WARNINGS
Fetal/Neonatal Morbidity and Mortality
Drugs that act directly on the renin-angiotensin 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,
losartan potassium 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 losartan potassium as soon as possible.
Rarely (probably less often than once in every thousand
pregnancies), no alternative to an angiotensin II 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 intraamniotic environment.
If oligohydramnios is observed, losartan potassium 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.
Losartan potassium has been shown to produce adverse
effects in rat fetuses and neonates, including decreased
body weight, delayed physical and behavioral development,
mortality and renal toxicity. With the exception of neonatal
weight (which was affected at doses as low as 10 mg/kg/day),
doses associated with these effects exceeded 25 mg/kg/day
(approximately three times the maximum recommended human
dose of 100 mg on a mg/m2 basis). These findings are attributed
to drug exposure in late gestation and during lactation.
Significant levels of losartan and its active metabolite
were shown to be present in rat fetal plasma during late
gestation and in rat milk.
Hypotension - Volume Depleted Patients
In patients who are intravascularly volume-depleted (e.g.,
those treated with diuretics), symptomatic hypotension
may occur after initiation of therapy with losartan potassium.
These conditions should be corrected prior to administration
of losartan potassium, or a lower starting dose should
be used (see DOSAGE AND ADMINISTRATION).
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. 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. Losartan
potassium 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
losartan potassium in patients with unilateral or bilateral
renal artery stenosis, but a similar effect should be
anticipated.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
Losartan potassium was not carcinogenic when administered
at maximally tolerated dosages to rats and mice for 105
and 92 weeks, respectively. Female rats given the highest
dose (270 mg/kg/day) had a slightly higher incidence of
pancreatic acinar adenoma. The maximally tolerated dosages
(270 mg/kg/day in rats, 200 mg/kg/day in mice) provided
systemic exposures for losartan and its pharmacologically
active metabolite that were approximately 160- and 90-times
(rats) and 30- and 15-times (mice) the exposure of a 50
kg human given 100 mg per day.
Losartan potassium was negative in the microbial mutagenesis
and V-79 mammalian cell mutagenesis assays and in the
in vitro alkaline elution and in vitro and in vivo chromosomal
aberration assays. In addition, the active metabolite
showed no evidence of genotoxicity in the microbial mutagenesis,
in vitro alkaline elution, and in vitro chromosomal aberration
assays.
Fertility and reproductive performance were not affected
in studies with male rats given oral doses of losartan
potassium up to approximately 150 mg/kg/day. The administration
of toxic dosage levels in females (300/200 mg/kg/day)
was associated with a significant (p <0.05) decrease
in the number of corporalutea/female, implants/female,
and live fetuses/female at C-section. At 100 mg/kg/day
only a decrease in the certain number of corpora lutea/female
was observed. The relationship of these findings to drug-treatment
is uncertain since there was no effect at these dosage
levels on implants/pregnant female, percent post-implantation
loss, or live animals/litter at parturition. In nonpregnant
rats dosed at 135 mg/kg/day for 7 days, systemic exposure
(AUCs) for losartan and its active metabolite were approximately
66 and 26 times the exposure achieved in man at the maximum
recommended human daily dosage (100 mg).
Pregnancy
Pregnancy Categories C (first trimester) and Dy (second
and third trimesters). See
WARNINGS
, Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
It is not known whether losartan is excreted in human
milk, but significant levels of losartan and its active
metabolite were 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.
Use in the Elderly
Of the total number of patients receiving losartan potassium
in controlled clinical studies, 391 patients (19%) were
65 years and over, whole 37 patients (2%) 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.
Impaired Hepatic Function
Based on pharmacokinetic data which demonstrates significantly
increased plasma concentrations of losartan in cirrhotic
patients, a lower dose should be considered for patients
with impaired liver function (see DOSAGE AND ADMINISTRATION
and CLINICAL PHARMACOLOGY, Pharmacokinetics).
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