8.1 Pregnancy
PLLR Conversion:
Risk Summary
BENICAR HCT can cause fetal harm when administered to
a pregnant woman. Use of drugs that act on the renin-angiotensin system during
the second and third trimesters of pregnancy reduces fetal renal function and
increases fetal and neonatal morbidity and death. Most epidemiologic studies
examining fetal abnormalities after exposure to antihypertensive use in the
first trimester have not distinguished drugs affecting the renin-angiotensin
system from other antihypertensive agents.
When pregnancy is detected, discontinue BENICAR HCT as
soon as possible. Use alternative antihypertensive therapy during pregnancy.
The estimated background risk of major birth defects
and miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss or other adverse outcomes. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Hypertension in pregnancy increases the maternal
risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications
(e.g., need for cesarean section and post-partum hemorrhage). Hypertension
increases the fetal risk for intrauterine growth restriction and intrauterine
death. Pregnant women with hypertension should be carefully monitored and
managed accordingly.
Fetal/Neonatal Adverse Reactions Olmesartan
Oligohydramnios in pregnant women who use drugs affecting
the renin-angiotensin system in the second and third trimesters of pregnancy
can result in the following: reduced fetal renal function leading to anuria and
renal failure, fetal lung hypoplasia, skeletal deformations, including skull
hypoplasia, hypotension, and death.
Perform serial ultrasound examinations to assess the
intra-amniotic environment. Fetal testing may be appropriate, based on the week
of gestation. Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has sustained irreversible
injury.
Closely observe infants with histories of in utero exposure to BENICAR HCT for
hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur,
utilize measures to maintain adequate blood pressure and renal perfusion. Exchange
transfusions or dialysis may be required as a means of reversing hypotension
and supporting renal function [see Use in
Specific Populations (8.4)].
Hydrochlorothiazide
Thiazides can cross the placenta, and concentrations
reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide,
like other diuretics, can cause placental hypoperfusion. It
accumulates in the amniotic fluid, with reported concentrations
up to 19 times that in umbilical vein plasma. Use of thiazides during pregnancy
is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since
they do not prevent or alter the course of preeclampsia, these drugs should not
be used to treat hypertension in pregnant women. The use of HCTZ for other
indications (e.g., heart disease) in pregnancy should be avoided.
Data
Animal Data
Olmesartan
No teratogenic effects were observed when olmesartan
medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day
(240 times the maximum recommended human dose [MRHD] on a mg/m2
basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a
mg/m2 basis; higher doses could not be evaluated for effects on
fetal development as they were lethal to the does). In rats, significant
decreases in pup birth weight and weight gain were observed at doses ?1.6
mg/kg/day, and delays in developmental milestones (delayed separation of ear
auricula, eruption of lower incisors, appearance of abdominal hair, descent of
testes, and separation of eyelids) and dose-dependent increases in the
incidence of dilation of the renal pelvis were observed at doses ? 8 mg/kg/day.
The no observed effect dose for developmental toxicity in rats is 0.3
mg/kg/day, about one-tenth the MRHD of 40 mg/day.
Olmesartan medoxomil and Hydrochlorothiazide.
No teratogenic effects were observed when 1.6:1
combinations of olmesartan medoxomil and hydrochlorothiazide were administered
to pregnant mice at oral doses up to 1625 mg/kg/day (122 times the maximum recommended
human dose MRHD on a mg/m2 basis) or pregnant rats at oral doses up
to 1625 mg/kg/day (243 times the MRHD on a mg/m2 basis). In rats, however,
fetal body weights at 1625 mg/kg/day (a toxic, sometimes lethal dose in the
dams) were significantly lower than control. The no observed effect dose for developmental
toxicity in rats,
162.5 mg/kg/day, is about 24 times, on a mg/m2
basis, the MRHD of 40 mg olmesartan medoxomil /25 mg hydrochlorothiazide/day
(calculations based on a 60 kg patient).
Hydrochlorothiazide
No teratogenic effects were observed when
hydrochlorothiazide was administered to mice and rats via gavage at doses up to
3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD), on
gestation days 6 through 15.
8.2 Lactation
PLLR
Conversion:
Risk
Summary
There
is limited information regarding the presence of BENICAR HCT in human milk, the
effects on the breastfed infant, or the effects on milk production. Olmesartan is
present in rat milk (see Data). Hydrochlorothiazide
is present in human milk. Because of the potential for adverse effects on the
nursing infant, advise a nursing woman that breastfeeding is not recommended
during treatment with BENICAR HCT.
Data
Presence
of olmesartan in milk was observed after a single oral administration of 5 mg/kg
[14C] olmesartan medoxomil to lactating rats.
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