Rx Only
O t ^ a c e a
(doxycycline, USP)?0%'S№SX*
Brief Summary of Full Prescribing Information
IND
ICATIONS
AND
USAGE
ORACEA
is ind
icated
on
ly
for the
treatment of inflammatory
lesions (papu
les and
pustu
les) of rosacea
in
adu
lt patients.
The
dosage
of ORACEA
d
iffers from
that of doxycycline
used
to
treat infections. To
reduce
the
deve
lopment
of resistant bacteria
as we
ll as to
ma
inta
in
the
effectiveness of other antibacteria
l drugs, ORACEA
shou
ld
be
used
on
ly
as ind
icated
.
CLIN
ICAL
PHARMACOLOGY
Pharmacokinetics
ORACEA
capsu
les are
not b
ioequ
iva
lent to
other doxycycline
products.
CONTRA
IND
ICATIONS
Th
is drug
is contra
ind
icated
in
persons who
have
shown
hypersensitiv
ity
to
doxycycline
or any
of the
other
tetracyclines.
WARN
INGS
Teratogen
ic effects:
1
) Doxycycline, like other tetracycline-class antib
iotics, can
cause fetal harm
when
adm
in
istered
to
a pregnant woman. If any tetracycline is used
during
pregnancy or if the
patient becomes pregnant wh
ile taking
these
drugs, the
patient shou
ld
be
informed
of the
potential
hazard
to
the
fetus and
treatment stopped
immed
iately.
ORACEA
shou
ld
not be
used
during
pregnancy
(see
PRECAUTIONS: Pregnancy).
2
) The
use of drugs of the
tetracycline class during
tooth
development (last half of pregnancy,
infancy, and
ch
ildhood
up
to
the
age
of 8
years) may cause permanent d
isco
loration
of the
teeth
(yellow
-gray-brown). Th
is adverse
reaction
is more
common
during
long
-term
use
of the
drug
but has been
observed
fo
llow
ing
repeated
short-term
courses. Ename
l hypop
lasia
has also
been
reported
. Tetracycline
drugs, therefore, shou
ld
not be
used
during
tooth
development unless other drugs are
not likely to
be
effective
or are contraind
icated.
3
) A
ll tetracyclines form
a
stab
le
calcium
comp
lex
in
any
bone-form
ing
tissue. A
decrease
in
fibu
la
grow
th
rate
has been
observed
in
premature
human
infants g
iven
ora
l tetracycline
in
doses of
25
mg/kg
every
6
hours.
Th
is reaction
was shown
to
be
reversib
le
when
the
drug
was d
iscontinued
.
Resu
lts of an
ima
l stud
ies ind
icate
that tetracyclines cross the
p
lacenta, are
found
in
feta
l tissues, and
can
cause
retardation
of ske
leta
l deve
lopment on
the
deve
lop
ing
fetus. Ev
idence
of embryotox
ic
ity
has been
noted
in
an
imals treated
early in
pregnancy
(see
PRECAUTIONS: Pregnancy section).
Gastro
intestinal effects: Pseudomembranous co
litis has been
reported
w
ith
nearly all antibacterial
agents and
may range
from
m
ild
to
life-threaten
ing. Therefore, it is important to
consider th
is d
iagnosis
in
patients who
present w
ith
d
iarrhea subsequent to
the
adm
in
istration
of antibacterial agents.
Treatment w
ith
antibacteria
l agents a
lters the
norma
l flora
of the
co
lon
and
may
perm
it overgrow
th
of clostrid
ia.
Stud
ies ind
icate
that a
tox
in
produced
by
C
lostrid
ium
d
ifficile
is a
primary
cause
of “antib
iotic-associated
co
litis”
.
If a
d
iagnosis of pseudomembranous co
litis has been
estab
lished
, therapeutic
measures shou
ld
be
in
itiated
. M
ild
cases of pseudomembranous co
litis usually respond
to
d
iscontinuation
of the
drug
a
lone. In
moderate
to
severe
cases, consideration
shou
ld
be
g
iven
to
management w
ith
flu
ids and
e
lectro
lytes, prote
in
supp
lementation
, and
treatment w
ith
an
antibacteria
l drug
clin
ically effective
aga
inst C
lostrid
ium
d
ifficile
co
litis.
Metabo
lic effects: The
anti-anabo
lic action
of the
tetracyclines may
cause
an
increase
in
BUN
. Wh
ile
th
is
is not a
prob
lem
in
those
w
ith
norma
l rena
l function
, in
patients w
ith
sign
ificantly impa
ired
function
, h
igher
serum
leve
ls of tetracycline-class antib
iotics may
lead
to
azotem
ia, hyperphosphatem
ia, and
acidosis. If rena
l
impa
irment ex
ists, even
usua
l ora
l or parentera
l doses may
lead
to
excessive
system
ic accumu
lations of the
drug
and
possib
le
liver tox
ic
ity. Under such
cond
itions, lower than
usua
l tota
l doses are
ind
icated
, and
if therapy
is pro
longed
, serum
leve
l determ
inations of the
drug
may
be
adv
isab
le.
Photosensitivity: Photosensitiv
ity
man
ifested
by
an
exaggerated
sunburn
reaction
has been
observed
in
some
ind
iv
idua
ls tak
ing
tetracyclines. A
lthough
th
is was not observed
during
the
duration
of the
clin
ical stud
ies
w
ith
ORACEA
, patients shou
ld
m
in
im
ize
or avo
id
exposure
to
natura
l or artificia
l sun
light (tann
ing
beds or
UVA
/B
treatment) wh
ile
using
ORACEA
. If patients need
to
be
outdoors wh
ile
using
ORACEA
, they
shou
ld
wear loose-fitting
clothes that protect sk
in
from
sun
exposure
and
d
iscuss other sun
protection
measures
w
ith
the
ir physician
.
PRECAUTIONS
General: Safety
of ORACEA
beyond
9
months has not been
estab
lished
.
As w
ith
other antib
iotic
preparations, use
of ORACEA
may
resu
lt in
overgrow
th
of non
-susceptib
le
m
icro
-
organ
isms, includ
ing
fung
i. If superinfection
occurs, ORACEA
shou
ld
be
d
iscontinued
and
appropriate
therapy
instituted
. A
lthough
not observed
in
clin
ical tria
ls w
ith
ORACEA
, the
use
of tetracyclines may
increase
the
incidence
of vag
ina
l cand
id
iasis.
ORACEA
shou
ld
be
used
w
ith
caution
in
patients w
ith
a
h
istory
of or pred
isposition
to
cand
id
iasis overgrow
th
.
Bacteria
l resistance
to
tetracyclines may
deve
lop
in
patients using
ORACEA
. Because
of the
potentia
l for drug
-
resistant bacteria
to
deve
lop
during
the
use
of ORACEA
, it shou
ld
be
used
on
ly
as ind
icated
.
Auto
immune
Syndromes: Tetracyclines have
been
associated
w
ith
the
deve
lopment of auto
immune
syndromes. Symptoms may
be
man
ifested
by
fever, rash
, arthra
lg
ia, and
mala
ise. In
symptomatic
patients,
liver function
tests, ANA
, CBC, and
other appropriate
tests shou
ld
be
performed
to
eva
luate
the
patients. Use
of a
ll tetracycline-class drugs shou
ld
be
d
iscontinued
immed
iate
ly.
Tissue Hyperp
igmentation: Tetracycline
class antib
iotics are
known
to
cause
hyperp
igmentation
. Tetracycline
therapy
may
induce
hyperp
igmentation
in
many
organs, includ
ing
na
ils, bone
, sk
in
, eyes, thyro
id
, v
isceral
tissue, ora
l cav
ity (teeth
, mucosa, a
lveo
lar bone), sclerae
and
heart va
lves. Sk
in
and
ora
l p
igmentation
has
been
reported
to
occur independently
of time
or amount of drug
adm
in
istration
, whereas other p
igmentation
has been
reported
to
occur upon
pro
longed
adm
in
istration
. Sk
in
p
igmentation
includes d
iffuse
p
igmentation
as we
ll as over sites of scars or in
jury.
Pseudotumor cerebri: Bu
lg
ing
fontane
ls in
infants and
ben
ign
intracran
ia
l hypertension
in
adu
lts have
been
reported
in
ind
iv
iduals rece
iv
ing
tetracyclines. These
cond
itions d
isappeared
when
the
drug
was
d
iscontinued
.
Laboratory Tests: Period
ic laboratory
eva
luations of organ
systems, includ
ing
hematopo
ietic, rena
l and
hepatic
stud
ies shou
ld
be
performed
. Appropriate
tests for auto
immune
syndromes shou
ld
be
performed
as ind
icated
.
Drug
Interactions:
1
. Because
tetracyclines have
been
shown
to
depress p
lasma
prothromb
in
activ
ity,
patients who
are
on
anticoagu
lant therapy
may
requ
ire
downward
ad
justment of the
ir anticoagu
lant dosage.
2
. S
ince
bacteriostatic drugs may
interfere
w
ith
the
bactericida
l action
of pen
icillin
, it is adv
isab
le
to
avo
id
g
iv
ing
tetracycline-class drugs in
con
junction
w
ith
pen
icillin
.
3
. The
concurrent use
of tetracycline
and
methoxyflurane
has been
reported
to
resu
lt in
fata
l rena
l tox
ic
ity.
4
. Absorption
of tetracyclines is impa
ired
by
b
ismuth
subsa
licylate, proton
pump
inh
ib
itors, antacids conta
in
ing
a
lum
inum
, calcium
or magnesium
and
iron
-
conta
in
ing
preparations.
5
. Doxycycline
may
interfere
w
ith
the
effectiveness of low
dose
ora
l contraceptives. To
avo
id
contraceptive
fa
ilure, fema
les are
adv
ised
to
use
a
second
form
of contraceptive
during
treatment w
ith
doxycycline. 6
. There
have
been
reports of pseudotumor cerebri (ben
ign
intracran
ia
l hypertension) associated
w
ith
the
concom
itant use
of isotretino
in
and
tetracyclines. S
ince
both
ora
l retino
ids, includ
ing
isotretino
in
and
ac
itretin
, and
the
tetracyclines, primarily m
inocycline, can
cause
increased
intracran
ia
l pressure, the
concurrent use
of an
ora
l retino
id
and
a
tetracycline
shou
ld
be
avo
ided
.
QnoB-dalfy
40
mg CapaUBB
Keep out of reach of children.
The
p
lasma
concentrations of doxycycline
ach
ieved
w
ith
ORACEA
during
adm
in
istration
(see
DOSAGE
AND
ADM
IN
ISTRATION) are
less than
the
concentration
requ
ired
to
treat bacteria
l d
iseases.
In
vivo
m
icrob
io
log
ica
l
stud
ies utiliz
ing
a
sim
ilar drug
exposure
for up
to
18
months demonstrated
no
detectab
le
long
-term
effects on
bacteria
l flora
of the
ora
l cav
ity, sk
in
, intestina
l tract, and
vag
ina.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline
was assessed
for potentia
l to
induce
carcinogenesis in
a
study
in
wh
ich
the
compound
was adm
in
istered
to
Sprague-Daw
ley rats by
gavage
at
dosages of
20
,
75
, and
200
mg/kg/day for two
years. An
increased
incidence
of uterine
po
lyps was observed
in
female
rats that rece
ived
200
mg/kg/day, a
dosage
that resu
lted
in
a
system
ic exposure
to
doxycycline
approx
imate
ly
12.2
times that observed
in
fema
le
humans who
use
ORACEA
(exposure
comparison
based
upon
area
under the
curve
(AUC) va
lues). No
impact upon
tumor incidence
was observed
in
ma
le
rats at
200
mg/kg/
day, or in
e
ither gender at the
other dosages stud
ied
. Ev
idence
of oncogen
ic
activ
ity
was obta
ined
in
stud
ies w
ith
re
lated
compounds, i.e., oxytetracycline
(adrena
l and
p
itu
itary
tumors) and
m
inocycline
(thyro
id
tumors).
Doxycycline
demonstrated
no
potentia
l to
cause
genetic
tox
ic
ity
in
an
in
v
itro
po
int mutation
study
w
ith
mamma
lian
cells (CHO
/HGPRT
forward
mutation
assay) or in
an
in
v
ivo
m
icronucleus assay conducted
in
CD
-1
m
ice. However, data
from
an
in
v
itro
assay w
ith
CHO
ce
lls for potentia
l to
cause
chromosoma
l aberrations
suggest that doxycycline
is a
weak
clastogen
.
O
ra
l adm
in
istration
of doxycycline
to
ma
le
and
fema
le
Sprague-Daw
ley rats adverse
ly
affected
fertility
and
reproductive
performance, as ev
idenced
by
increased
time
for mating
to
occur, reduced
sperm
motility, ve
loc
ity,
and
concentration
, abnorma
l sperm
morpho
logy, and
increased
pre-and
post-imp
lantation
losses. Doxycycline
induced
reproductive
tox
icity
at a
ll dosages that were
exam
ined
in
th
is study, as even
the
lowest dosage
tested
(50
mg/kg/day) induced
a
statistically sign
ificant reduction
in
sperm
ve
loc
ity. Note
that
50
mg/kg/day is
approx
imate
ly
3.6
times the
amount of doxycycline
conta
ined
in
the
recommended
da
ily dose
of ORACEA
for a
60
-kg
human
when
compared
on
the
basis of AUC
estimates. A
lthough
doxycycline
impa
irs the
fertility
of rats
when
adm
in
istered
at sufficient dosage, the
effect of ORACEA
on
human
fertility
is unknown
.
Pregnancy: Teratogen
ic Effects: Pregnancy Category
D
. (see
WARN
INGS
section). Resu
lts from
an
ima
l
stud
ies ind
icate
that doxycycline
crosses the
p
lacenta
and
is found
in
feta
l tissues.
Nonteratogen
ic effects: (see
WARN
INGS
section).
Labor and
Delivery: The
effect of tetracyclines on
labor and
de
livery
is unknown
.
Nursing
Mothers: Tetracyclines are
excreted
in
human
m
ilk. Because
of the
potentia
l for serious adverse
reactions
in
infants from
doxycycline
, ORACEA
shou
ld
not be
used
in
mothers who
breastfeed
. (see
WARN
INGS
section).
Ped
iatric Use: ORACEA
shou
ld
not be
used
in
infants and
ch
ildren
less than
8
years of age
(see
WARN
INGS
section). ORACEA
has not been
stud
ied
in
ch
ildren
of any age
w
ith
regard
to
safety
or efficacy, therefore
use
in
ch
ildren
is not recommended
.
ADVERSE
REACTIONS
M
ICROBIOLOGY
Adverse
Reactions in
Clinical Trials of ORACEA
: In
contro
lled
clin
ical trials of adu
lt patients w
ith
m
ild
to
moderate
rosacea,
537
patients rece
ived
ORACEA
or p
lacebo
over a
16
-week
period
. The
most frequent
adverse
reactions occurring
in
these
stud
ies are
listed
in
the
tab
le
be
low
.
Incidence
(%) of Se
lected
Adverse
Reactions in
C
lin
ical Trials of ORACEA
(n=
269
) vs. P
lacebo
(n=
268
)
ORACEA
P
lacebo
Nasopharyng
itis
13
(
4
.
8
)
9
(
3
.
4
)
Pharyngo
laryngea
l Pa
in
3
(
1
.
1
)
2
(
0
.
7
)
S
inusitis
7
(2.6)
2
(
0
.
7
)
Nasal Congestion
4
(
1
.
5
)
2
(
0
.
7
)
Fungal Infection
5
(
1
.
9
)
1
(
0
.
4
)
Influenza
5
(
1
.
9
)
3
(
1
.
1
)
D
iarrhea
12
(
4
.
5
)
7
(2.6)
Abdom
ina
l Pa
in
Upper
5
(
1
.
9
)
1
(
0
.
4
)
Abdom
ina
l D
istention
3
(
1
.
1
)
1
(
0
.
4
)
Abdom
ina
l Pa
in
3
(
1
.
1
)
1
(
0
.
4
)
Stomach
D
iscom
fort
3
(
1
.
1
)
2
(
0
.
7
)
Note: Percentages based
on
tota
l number of study
participants in
each
treatment group
.
Adverse
Reactions for Tetracyclines: The
fo
llow
ing
adverse
reactions have
been
observed
in
patients
rece
iv
ing
tetracyclines at h
igher, antim
icrob
ia
l doses:
Gastro
intestina
l: anorex
ia, nausea, vom
iting
, d
iarrhea, g
lossitis, dysphag
ia, enteroco
litis, and
inflammatory
lesions (w
ith
vag
ina
l cand
id
iasis) in
the
anogen
ita
l reg
ion
. Hepatotox
ic
ity
has been
reported
rare
ly. Rare
instances
of esophag
itis and
esophagea
l u
lcerations have
been
reported
in
patients rece
iv
ing
the
capsu
le
forms of the
drugs in
the
tetracycline
class. Most of the
patients experienc
ing
esophag
itis and
/or esophagea
l u
lceration
took
the
ir med
ication
immed
iate
ly
before
ly
ing
down
. (see
DOSAGE
AND
ADM
IN
ISTRATION
section).
Skin: macu
lopapu
lar and
erythematous rashes. Exfo
liative
dermatitis has been
reported
but is uncommon
.
Photosensitiv
ity
is d
iscussed
above
. (see
WARN
INGS
section).
Renal toxicity: R
ise
in
BUN
has been
reported
and
is apparently
dose-re
lated
.(see
WARN
INGS
section).
Hypersensitiv
ity
reactions: urticaria, ang
ioneurotic
edema, anaphylax
is, anaphylacto
id
purpura, serum
sickness,
pericard
itis, and
exacerbation
of system
ic lupus erythematosus.
B
lood
: Hemo
lytic
anem
ia, thrombocytopen
ia, neutropen
ia, and
eosinoph
ilia
have
been
reported
.
OVERDOSAGE
In
case
of overdosage, d
iscontinue
med
ication
, treat symptomatica
lly, and
institute
supportive
measures.
D
ialysis does not a
lter serum
half-life
and
thus wou
ld
not be
of benefit in
treating
cases of overdose
.
DOSAGE
AND
ADM
IN
ISTRATION
THE
DOSAGE
OF
ORACEA
D
IFFERS
FROM
THAT
OF
DOXYCYCLINE
USED
TO
TREAT
INFECTIONS.
EXCEED
ING
THE
RECOMMENDED
DOSAGE
MAY
RESULT
IN
AN
INCREASED
INCIDENCE
OF
SIDE
EFFECTS INCLUD
ING
THE
DEVELOPMENT
OF
RESISTANT
M
ICROORGAN
ISMS.
One
ORACEA
Capsu
le
(40
mg) shou
ld
be
taken
once
da
ily
in
the
morn
ing
on
an
empty
stomach
, preferab
ly
at
least one
hour prior to
or two
hours after mea
ls.
Efficacy beyond
16
weeks and
safety
beyond
9
months have
not been
estab
lished
.
Adm
in
istration
of adequate
amounts of flu
id
a
long
w
ith
the
capsu
les is recommended
to
wash
down
the
capsu
le
to
reduce
the
risk of esophagea
l irritation
and
u
lceration
. (see
ADVERSE
REACTIONS
section).
HOW
SUPPLIED
ORACEA
(be
ige
opaque
capsu
le
printed
w
ith
CGPI
40
) conta
in
ing
doxycycline, USP
in
an
amount equ
iva
lent to
40
mg
of anhydrous doxycycline. Bottle
of
30
(NDC
64682
-
009
-
01
).
Storage: A
ll products are
to
be
stored
at contro
lled
room
temperatures of
15
°C-
30
°C (
59
°F-
86
°F) and
d
ispensed
in
tight, light-resistant conta
iners (USP). Keep
out of reach
of ch
ildren
.
Patent Information
: U
.S. Patents
5
,
789
,
395
;
5
,
919
,
775
;
7
,
232
,
572
;
7
,
211,267
and
patents pend
ing
.
ORACEA
is a
reg
istered
trademark
of Co
llaGenex
Pharmaceuticals, Inc.
Manufactured
by:
Marketed
by:
G A L D E R M A
Card
ina
lHea
lth
Ga
lderma
Laboratories, L
.P
.
W
inchester, KY
40391
Fort Worth
, TX
76177
7961-01
BPI
01/09
Comm
itted to the future
of dermatology
