A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Teveten Warnings, Precautions, Pregnancy, Nursing, Abuse - Eprosartan Mesylate
Teveten Warnings, Precautions, Pregnancy, Nursing, Abuse - Eprosartan Mesylate
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, TEVETEN® (eprosartan mesylate) Tablets 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 advise the patient to discontinue
the use of eprosartan 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, TEVETEN® Tablets 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.
Eprosartan mesylate has been shown to produce maternal and fetal toxicities
(maternal and fetal mortality, low maternal body weight and food consumption,
resorptions, abortions and litter loss) in pregnant rabbits given oral
doses as low as 10 mg eprosartan/kg/day. No maternal or fetal adverse
effects were, observed at 3 mg/kg/day; this oral dose yielded a systemic
exposure (AUC) to unbound eprosartan 0.8 times that achieved in humans
given 400 mg b.i.d. No adverse effects on in utero or postnatal
development and maturation of offspring were observed when eprosartan
mesylate was administered to pregnant rats at oral doses up to 1000 mg
eprosartan/kg/day (the 1000 mg eprosartan/kg/day dose in non-pregnant
rats yielded systemic exposure to unbound eprosartan approximately 0.6
times the exposure achieved in humans given 400 mg b.i.d.).
Hypotension in Volume- and/or 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 TEVETEN® Tablets, or the treatment should start
under close medical supervision. 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
Risk of Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system,
changes in renal function have been reported in susceptible individuals
treated with angiotensin II antagonists; in some patients, these changes
in renal function were reversible upon discontinuation of therapy. 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 and angiotensin II receptor
antagonists has been associated with oliguria and/or progressive azotemia
and (rarely) with acute renal failure and/or death. TEVETEN® (eprosartan
mesylate) Tablets 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. Similar effects have been reported with angiotensin II antagonists;
in some patients, these effects were reversible upon discontinuation of
therapy.
Information for Patients
See PATIENT INFORMATION section.
Drug Interactions
See DRUG INTERACTIONS section.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Eprosartan mesylate was not carcinogenic in dietary restricted rats or
ad libitum fed mice dosed at 600 mg and 2000 mg eprosartan/kg/day, respectively,
for up to 2 years. In male and female rats the systemic exposure (AUC)
to unbound eprosartan at the dose evaluated was only approximately 20%
of the exposure achieved in humans given 400 mg b.i.d. In mice, the systemic
exposure (AUC) to unbound eprosartan was approximately 25 times the exposure
achieved in humans given 400 mg b.i.d.
Eprosartan mesylate was not mutagenic in vitro in bacteria or
mammalian cells (mouse lymphoma assay). Eprosartan mesylate also did not
cause structural chromosomal damage in vivo (mouse micronucleus
assay). In human peripheral lymphocytes in vitro, eprosartan mesylate
was equivocal for clastogenicity with metabolic activation and was negative
without metabolic activation. In the same assay, eprosartan mesylate was
positive for polyploidy with metabolic activation and equivocal for polyploidy
without metabolic activation.
Eprosartan mesylate had no adverse effects on the reproductive performance
of male or female rats at oral doses up to 1000 mg eprosartan/kg/day.
This dose provided systemic exposure (AUC) to unbound eprosartan approximately
0.6 times the exposure achieved in humans given 400 mg b.i.d.
Pregnancy
Pregnancy Category C (first trimester) and D (second and third
trimesters): See WARNINGS
: Fetal/Neonatal
Morbidity and Mortality.
Nursing Mothers
Eprosartan is excreted in animal milk; it is not known whether eprosartan
is excreted in human milk. Because many drugs are excreted in human milk
and because of the potential for serious adverse reactions in nursing
infants from eprosartan, 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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the total number of patients receiving TEVETEN® Tablets in clinical
studies, 29% (681 of 2,334) were 65 years and over, while 5% (124 of 2,334)
were 75 years and over. Based on the pooled data from randomized trials,
the decrease in diastolic blood pressure and systolic blood pressure with
TEVETEN® Tablets was slightly less in patients ³65
years of age compared to younger patients. In a study of only patients
over the age of 65, TEVETEN® Tablets at 200 mg twice daily (and increased
optionally up to 300 mg twice daily) decreased diastolic blood pressure
on average by 3 mmHg (placebo corrected). Adverse experiences were similar
in younger and older patients.
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