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, AVAPRO 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
Il 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
AVAPRO 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 intraamniotic environment.
If oligohydramnios is observed, AVAPRO 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 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.
When pregnant rats were treated with irbesartan from day
0 to day 20 of gestation (oral doses of 50, 180, and 650
mg/kg/day), increased incidences of renal pelvic cavitation,
hydroureter and/or absence of renal papilla were observed
in fetuses at doses >/=50 mg/kg/day [approximately equivalent
to the maximum recommended human dose (MRHD), 300 mg/day,
on a body surface area basis]. Subcutaneous edema was observed
in fetuses at doses >/=180 mg/kg/day (about 4 times the
MRHD on a body surface area basis). As these anomalies were
not observed in rats in which irbesartan exposure (oral
doses of 50, 150 and 450 mg/kg/day) was limited to gestation
days 6–15, they appear to reflect late gestational
effects of the drug. In pregnant rabbits, oral doses of
30 mg irbesartan/kg/day were associated with maternal mortality
and abortion. Surviving females receiving this dose (about
1.5 times the MRHD on a body surface area basis) had a slight
increase in early resorptions and a corresponding decrease
in live fetuses. Irbesartan was found to cross the placental
barrier in rats and rabbits.
Radioactivity was present in the rat and rabbit fetus during
late gestation and in rat milk following oral doses of radiolabeled
irbesartan.
Hypotension in Volume-or Salt-depleted Patients
Excessive reduction of blood pressure was rarely
seen (< 0.1%) in patients with uncomplicated hypertension.
Initiation of antihypertensive therapy may cause symptomatic
hypotension in patients with intravascular volume-or sodium-depletion,
e. g., in patients treated vigorously with diuretics or
in patients on dialysis. Such volume depletion should be
corrected prior to administration of AVAPRO (irbesartan),
or a low starting dose should be used (see DOSAGE AND ADMINISTRATION).
If hypotension occurs, the patient 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
Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in
susceptible individuals. In patients whose renal function
may depend on the activity of the renin-angiotensin-aldosterone
system (e. g., patients with severe congestive heart failure),
treatment with angiotensin-converting-enzyme inhibitors
has been associated with oliguria and/or progressive azotemia
and (rarely) with acute renal failure and/or death. AVAPRO
would be expected to behave similarly. In studies of ACE
inhibitors in patients with unilateral or bilateral renal
artery stenosis, increases in serum creatinine or BUN have
been reported. There has been no known use of AVAPRO in
patients with unilateral or bilateral renal artery stenosis,
but a similar effect should be anticipated.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenicity was observed when
irbesartan was administered at doses of up to 500/1000 mg/kg/day
(males/females, respectively) in rats and 1000 mg/kg/day
in mice for up to two years. For male and female rats, 500
mg/kg/day provided an average systemic exposure to irbesartan
(AUC0-24h , bound plus unbound) about 3 and 11 times, respectively,
the average systemic exposure in humans receiving the maximum
recommended dose (MRD) of 300 mg irbesartan/day, whereas
1000 mg/kg/day (administered to females only) provided an
average systemic exposure about 21 times that reported for
humans at the MADE For male and female mice, 1000 mg/kg/day
provided an exposure to irbesartan about 3 and 5 times,
respectively, the human exposure at 300 mg/day.
Irbesartan was not mutagenic in a battery of in vitro tests
(Ames microbial test, rat hepatocyte DNA repair test, V79
mammaliancell forward gene-mutation assay). Irbesartan was
negative in several tests for induction of chromosomal aberrations
(in vitrohuman lymphocyte assay; in vivo-mouse micronucleus
study). Irbesartan had no adverse effects on fertility or
mating of male or female rats at oral doses </=650 mg/kg/day,
the highest dose providing a systemic exposure to irbesartan
(AUC0-24h , bound plus unbound) about 5 times that found
in humans receiving the maximum recommended dose of 300
mg/day.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and
third trimester). See
WARNINGS
: Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether irbesartan is excreted
in human milk, but irbesartan or some metabolite of irbesartan
is secreted at low concentration in the milk of lactating
rats. 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 patients receiving AVAPRO
(irbesartan) in controlled clinical studies, 911 patients
(18.5%) were 65 years and over, while 150 patients (3.0%)
were 75 years and over. No overall differences in effectiveness
or safety were observed between these patients and younger
patients, but greater sensitivity of some older individuals
cannot be ruled out.
See also DRUG INTERACTIONS, PATIENT
INFORMATION.
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