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, ATACAND 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
ATACAND 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, ATACAND 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 ATACAND
in pregnant women. Oral doses ³10 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
on 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 ATACAND, 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 Hepatic Function: Based on pharmacokinetic
data which demonstrate significant increases in candesartan
AUC and Cmax in patients with moderate hepatic impairment,
a lower initiating dose should be considered for patients
with moderate hepatic impairment. (See DOSAGE AND ADMINISTRATION,
and CLINICAL PHARMACOLOGY, Special Populations.)
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 ATACAND. 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 ATACAND (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 ATACAND in patients with unilateral
or bilateral renal artery stenosis, but similar results
may be expected.
Information for Patients 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.
Drug Interactions
No significant drug interactions have been reported
in studies of candesartan cilexetil given with other drugs
such as glyburide, nifedipine, digoxin, warfarin, hydrochlorothiazide
and oral contraceptives in healthy volunteers. Because candesartan
is not metabolized by the cytochrome P450 system and has
no effects on P450 enzymes, interactions with drugs that
inhibit, or are metabolized by, those enzymes would not
be expected.
Carcinogenesis Mutagenesis 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).
Candesartan and its O-deethyl metabolite tested positive
for genotoxicty in the in vitro Chinese hamster lung (CHL)
chromosomal aberration assay. Neither compound tested positive
in the Ames microbial mutagenesis assay or the in vitro
mouse lymphoma cell assay. Candesartan (but not its O-deethyl
metabolite) was also evaluated in vivo in the mouse micronucleus
test and in vitro in the Chinese hamster ovary (CHO) gene
mutation assay, in both cases with negative results. Candesartan
cilexetil was evaluated in the Ames test, the in vitro mouse
lymphoma cell and rat hepatocyte unscheduled DNA synthesis
assays and the in vivo mouse micronucleus test, in each
case with negative results. Candesartan cilexetil was not
evaluated in the CHL chromosomal aberration or CHO gene
mutation assay.
Pregnancy Pregnancy Categories
C (first trimester) and 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 ATACAND, 21% (683/3260) were 65% and over, while 3%
(87/3260) 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.
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