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Risk Summary
Limited data from postmarketing experience with DYMISTA in pregnant
women have not identified any drug associated risks of miscarriage,
birth defects, or other adverse maternal or fetal
outcomes. The individual components
of DYMISTA have been marketed for decades.
While the data regarding the use of nasal preparations
of fluticasone propionate in pregnancy are limited, data
from clinical studies of inhaled fluticasone
propionate do not indicate an
increased risk of adverse maternal or fetal outcomes.
Animal reproduction studies with DYMISTA are not
available; however, studies are
available with its individual
components, azelastine
hydrochloride and fluticasone
propionate. In animal reproduction
studies, there was no evidence
of fetal harm in animals at
oral doses of azelastine hydrochloride approximately 10 times
the clinical daily dose. Oral administration
of azelastine hydrochloride to
pregnant mice, rats, and
rabbits, during the period
of organogenesis, produced
developmental toxicity that included
structural abnormalities, decreased embryo-fetal survival, and decreased
fetal body weights at
doses 530 times and higher
than the maximum recommended
human daily intranasal dose (MRHDID) of 0.548 mg.
However, the relevance of these findings in animals to pregnant women
was considered questionable based upon the high animal to human dose multiple.
In animal reproduction
studies, fluticasone propionate
administered via nose-only inhalation to rats decreased fetal body weight,
but did not induce teratogenicity at a maternal toxic dose less than
the MRHDID on a mcg/m2 basis.
Teratogenicity, characteristic of corticosteroids, decreased
fetal body weight and/or skeletal
variations, in rats, mice, and
rabbits were observed with subcutaneously administered maternal toxic doses of fluticasone propionate less than
the MRHDID of 200 mcg on a mcg/m2 basis
(see Data). Experience with
corticosteroids suggests
that rodents are more prone
to teratogenic effects
from corticosteroids than humans.
The estimated background
risk of major birth defects
and miscarriage for the indicated
populations 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.
Data
Animal Data
Azelastine hydrochloride: In an embryo-fetal development study in mice dosed during
the period of organogenesis, azelastine hydrochloride caused
embryo-fetal death, structural abnormalities (cleft palate; short or absent tail; fused, absent or branched
ribs), delayed ossification, and decreased fetal weight at approximately 610 times the MRHDID in adults (on a mg/m2 basis at a maternal
oral dose of 68.6 mg/kg/day), which also caused maternal toxicity
as evidenced by decreased maternal body
weight. Neither fetal nor maternal
effects occurred in mice
at approximately 25 times the MRHDID
in adults (on a mg/m2 basis at a maternal
oral dose of 3 mg/kg/day).
In an embryo-fetal
development study in pregnant rats
dosed during the period of organogenesis from gestation days 7 to 17, azelastine hydrochloride caused structural abnormalities
(oligo-and brachydactylia), delayed ossification, and skeletal variations,
in the absence of
maternal toxicity, at
approximately 530 times the
MRHDID in adults (on a mg/m2 basis
at a maternal oral dose of 30
mg/kg/day). Azelastine hydrochloride caused embryo-fetal
death and decreased fetal weight and
severe maternal toxicity at approximately 1200 times the MRHDID
(on a mg/m2 basis
at a maternal oral dose of 68.6
mg/kg/day). Neither fetal nor maternal effects occurred
at approximately 55
times the MRHDID (on a mg/m2 basis
at a maternal oral dose
of 3 mg/kg/day).
In an embryo-fetal
development study in pregnant rabbits
dosed during the period of
organogenesis from gestation
days 6 to 18, azelastine hydrochloride caused abortion,
delayed ossification and decreased fetal weight and severe maternal toxicity at
approximately 1100 times the MRHDID in adults (on a mg/m2 basis
at a maternal oral dose of 30 mg/kg/day). Neither
fetal nor maternal
effects occurred at approximately 10 times the
MRHDID (on a mg/m2 basis
at a maternal oral dose of 0.3 mg/kg/day).
In a
prenatal and postnatal development study in pregnant rats dosed from late in
the gestation period and through
the lactation period from gestation
day 17 through lactation day 21, azelastine
hydrochloride produced no adverse developmental effects
on pups at maternal
doses up to approximately 530 times
the MRHDID (on mg/m2 basis
at a maternal dose of 30
mg/kg/day).
Fluticasone
propionate:
In embryofetal
development studies with pregnant
rats and mice dosed by the subcutaneous route throughout
the period of organogenesis, fluticasone
propionate was teratogenic in
both species.
In an embryo-fetal development study in pregnant
rats dosed during the period of organogenesis from gestation
days 7 to 17, azelastine hydrochloride
caused structural abnormalities (oligo-and brachydactylia), delayed ossification, and skeletal variations,
in the absence of
maternal toxicity, at
approximately 530 times the
MRHDID in adults (on a mg/m2 basis
at a maternal oral dose of 30
mg/kg/day). Azelastine hydrochloride caused embryo-fetal
death and decreased fetal weight and
severe maternal toxicity at approximately 1200 times the MRHDID
(on a mg/m2 basis
at a maternal oral dose of 68.6
mg/kg/day). Neither fetal nor maternal effects occurred
at approximately 55
times the MRHDID (on a mg/m2 basis
at a maternal oral dose
of 3 mg/kg/day).
In an embryo-fetal development study in pregnant rabbits dosed during the period
of organogenesis
from gestation
days 6 to 18, azelastine hydrochloride caused abortion,
delayed ossification and decreased fetal weight and severe maternal toxicity at
approximately 1100 times the MRHDID in adults (on a mg/m2 basis
at a maternal oral dose of 30 mg/kg/day). Neither
fetal nor maternal
effects occurred at approximately 10 times the
MRHDID (on a mg/m2 basis
at a maternal oral dose of 0.3 mg/kg/day).
In a
prenatal and postnatal development study in pregnant rats dosed from late in
the gestation period and through
the lactation period from gestation
day 17 through lactation day 21, azelastine
hydrochloride produced no adverse developmental effects
on pups at maternal
doses up to approximately 530 times
the MRHDID (on mg/m2 basis
at a maternal dose of 30
mg/kg/day).
Fluticasone
propionate:
In embryofetal
development studies with pregnant
rats and mice dosed by the subcutaneous route throughout
the period of organogenesis, fluticasone
propionate was teratogenic in
both species.
Omphalocele, decreased body weight, and skeletal variations
were observed in rat fetuses,
in the presence of maternal toxicity, at a dose approximately 5 times
the MRHDID (on a mg/m2 basis with
a maternal subcutaneous dose of 100
mcg/kg/day). Neither fetal
nor maternal effects occurred in rats at approximately 1 times the MRHDID (on a mg/m2 basis
with a maternal subcutaneous dose of 30 mcg/kg/day).
Cleft palate and fetal skeletal
variations were observed in mouse fetuses at
a dose approximately 1 times the
MRHDID (on a mg/m2 basis
with a maternal subcutaneous dose of 45 mcg/kg/day). Neither fetal
nor maternal effects occurred in
mice with a dose approximately 0.4 times the MRHDID (on a mg/m2 basis
with a maternal subcutaneous dose of 15 mcg/kg/day).
In an embryofetal
development study with
pregnant rats dosed by the nose-only inhalation
route throughout the period of organogenesis, fluticasone propionate produced decreased fetal body weights and skeletal variations,
in the presence of maternal
toxicity, at a dose approximately 1 times the
MRHDID (on a mg/m2 basis
with a maternal nose-only inhalation dose of 25.7 mcg/kg/day); however, there was no evidence of teratogenicity.
Neither fetal nor maternal effects occurred in rats with a dose approximately 0.25 times the MRHDID (on a mg/m2 basis
with a maternal nose-only inhalation dose of 5.5 mcg/kg/day).
In an embryofetal
development study in pregnant
rabbits that were dosed by the subcutaneous route throughout organogenesis, fluticasone propionate
produced reductions of fetal body weights,
in the presence of
maternal toxicity, at doses approximately 0.06 times the
MRHDID and higher
(on a mg/m2 basis
with a maternal subcutaneous
dose of 0.57 mcg/kg/day).
Teratogenicity was evident based upon a finding
of cleft palate for 1 fetus
at dose approximately 0.4 times the MRHDID (on a
mg/m2 basis
with a maternal subcutaneous
dose of 4 mcg/kg/day). Neither
fetal nor maternal effects occurred
in rabbits with a dose
approximately 0.01 times the
MRHDID (on a mg/m2 basis
with a maternal subcutaneous
dose of 0.08 mcg/kg/day).
Fluticasone propionate crossed the placenta following subcutaneous administration to mice and rats
and oral administration to rabbits.
In a
pre- and post-natal development study in
pregnant rats dosed from late gestation through delivery and
lactation (Gestation Day 17 to Postpartum Day 22), fluticasone propionate was not associated
with decreases in pup body weight,
and
had no effects on developmental landmarks, learning,
memory, reflexes, or fertility at
doses up to 2 times the MRHDID
(on a mg/m2 basis with
maternal subcutaneous doses up to 50 mcg/kg/day).
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