Atacand® Plus
Candesartan
Cilexetil--Hydrochlorothiazide
Angiotensin II AT1 Receptor Blocker--Diuretic
AstraZeneca
http://www.astrazeneca-us.com/default.asp
Atacand Plus Monograph PDF download here.
CPS:PIS_m070375
Date of Preparation: May 29, 2001
Date of Revision: April 13, 2004
Pharmacology
Atacand Plus combines the actions of candesartan
cilexetil, an angiotensin II AT1 receptor blocker, and that of a
thiazide diuretic, hydrochlorothiazide.
Candesartan Cilexetil: Candesartan cilexetil
antagonizes the action of angiotensin II by blocking the angiotensin type 1 (AT1)
receptor. Angiotensin II is the primary vasoactive hormone of the
renin-angiotensin-aldosterone system with effects that include
vasoconstriction, stimulation of aldosterone secretion, and renal reabsorption
of sodium.
Candesartan cilexetil,
a prodrug, is rapidly converted to the active drug, candesartan, during
absorption from the gastrointestinal tract.
Candesartan blocks the
vasoconstrictor and aldosterone secreting effects of angiotensin II by
selectively blocking the binding of angiotensin II to the AT1
receptor in many tissues, such as vascular smooth muscle and the adrenal gland.
Its action is therefore independent of the pathways for angiotensin II
synthesis. There are also AT2 receptors found in many tissues, but
they play no known role in cardiovascular homeostasis to date. Candesartan has
a much greater affinity (>10,000-fold) for the AT1 receptor than
for the AT2 receptor.
Candesartan does not
inhibit angiotensin converting enzyme (ACE), also known as kininase II, the
enzyme that converts angiotensin I to angiotensin II and degrades bradykinin,
nor does it bind to or block other hormone receptors or ion channels known to
be important in cardiovascular regulation.
Hydrochlorothiazide: Hydrochlorothiazide is a
diuretic and antihypertensive which interferes with the renal tubular mechanism
of electrolyte reabsorption. It 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
dose-dependently, while calcium is reabsorbed to a greater extent. While this
compound is predominantly a saluretic agent, in vitro studies have shown that
it has a carbonic anhydrase inhibitory action which seems to be relatively
specific for the renal tubular mechanism. It does not appear to be concentrated
in erythrocytes or the brain in sufficient amounts to influence the activity of
carbonic anhydrase in those tissues.
Hydrochlorothiazide is
useful in the treatment of hypertension. It may be used alone or as an adjunct
to other antihypertensive drugs. Hydrochlorothiazide does not affect normal
blood pressure.
Pharmacokinetics
Candesartan Cilexetil: Candesartan cilexetil is
rapidly and completely bioactivated by ester hydrolysis during absorption from
the gastrointestinal tract to candesartan. Candesartan is mainly excreted
unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism
by O-deethylation to an inactive metabolite. In vitro studies indicate that
cytochrome P450 isoenzyme CYP 2C9 is involved in the biotransformation of
candesartan to its inactive metabolite. 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 elimination half-life of candesartan is approximately 9 hours.
After single and repeated administration, the pharmacokinetics of candesartan
are linear, for oral doses up to 32 mg. Candesartan and its inactive metabolite
do not accumulate in serum upon repeated once-daily dosing.
Following oral
administration of candesartan cilexetil as a tablet, the absolute
bioavailability of candesartan was estimated to be approximately 15%. After
tablet ingestion, the peak serum concentration (Cmax) is reached
after 3 to 4 hours. Food does not affect the bioavailability of candesartan
after candesartan cilexetil administration.
Total plasma clearance
of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg.
When candesartan cilexetil is administered orally, about 26% of the dose is
excreted as candesartan in urine. Following an oral dose of 14C-labeled
candesartan cilexetil, approximately 33% of radioactivity is recovered in urine
and approximately 67% in feces. Following an i.v. dose of 14C-labeled
candesartan, approximately 59% of radioactivity is recovered in urine and
approximately 36% in feces. Biliary excretion contributes to the elimination of
candesartan.
The volume of
distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma
proteins (>99%) and does not penetrate red blood cells. The protein binding
is constant at candesartan plasma concentrations well above the range achieved
with recommended doses. In rats, it has been demonstrated that candesartan does
cross the blood-brain barrier. It has also been demonstrated in rats that
candesartan passes across the placental barrier and is distributed in the
fetus.
The plasma
concentration of candesartan was higher in the elderly (≥ 65 years) (Cmax
was approximately 50% higher, and AUC was approximately 80% higher) compared to
younger subjects administered the same dose. The pharmacokinetics of
candesartan were linear in the elderly, and candesartan and its inactive
metabolite did not accumulate in the serum of these subjects upon repeated,
once-daily administration.
No gender-related
differences in the pharmacokinetics of candesartan have been observed.
In patients with mild
to moderate renal impairment (Clcreat 31 to 60 mL/min/1.73 m2),
Cmax and AUC of candesartan increased by 40 to 60% and 50 to
90%, respectively, but t1/2 was not altered, compared to patients
with normal renal function (Clcreat >60 mL/min/1.73 m2)
during repeated dosing. There was no drug accumulation in plasma in patients
with mild to moderate renal impairment. The increases in Cmax and
AUC in patients with severe renal impairment (Clcreat 15 to 30
mL/min/1.73 m2) were 40 to 60% and 110%, respectively. The
terminal t1/2 of candesartan was approximately doubled in patients
with severe renal impairment, and these changes resulted in some accumulation
in plasma. The pharmacokinetics of candesartan in patients undergoing
hemodialysis were similar to those in patients with severe renal impairment
(see Dosage, Impaired Renal Function).
In patients with mild
to moderate hepatic impairment, there was an increase in the AUC of candesartan
of approximately 20%. There was no drug accumulation in plasma in these
patients. In patients with moderate to severe hepatic impairment, the Cmax
and AUC increased up to 5 times in a very small group administered a single
dose of 16 mg candesartan (see Dosage, Impaired Hepatic Function).
Hydrochlorothiazide: Hydrochlorothiazide is
rapidly absorbed from the gastrointestinal tract with an absolute
bioavailability of approximately 70%. Concomitant food intake increases the
absorption by approximately 15%. The bioavailability may decrease in patients
with cardiac failure and pronounced edema. The plasma protein binding of
hydrochlorothiazide is approximately 60%. The apparent volume of distribution
is approximately 0.8 L/kg.
Hydrochlorothiazide is
not metabolized and is excreted almost entirely as unchanged drug by glomerular
filtration and active tubular secretion. The terminal t1/2 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 (8 hours) after administration of
hydrochlorothiazide in combination with candesartan cilexetil. No accumulation
of hydrochlorothiazide occurs after repeated doses of the combination compared
to monotherapy.
The terminal t1/2
of hydrochlorothiazide is prolonged in the elderly and in patients with renal
failure or chronic heart failure.
Hydrochlorothiazide
crosses the placental but not the blood-brain barrier and is excreted in breast
milk.
Pharmacodynamics: Candesartan Cilexetil:
Candesartan inhibits the pressor effects of angiotensin II infusion in a
dose-dependent manner. After 1 week of once-daily dosing of 8 mg candesartan
cilexetil, the pressor effect was inhibited by approximately 90% at peak (4 to
8 hours after dosing) with approximately 50% inhibition persisting at 24 hours.
Plasma concentrations of angiotensin I, angiotensin II, and plasma renin
activity, increased in a dose-dependent manner after single and repeated
administration of candesartan cilexetil to healthy subjects and hypertensive
patients. A decrease in the plasma concentration of aldosterone was observed
when 32 mg of candesartan cilexetil was administered to hypertensive patients.
In hypertension,
candesartan cilexetil causes a dose-dependent reduction in arterial blood
pressure. Systemic peripheral resistance is decreased, while heart rate, stroke
volume and cardiac output are not significantly affected. No first-dose
hypotension was observed during controlled clinical trials with candesartan
cilexetil.
Most of the
antihypertensive effect was seen within 2 weeks of initial dosing, and the full
effect in 4 weeks. With once-daily dosing, blood pressure effect was maintained
over 24 hours, with trough to peak ratios of blood pressure effect generally
greater than 80%. Candesartan cilexetil had an additional blood pressure
lowering effect when added to hydrochlorothiazide.
The antihypertensive
effect was similar in men and women and in patients older and younger than 65.
Candesartan was effective in reducing blood pressure regardless of race,
although the effect was somewhat less in black patients (usually a low-renin
population) than in Caucasian patients.
In long-term studies of
up to 1 year, the antihypertensive effectiveness of candesartan cilexetil was
maintained, and there was no rebound after abrupt withdrawal.
Comparative Effects: The antihypertensive
efficacy of candesartan cilexetil and losartan potassium have been compared at
their approved once daily maximum doses, 32 mg and 100 mg, respectively, in
patients with mild to moderate essential hypertension. Candesartan cilexetil lowered
systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than
losartan potassium when measured at the time of either peak or trough effect.
Both agents were well tolerated.
ATACAND also reduces
urinary albumin excretion in patients with type II diabetes mellitus,
hypertension and microalbuminuria. In a 12-week study of 161 mildly
hypertensive patients with type II diabetes mellitus, candesartan cilexetil 8
to 16 mg had no effect on mean HbA1c.
Hydrochlorothiazide: Onset of the diuretic
action following oral administration occurs in 2 hours and the peak action in
about 4 hours. Diuretic activity lasts about 6 to 12 hours.
Candesartan Cilexetil/Hydrochlorothiazide:
Candesartan cilexetil and hydrochlorothiazide have additive antihypertensive
effects. After administration of a single dose of Atacand Plus in hypertensive
patients, onset of the antihypertensive effect generally occurs within 2 hours.
With continuous treatment, most of the reduction in blood pressure is attained
within 4 weeks and is sustained during long term treatment. Atacand Plus given
once daily provides effective and smooth blood pressure reduction over 24
hours, with little difference between maximum and trough effects during the
dosing interval and without reflex increase in heart rate. There is no
indication of serious or exaggerated first dose hypotension or rebound effect
after cessation of treatment.
Candesartan
cilexetil/hydrochlorothiazide is similarly effective in patients irrespective
of age and gender.
Indications
For the treatment of essential hypertension in
patients for whom combination therapy is appropriate. Atacand Plus is not
indicated for initial therapy (see Dosage).
Contraindications
In patients who are hypersensitive to any
component of this product. Because of the hydrochlorothiazide component, it is
also contraindicated in patients with anuria, and in patients who are
hypersensitive to other sulfonamide-derived drugs (see Supplied).
Warnings
Pregnancy
Drugs that act directly on the renin-angiotensin
system can cause fetal and neonatal morbidity and death when administered to
pregnant women. When pregnancy is detected, Atacand Plus should be discontinued
as soon as possible.
The use of drugs that
act directly on the renin-angiotensin system during the 2nd and 3rd trimesters
of pregnancy has been associated with fetal and neonatal injury, including
hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible
renal failure, and death. Oligohydramnios has also been reported, presumably
resulting from decreased fetal renal function; oligohydramnios in this setting
has been associated with fetal limb contractures, craniofacial deformation, and
hypoplastic lung development.
Prematurity,
intrauterine growth retardation and patent ductus arteriosus have also been
reported, although it is not clear whether these occurrences were due to
exposure to the drug. These adverse effects do not appear to have resulted from
intrauterine drug exposure that has been limited to the first trimester.
Mothers whose embryos
and fetuses are exposed to an angiotensin II AT1 receptor antagonist
during the first trimester should be so informed. Nonetheless, when patients
become pregnant, physicians should have the patient discontinue the use of candesartan
cilexetil as soon as possible.
Rarely (probably less
than 1 in every 1000 pregnancies), no alternative to an angiotensin II AT1
receptor antagonist will be found. In these rare cases, the mothers should be
apprised of the potential hazards to their fetuses and serial ultrasound
examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is
observed, candesartan cilexetil should be discontinued unless it is considered
life-saving for the mother. Contraction stress testing (CST), a non-stress test
(NST) or biophysical profiling (BPP) may be appropriate, depending on the week
of pregnancy. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible
injury.
Infants with histories
of in utero exposure to an angiotensin II AT1 receptor antagonist
should be closely observed for hypotension, oliguria, and hyperkalemia. If
oliguria occurs, attention should be directed toward support of blood pressure
and renal perfusion. Exchange transfusion may be required as a means of
reversing hypotension and/or substituting for impaired renal function.
Candesartan cilexetil is not removed from plasma by dialysis.
Thiazides cross the
placental barrier and appear in cord blood. The routine use of diuretics in
otherwise healthy pregnant women is not recommended and exposes mother and
fetus to unnecessary hazard including fetal or neonatal jaundice,
thrombocytopenia and possibly other adverse experiences which have occurred in
the adult. Diuretics do not prevent development of toxemia of pregnancy and
there is no satisfactory evidence that they are useful in the treatment of
toxemia.
Animal Data: Oral doses ≥ 10 mg
candesartan cilexetil/kg/day administered to pregnant rats during late
gestation and continued through lactation were associated with reduced survival
and an increased incidence of hydronephrosis in the offspring. Candesartan
cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day caused
maternal toxicity (decreased body weight and death) but, in surviving dams, had
no adverse effects on fetal survival, fetal weight, or external, visceral, or
skeletal development. No maternal toxicity or adverse effects on fetal
development were observed when oral doses up to 1000 mg candesartan
cilexetil/kg/day were administered to pregnant mice.
Hypotension: Occasionally, symptomatic
hypotension has occurred after administration of candesartan cilexetil. It is
more likely to occur in patients who are volume-depleted by diuretic therapy,
dietary salt restriction, dialysis, diarrhea or vomiting, or undergoing surgery
with anesthesia. In these patients, because of the potential fall in blood
pressure, therapy should be started under close medical supervision. Similar
considerations apply to patients with ischemic heart or cerebrovascular
disease, in whom an excessive fall in blood pressure could result in myocardial
infarction or cerebrovascular accident.
Azotemia: Azotemia may be precipitated or
increased by hydrochlorothiazide. Cumulative effects of the drug may develop in
patients with impaired renal function. If increasing azotemia and oliguria
occur during treatment of severe progressive renal disease the diuretic should
be discontinued.
Hypersensitivity Reactions: Sensitivity
reactions to hydrochlorothiazide may occur in patients with or without a
history of allergy or bronchial asthma.
The possibility of
exacerbation or activation of systemic lupus erythematosus has been reported in
patients treated with hydrochlorothiazide.
Precautions
Renal Impairment: As a consequence of inhibiting
the renin-angiotensin-aldosterone system, changes in renal function have been
seen in susceptible individuals. In patients whose renal function may depend on
the activity of the renin-angiotensin-aldosterone system, such as patients with
bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary
kidney, or severe congestive heart failure, treatment with agents that inhibit
this system has been associated with oliguria, progressive azotemia, and
rarely, acute renal failure and/or death. In susceptible patients, concomitant
diuretic use may further increase risk.
Use of candesartan
cilexetil should include appropriate assessment of renal function.
Thiazides should be
used with caution.
Because of the
hydrochlorothiazide component, Atacand Plus (candesartan
cilexetil/hydrochlorothiazide) is not recommended in patients with severe renal
impairment (creatinine clearance <30 mL/min/1.73 m2 BSA).
Liver Impairment: Thiazides should be used with
caution in patients with impaired hepatic function or progressive liver
disease, since minor alterations of fluid or electrolyte balance may
precipitate hepatic coma (see Dosage, Impaired Hepatic Function).
No studies were carried
out with candesartan cilexetil/hydrochlorothiazide fixed combination in
patients with impaired hepatic function.
Metabolism: Patients receiving thiazides should
be carefully observed for clinical signs of fluid and electrolyte imbalance
(hyponatremia, hypochloremic alkalosis and hypokalemia). Periodic
determinations of serum electrolytes, to detect possible electrolyte
disturbance, should be performed at appropriate intervals. Warning signs or
symptoms of fluid and electrolyte imbalance include dryness of the mouth,
thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps,
muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal
disturbances such as nausea and vomiting.
Hypokalemia may
develop, especially with brisk diuresis, when severe cirrhosis is present, or
after prolonged therapy.
Interference with
adequate oral electrolyte intake will also contribute to hypokalemia.
Hypokalemia can sensitize or exaggerate the response of the heart to the toxic
effects of digitalis (e.g., increased ventricular irritability).
Any chloride deficit
during thiazide therapy is generally mild and usually does not require specific
treatment except under extraordinary circumstances (as in liver disease or
renal disease). Dilutional hyponatremia may occur in edematous patients in hot
weather. Appropriate therapy is water restriction rather than administration of
salt, except in rare instances, when the hyponatremia is life threatening. In
actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur
or acute gout may be precipitated in certain patients receiving thiazide
therapy.
Thiazides may decrease
serum PBI levels without signs of thyroid disturbance.
Thiazides have been
shown to increase excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease
urinary calcium excretion and may cause intermittent and slight elevation of
serum calcium in the absence of known disorders of calcium metabolism. Marked
hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should
be discontinued before carrying out tests for parathyroid function.
Increase in
cholesterol, triglycerides and glucose levels may be associated with thiazide
diuretic therapy. However, at the 12.5 mg dose, present in Atacand Plus,
minimal or no effect was reported.
Valvular Stenosis: There is concern on
theoretical grounds that patients with aortic stenosis might be at particular
risk of decreased coronary perfusion when treated with vasodilators because
they do not develop as much afterload reduction.
Lactation
It is not known whether candesartan is excreted
in human milk, but it is excreted in the milk of lactating rats. Thiazides
appear in human milk. Because many drugs are excreted in human milk, and
because of their potential for affecting the nursing infant adversely, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.
Children
The safety and efficacy of Atacand Plus have not
been established in children.
Geriatrics
No overall differences in safety or
effectiveness were observed between the younger and elderly patients but
greater sensitivity of some older patients cannot be ruled out and appropriate
caution is recommended.
Drug Interactions
Diuretics: Patients on diuretics, and especially
those in whom diuretic therapy was recently instituted, may occasionally
experience an excessive reduction of blood pressure after initiation of therapy
with candesartan cilexetil. The possibility of symptomatic hypotension with the
use of candesartan cilexetil can be minimized by discontinuing the diuretic
prior to initiation of treatment and/or lowering the initial dose of
candesartan cilexetil (see Warnings, Hypotension and Dosage). No drug
interaction of clinical significance has been identified in patients treated
with hydrochlorothiazide and candesartan cilexetil.
Agents Increasing Serum Potassium: Since
candesartan cilexetil decreases the production of aldosterone,
potassium-sparing diuretics or potassium supplements should be given only for
documented hypokalemia and with frequent monitoring of serum potassium.
Potassium-containing salt substitutes should also be used with caution.
Concomitant thiazide
diuretic use may attenuate any effect that candesartan cilexetil may have on
serum potassium.
Lithium Salts: As with other drugs which
eliminate sodium, lithium clearance may be reduced. Therefore, serum lithium
levels should be monitored carefully if lithium salts are to be administered.
Lithium generally
should not be given with diuretics. Diuretic agents reduce the renal clearance
of lithium and add a high risk of lithium toxicity.
Warfarin: When candesartan cilexetil was
administered at 16 mg once daily under steady-state conditions, no
pharmacodynamic effect on prothrombin time was demonstrated in subjects
stabilized on warfarin.
Digoxin: Combination treatment with candesartan
cilexetil and digoxin in healthy volunteers had no effect on AUC or Cmax
values for digoxin compared to digoxin alone. Similarly, combination treatment
had no effect on AUC or Cmax values for candesartan compared to
candesartan cilexetil alone.
Thiazide-induced
electrolyte disturbances may predispose to digitalis-induced arrhythmias.
d-Tubocurarine: Thiazide drugs may increase the
responsiveness to tubocurarine.
Insulin: Insulin requirements in diabetic
patients treated with diuretics may be increased, decreased or unchanged.
Diabetes mellitus which has been latent may become manifest during thiazide
administration.
Alcohol, Barbiturates or Narcotics: Thiazide
diuretic potentiation of orthostatic hypotension may occur.
Corticosteroids, ACTH: Intensified electrolyte
depletion, particularly hypokalemia, may occur when given concomitantly with
thiazide diuretics.
Pressor Amines (e.g., norepinephrine): In the
presence of thiazide diuretics possible decreased response to pressor amines
may be seen but not sufficient to preclude their use.
NSAIDs: In some patients, the administration of
an NSAID can reduce the diuretic, natriuretic, and antihypertensive effects of
loop, potassium-sparing and thiazide diuretics. Therefore, when Atacand Plus
and NSAIDs are used concomitantly, the patient should be observed closely to
determine if the desired effect of the diuretic is obtained.
Other: No significant drug interactions have
been reported with glyburide, nifedipine or oral contraceptives coadministered
with candesartan cilexetil to healthy volunteers.
Coadministration of
thiazide diuretics may increase the incidence of hypersensitivity reactions to
allopurinol, may increase the risk of adverse effects caused by amantadine, may
enhance the hyperglycemic effect of diazoxide, and may reduce the renal
excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and
potentiate their myelosuppressive effects.
The bioavailability of
thiazide diuretics may be increased by anticholinergic agents (e.g. atropine,
biperiden), apparently due to a decrease in gastrointestinal motility and the
stomach emptying rate.
There have been reports
in the literature of hemolytic anemia occurring with concomitant use of
hydrochlorothiazide and methyldopa.
Absorption of thiazide
diuretics is decreased by cholestyramine.
Administration of
thiazide diuretics with vitamin D or with calcium salts may potentiate the rise
in serum calcium.
Concomitant treatment
with cyclosporine may increase the risk of hyperuricemia and gout type
complications.
Adverse Effects
Atacand Plus has been evaluated for safety in
over 2500 patients treated for hypertension, including more than
700 treated for 6 months or more, and 500 for about 1 year or more. In placebo-controlled
double-blind trials candesartan cilexetil/hydrochlorothiazide combination was
administered to 1025 hypertensive patients. Approximately 600 patients received
Atacand Plus 16/12.5 mg. The overall exposure to the candesartan cilexetil/hydrochlorothiazide
combination amounts to 977 patient-years.
In general, adverse
events were mild and transient in placebo-controlled clinical studies with
various doses of candesartan cilexetil/hydrochlorothiazide up to 16/25 mg. In
controlled clinical trials, discontinuation due to adverse events occurred in
3.3% and 2.7% of patients treated with Atacand Plus and placebo, respectively.
The incidence of serious adverse events observed with candesartan
cilexetil/hydrochlorothiazide was 2.7% (71 out of 2582 patients).
In the double-blind,
placebo-controlled trials, the overall incidence of adverse events showed no
association with age or gender. In these trials, the following adverse
reactions reported with candesartan cilexetil/hydrochlorothiazide occurred in
≥ 1% of patients, regardless of drug relationship (see Table 1).
CPS:AtacandPlus_t1Click here for Table 1
Table 1: Atacand Plus
Adverse Events Reported with Candesartan
Cilexetil/Hydrochlorothiazide
in ≥% of Patients Regardless of Causality
|
|
Candesartan cilexetil/
hydrochlorothiazide
(n=1025)
|
Candesartan cilexetil
(n=749)
|
Hydrochlorothiazide
(n=603)
|
Placebo
(n=526)
|
|
|
|
(%)
|
(%)
|
(%)
|
(%)
|
|
|
Bodyas a Whole
|
|
Back Pain
|
3.8
|
5.5
|
5.1
|
3.0
|
|
|
Arthralgia
|
1.5
|
1.3
|
1.3
|
0.8
|
|
|
Fatigue
|
1.4
|
1.2
|
1.7
|
1.0
|
|
|
Abdominal Pain
|
1.3
|
1.7
|
0.7
|
1.1
|
|
|
Urinary
|
|
Urinary Tract Infection
|
1.6
|
1.3
|
1.8
|
1.0
|
|
|
Digestive
|
|
Nausea
|
1.5
|
0.9
|
1.2
|
0.6
|
|
|
Diarrhea
|
1.1
|
0.7
|
0.5
|
1.3
|
|
|
Gastroenteritis
|
1.0
|
0.5
|
1.0
|
0.4
|
|
|
Cardiovascular
|
|
Tachycardia
|
1.3
|
0.9
|
1.2
|
0.8
|
|
|
ECG Abnormal
|
1.2
|
1.2
|
0.3
|
0.8
|
|
|
Edema Peripheral
|
1.1
|
1.6
|
2.2
|
1.3
|
|
|
Chest Pain
|
1.0
|
0.7
|
1.0
|
0.6
|
|
|
MetabolicDisorders
|
|
Hyperuricemia
|
1.1
|
0.7
|
0.8
|
0.4
|
|
|
Hyperglycemia
|
1.0
|
0.9
|
0.5
|
0.2
|
|
|
Nervous/Psychiatric
|
|
Headache
|
4.3
|
7.6
|
7.6
|
7.0
|
|
|
Dizziness
|
3.1
|
3.9
|
2.0
|
1.5
|
|
|
Inflicted Injury
|
2.0
|
2.0
|
3.0
|
1.9
|
|
|
Respiratory
|
|
Upper Respiratory Tract Infection
|
3.7
|
5.1
|
5.6
|
1.9
|
|
|
Influenza-like Symptoms
|
2.8
|
2.3
|
3.0
|
2.9
|
|
|
Sinusitis
|
2.3
|
2.9
|
3.5
|
1.9
|
|
|
Bronchitis
|
2.1
|
2.8
|
2.5
|
2.5
|
|
|
Pharyngitis
|
1.4
|
0.9
|
1.0
|
1.7
|
|
|
Cough
|
0.9
|
2.3
|
1.7
|
1.0
|
|
|
Rhinitis
|
1.2
|
1.5
|
1.2
|
0.4
|
|
a At least 653 hypertensive patients
have
been treated with candesartan
cilexetil/hydrochlorothiazide 16/12.5 mg tablets.
Candesartan Cilexetil: The following adverse
events were reported at an incidence of <1% in controlled clinical trials
(in more than 1 patient, with higher frequency than placebo):
Body as a Whole
allergy, asthenia, pain, syncope.
Cardiovascular
angina pectoris, circulatory failure, flushing,
hypotension, myocardial infarction, peripheral ischemia, thrombophlebitis.
Central and Peripheral Nervous System
hypertonia, hypoesthesia, paresthesia, vertigo.
Gastrointestinal
constipation, dyspepsia, dry mouth, toothache.
Hearing
tinnitus.
Metabolic and Nutritional
diabetes mellitus, hyperkalaemia, hyponatraemia.
Musculoskeletal
arthritis, arthropathy, myalgia, myopathy,
skeletal pain, tendon disorder.
Blood
anemia, epistaxis.
Psychiatric
depression, impotence, neurosis.
Reproductive
menopausal symptoms.
Resistance Mechanism
otitis.
Respiratory
laryngitis.
Skin
eczema, pruritus, rash, skin disorder, sweating,
(rarely) urticaria.
