders
Hepatobiliary disorders

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

Skin and subcutaneous tissue Very rare
disorders
Musculoskeletal
and Very rare
connective tissue disorders
Renal and urinary disorders
Very rare

Undesirable Effect
Respiratory infection
Leukopenia,
neutropenia
and agranulocytosis
Hyperkalaemia,
hyponatraemia
Dizziness/vertigo, headache
Cough
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)

The table below presents adverse reactions with hydrochlorothiazide
monotherapy usually with doses of 25 mg or higher.
System Organ Class
Frequency
Blood and lymphatic system Rare
disorders

Immune system disorders
Metabolism
disorders

and

Rare

nutrition Common

Psychiatric disorders

Rare

Nervous system disorders

Common
Rare
Rare
Not known

Eye disorders

Cardiac disorders
Vascular disorders

Respiratory,
thoracic
mediastinal disorders

Rare
Uncommon
Rare

and Rare

Gastrointestinal disorders

Uncommon

Hepatobiliary disorders

Rare
Rare

Skin and subcutaneous tissue Uncommon
disorders
Rare

Musculoskeletal
and Rare
connective tissue disorders
Renal and urinary disorders
Common

Undesirable Effect
Leukopenia,
neutropenia/agranulocytosis
, thrombocytopenia, aplastic
anaemia, bone marrow
depression,
haemolytic
anaemia
Anaphylactic reactions
Hyperglycaemia,
hyperuricaemia, electrolyte
imbalance
(including
hyponatraemia
and
hypokalaemia)
Sleep
disturbances,
depression, restlessness
Light-headedness, vertigo
Paraesthesia
Transient blurred vision
Acute myopia, acute angleclosure glaucoma
Cardiac arrhythmias
Postural hypotension
Necrotising
angiitis
(vasculitis,
cutaneous
vasculitis)
Respiratory
distress
(including pneumonitis and
pulmonary oedema)
Anorexia, loss of appetite,
gastric irritation, diarrhoea,
constipation
Pancreatitis
Jaundice
(intrahepatic
cholestatic jaundice)
Rash,
urticaria,
photosensitivity reactions
Toxic epidermal necrolysis,
systemic lupus
erythematosus, cutaneous
lupus erythematosus

Muscle spasm
Glycosuria

System Organ Class

Frequency
Rare

General
disorders
and Common
administration site conditions
Rare
Investigations
Common
Rare

Undesirable Effect
Renal dysfunction
interstitial nephritis
Weakness

and

Fever
Increases in cholesterol and
triglycerides
Increases in BUN and
serum creatinine

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 Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms
Based on pharmacological considerations, the main manifestation of an
overdose of candesartan cilexetil 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.
The main manifestation of an overdose of hydrochlorothiazide is acute loss of
fluid and electrolytes. Symptoms such as dizziness, hypotension, thirst,
tachycardia, ventricular arrhythmias, sedation/impairment of consciousness
and muscle cramps can also be observed.
Management
No specific information is available on the treatment of overdose with
Candesartan and Hydrochlorothiazide Tablets. The following measures are,
however, suggested in case of overdose.
When indicated, induction of vomiting or gastric lavage should be considered.
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 isotonic saline solution. Serum electrolyte and acid balance
should be checked and corrected, if needed. Sympathomimetic medicinal
products may be administered if the above-mentioned measures are not
sufficient.
Candesartan cannot be removed by haemodialysis. It is not known to what
extent hydrochlorothiazide is removed by haemodialysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmaco-therapeutic group: Angiotensin II antagonists and diuretics, ATC
code: C09DA06.
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 and other cardiovascular disorders. It also has a role in the
pathogenesis of organ hypertrophy and end organ 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 which is rapidly converted to the active
drug, 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.
Clinical efficacy and safety
Candesartan does not influence ACE or other enzyme systems usually
associated with the use of ACE inhibitors. Since there is no effect on the
degradation of kinins, or on the metabolism of other substances, such as
substance P, AIIRAs are unlikely to be associated with cough. In controlled
clinical trials comparing candesartan cilexetil 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
AT1 receptors results in dose related increases in plasma renin levels,
angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone
concentration.
The effects of candesartan cilexetil 8-16mg (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 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).

Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the
distal kidney tubules, and promotes the excretion of sodium, chloride and
water. The renal excretion of potassium and magnesium increases dosedependently, while calcium is reabsorbed to a greater extent.
Hydrochlorothiazide decreases plasma volume and extracellular fluid and
reduces cardiac output and blood pressure. During long-term therapy, reduced
peripheral resistance contributes to the blood pressure reduction.
Large clinical studies have shown that long-term treatment with
hydrochlorothiazide reduces the risk for cardiovascular morbidity and
mortality.
Candesartan and hydrochlorothiazide have additive antihypertensive effects.
In hypertensive patients, candesartan and hydrochlorothiazide result in a dosedependent and long-lasting reduction in arterial blood pressure 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 and hydrochlorothiazide, onset
of the antihypertensive effect generally occurs within 2 hours. With
continuous treatment, most of the reduction in blood pressure is attained
within four weeks and is sustained during long-term treatment. Candesartan
and hydrochlorothiazide once daily provides effective and smooth blood
pressure reduction over 24 hours, with little difference between maximum and
trough effects during the dosing interval. In a double-blind randomised study,
candesartan and hydrochlorothiazide 16 mg/12.5 mg once daily reduced blood
pressure significantly more, and controlled significantly more patients, than
the combination losartan/hydrochlorothiazide 50 mg/12.5 mg once daily.
In double-blind, randomised studies, the incidence of adverse events,
especially cough, was lower during treatment with candesartan and
hydrochlorothiazide than during treatment with combinations of ACE
inhibitors and hydrochlorothiazide.
In two clinical studies (randomised, double-blind, placebo controlled, parallel
group) including 275 and 1524 randomised patients, respectively, the
candesartan cilexetil and hydrochlorothiazide combinations 32 mg/12.5 mg
and 32 mg/25 mg resulted in blood pressure reductions of 22/15 mmHg and
21/14 mmHg, respectively, and were significantly more effective than the
respective monocomponents.
In a randomised, double-blind, parallel group clinical study including 1975
randomised patients not optimally controlled on 32 mg candesartan cilexetil
once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in
additional blood pressure reductions. The candesartan cilexetil and
hydrochlorothiazide combination 32 mg/25 mg was significantly more
effective than the 32 mg/12.5 mg combination, and the overall mean blood
pressure reductions were 16/10 mmHg and 13/9 mmHg, respectively.
Candesartan cilexetil/hydrochlorothiazide is similarly effective in patients
irrespective of age and gender.
Currently there are no data on the use of candesartan
cilexetil/hydrochlorothiazide in patients with renal disease/nephropathy,
reduced left ventricular function/congestive heart failure and post myocardial
infarction.

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 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 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
The European Medicines Agency has waived the obligation to submit the
results of studies with Candesartan and Hydrochlorothiazide Tablets in all
subsets of the paediatric population in essential hypertension (see section 4.2
for information on paediatric use).

5.2

Pharmacokinetic properties
Concomitant administration of candesartan cilexetil and hydrochlorothiazide
has no clinically significant effect on the pharmacokinetics of either medicinal
product.
Absorption and distribution
Candesartan cilexetil
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 a tablet formulation of candesartan cilexetil compared with
the same oral solution is approximately 34% with very little variability. 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.
Hydrochlorothiazide
Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an
absolute bioavailability of approximately 70%. Concomitant intake of food
increases the absorption by approximately 15%. The bioavailability may
decrease in patients with cardiac failure and pronounced oedema.
The plasma protein binding of hydrochlorothiazide is approximately 60%. The
apparent volume of distribution is approximately 0.8 l/kg.
Biotransformation and elimination
Candesartan cilexetil
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 medicinal
products whose metabolism is dependent upon cytochrome P450 isoenzymes
CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4.
The terminal half-life (t½) of candesartan is approximately 9 hours. There is no
accumulation following multiple doses. The half-life of candesartan remains
unchanged (approximately 9 h) after administration of candesartan cilexetil in
combination with hydrochlorothiazide. No additional accumulation of
candesartan occurs after repeated doses of the combination compared to
monotherapy.
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.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolised and is excreted almost entirely as
unchanged drug by glomerular filtration and active tubular secretion. The
terminal t½ of hydrochlorothiazide is approximately 8 hours. Approximately
70% of an oral dose is eliminated in the urine within 48 hours. The half-life of
hydrochlorothiazide remains unchanged (approximately 8 h) after
administration of hydrochlorothiazide in combination with candesartan
cilexetil. No additional accumulation of hydrochlorothiazide occurs after
repeated doses of the combination compared to monotherapy.
Pharmacokinetics in special populations
Candesartan cilexetil
In elderly subjects (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 and hydrochlorothiazide 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 the terminal 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 pharmacokinetics in patients undergoing haemodialysis were
similar to those 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.
Hydrochlorothiazide
The terminal t½ of hydrochlorothiazide is prolonged in patients with renal
impairment.

5.3

Preclinical safety data
There were no qualitative new toxic findings with the combination compared
to that observed for each component. In preclinical safety studies candesartan
itself 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 regeneration, dilatation and basophilia in 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. Addition of hydrochlorothiazide potentiates the nephrotoxicity
of candesartan. Furthermore, candesartan induced hyperplasia/hypertrophy of
the juxtaglomerular cells. These changes were considered to be caused by the
pharmacological action of candesartan and to be of little clinical relevance.
Foetotoxicity has been observed in late pregnancy with candesartan. The
addition of hydrochlorothiazide did not significantly affect the outcome of
foetal development studies in rats, mice or rabbits (see section 4.6).
Candesartan and hydrochlorothiazide both show genotoxic activity at very
high concentrations/doses. Data from in vitro and in vivo genotoxicity testing
indicate that candesartan and hydrochlorothiazide are unlikely to exert any
mutagenic or clastogenic activity under conditions of clinical use.
There was no evidence that either compound is carcinogenic.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Mannitol

Maize starch
Copovidone
Ferric oxide, yellow
Glycerol
Magnesium stearate

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/Aluminium/PVC-Aluminium blister packs containing 28 tablets.

6.6

Special precautions for disposal
No special requirements.

7

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

8

MARKETING AUTHORISATION NUMBER(S)

´PL 20416/0345

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/07/2017

10

DATE OF REVISION OF THE TEXT
14/07/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

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