CONTRAINDICATIONS
Candesartan cilexetil is contraindicated in patients who are hypersensitive to any component of this
product.
WARNINGS
Fetal/Neonatal Morbidity and Mortality
Drugs that act directly on the renin—angiotensin system can cause fetal and neonatal morbidity and
death when administered to pregnant women. Several dozen cases have been reported in the world
literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is
detected, candesartan cilexetil should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third
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
receptor antagonist only 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 often than once in every thousand pregnancies), no alternative to a drug
acting on the renin-angiotensin system 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 nonstress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon 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 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 or dialysis may be
required as means of reversing hypotension and/or substituting for disordered renal function.
There is no clinical experience with the use of candesartan cilexetil in pregnant women. Oral doses
³ 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. The 10-mg/kg/day dose in rats is approximately 2.8 times the
maximum recommended daily human dose (MRHD) of 32 mg on a mg/m2 basis (comparison
assumes human body weight of 50 kg). Candesartan cilexetil given to pregnant rabbits at an oral
dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m2 basis) 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 (approximately 138 times the MRHD on a mg/m2 basis) were administered to
pregnant mice.
Hypotension in Volume- and Salt-Depleted Patients
In patients with an activated renin—angiotensin system, such as volume- and/or salt-depleted
patients (e.g., those being treated with diuretics), symptomatic hypotension may occur. These
conditions should be corrected prior to administration of candesartan cilexetil, or the treatment
should start under close medical supervision. (See DOSAGE AND ADMINISTRATION.)
If hypotension occurs, the patients should be placed in the supine position and, if necessary, given an
intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to
further treatment which usually can be continued without difficulty once the blood pressure has
stabilized.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals treated with
candesartan cilexetil. In patients whose renal function may depend upon the activity of the
renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment
with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists has been
associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or
death. Similar results may be anticipated in patients treated with candesartan cilexetil. (See
CLINICAL PHARMACOLOGY, Special Populations.)
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in
serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term
use of candesartan cilexetil in patients with unilateral or bilateral renal artery stenosis, but similar
results may be expected.
Information for the Patient
Pregnancy: Female patients of childbearing age should be told about the consequences of second-
and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also
be told that these consequences do not appear to have resulted from intrauterine drug exposure that
has been limited to the first trimester. These patients should be asked to report pregnancies to their
physicians as soon as possible.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to
mice and rats for up to 104 weeks at doses up to 300 and 1000 mg/kg/day, respectively. Rats
received the drug by gavage; whereas, mice received the drug by dietary administration. These
(maximally tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan
(AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in
man at the maximum recommended daily human dose (32 mg).
Candesartan cilexetil was not genotoxic in the microbial mutagenesis and mammalian cell
mutagenesis assays and in the in vivo chromosomal aberration and rat unscheduled DNA synthesis
assays. In addition, candesartan was not genotoxic in the microbial mutagenesis, mammalian cell
mutagenesis, and in vitro and in vivo chromosome aberration assays.
Fertility and reproductive performance were not affected in studies with male and female rats given
oral doses of up to 300 mg/kg/day (83 times the maximum daily human dose of 32 mg on a body
surface area basis).
Pregnancy Category C (first Trimester) Pregnancy Category D (Second and Third
Trimesters)
See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether candesartan is excreted in human milk, but candesartan has been shown to
be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision
should be made whether to discontinue nursing or discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects in clinical studies of candesartan cilexetil, 21% were 65 and over,
while 3% were 75 and over. No overall differences in safety or effectiveness were observed
between these subjects and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out. In a placebo-controlled trial of about 200 elderly
hypertensive patients (ages 65 to 87 years), administration of candesartan cilexetil was well
tolerated and lowered blood pressure by about 12/6 mmHg more than placebo.