Rx Only
Keep out of reach of children.
O/^acea
(doxycycline, USP)?oWSSi£SL
Brief Summary of Full Prescribing Information
INDICATIONS AND
USAGE
ORACEA
is indicated only for the treatment of inflammatory lesions (papules and pustules) of rosacea in
adult
patients.
The dosage of ORACEA
differs from
that of doxycycline used to treat infections. To reduce the development
of resistant bacteria as well as to maintain
the effectiveness of other antibacterial drugs, ORACEA
should be
used only as indicated.
CLINICAL
PHARMACOLOGY
Pharmacokinetics
ORACEA
capsules are not bioequivalent to other doxycycline products.
CONTRAINDICATIONS
This drug is contraindicated in
persons who have shown hypersensitivity to doxycycline or any of the other
tetracyclines.
WARNINGS
Teratogenic effects: 1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm
when
adm
inistered to a pregnant woman. If any tetracycline is used during pregnancy or if the patient becomes
pregnant while taking these drugs, the patient should be informed of the potential hazard to the fetus and
treatment stopped immediately.
ORACEA
should 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
childhood up to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown).
This adverse reaction is more common during long-term
use of the drug but has been observed following
repeated short-term
courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore,
should not be used during tooth development unless other drugs are not likely to be effective or are
contraindicated.
3) A
ll tetracyclines form
a stable calcium
complex in
any bone-form
ing tissue. A decrease in
fibula growth rate
has been observed in
premature human infants given oral tetracycline in
doses of 25 mg/kg every 6 hours.
This reaction was shown to be reversible when the drug was discontinued.
Results of animal studies indicate that tetracyclines cross the placenta, are found in
fetal tissues, and can
cause retardation of skeletal development on the developing fetus. Evidence of embryotoxicity has been noted
in
animals treated early in
pregnancy (see PRECAUTIONS: Pregnancy section).
Gastrointestinal effects: Pseudomembranous colitis has been reported with nearly all antibacterial
agents and may range from
m
ild to life-threatening. Therefore, it is important to consider this diagnosis
in
patients who present with diarrhea subsequent to the adm
inistration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may perm
it overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium
difficile is a primary cause of “antibiotic-
associated colitis.”
If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated.
M
ild
cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In
moderate
to severe cases, consideration should be given to management with fluids and electrolytes, protein
supplementation, and treatment w
ith an antibacterial drug clinically effective against Clostridium
difficile
colitis.
Metabolic effects: The anti-anabolic action of the tetracyclines may cause an increase in
BUN
. While this is
not a problem
in
those w
ith normal renal function, in
patients with significantly impaired function, higher
serum
levels of tetracycline-class antibiotics may lead
to azotem
ia, hyperphosphatem
ia, and acidosis. If renal
impairment exists, even usual oral or parenteral doses may lead to excessive system
ic accumulations of the
drug and possible liver toxicity. Under such conditions, lower than usual total doses are indicated, and if
therapy is prolonged, serum
level determ
inations of the drug may be advisable.
Photosensitivity: Photosensitivity manifested by an exaggerated sunburn reaction has been observed in
some individuals taking tetracyclines. Although this was not observed during the duration of the clinical
studies with ORACEA
, patients should m
inim
ize or avoid exposure to natural or artificial sunlight (tanning
beds or UVA/B
treatment) while using ORACEA
. If patients need to be outdoors while using ORACEA
, they
should wear loose-fitting clothes that protect skin from
sun exposure and discuss other sun protection
measures with their physician.
PRECAUTIONS
General: Safety of ORACEA
beyond 9 months has not been established.
As w
ith other antibiotic preparations, use of ORACEA
may result in
overgrowth of non-susceptible m
icro-
organisms, including fungi. If superinfection occurs, ORAcEa should be discontinued and appropriate therapy
instituted. Although not observed in
clinical trials w
ith ORACEA
, the use of tetracyclines may increase the
incidence of vaginal candidiasis.
ORACEA
should be used w
ith caution in
patients w
ith a history of or predisposition to candidiasis overgrowth.
Bacterial resistance to tetracyclines may develop in
patients using ORACEA
. Because of the potential for drug-
resistant bacteria to develop during the use of ORACEA
, it should be used only as indicated.
Autoimmune Syndromes: Tetracyclines have been associated w
ith the development of autoimmune
syndromes. Symptoms may be manifested by fever, rash, arthralgia, and malaise. In
symptomatic patients,
liver function tests, ANA
, CBC, and other appropriate tests should be performed to evaluate the patients. Use
of all tetracycline-class drugs should be discontinued immediately.
Tissue Hyperpigmentation: Tetracycline-class antibiotics are known to cause hyperpigmentation. Tetracycline
therapy may induce hyperpigmentation in
many organs, including nails, bone, skin, eyes, thyroid, visceral
tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has
been reported to occur independently of time or amount of drug adm
inistration, whereas other pigmentation
has been reported to occur upon prolonged adm
inistration. Skin pigmentation includes diffuse pigmentation
as well as over sites of scars or injury.
Pseudotumor cerebri: Bulging fontanels in
infants and benign intracranial hypertension in
adults have been
reported in
individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.
Laboratory Tests: Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic
studies should be performed. Appropriate tests lor autoimmune syndromes should be performed as indicated.
Drug Interactions: 1. Because tetracyclines have been shown to depress plasma prothrombin activity,
patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
2. Since bacteriostatic drugs may interfere w
ith the bactericidal action of penicillin, it is advisable to avoid
giving tetracycline-class drugs in
conjunction with penicillin. 3. The concurrent use of tetracycline and
methoxyflurane has been reported to result in
fatal renal toxicity. 4. Absorption of tetracyclines is impaired by
bismuth subsalicylate, proton pump inhibitors, antacids containing alum
inum
, calcium
or magnesium
and
iron-containing preparations. 5. Doxycycline may interfere with the effectiveness of low
dose oral
contraceptives. To avoid contraceptive failure, females are advised to use a second form
of contraceptive
during treatment with doxycycline. 6. There have been reports of pseudotumor cerebri (benign intracranial
hypertension) associated w
ith the concom
itant use of isotretinoin and tetracyclines. Since both oral retinoids,
including isotretinoin and acitretin, and the tetracyclines, primarily m
inocycline, can cause increased
intracranial pressure, the concurrent use of an
oral retinoid
and a tetracycline should be avoided.
MICROBIOLOGY
The plasma concentration of doxycycline achieved w
ith ORACEA
during adm
inistration (see DOSAGE
AND
ADMINISTRATION) are less than the concentrations required
to treat bacterial diseases.
In
vivo
m
icrobiological
studies utilizing a sim
ilar drug exposure for up to 18 months demonstrated no detectable long-term
effects
on bacterial flora of the oral cavity, skin, intestinal tract, and vagina.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline was assessed for potential to induce
carcinogenesis in
a study in
which the compound was adm
inistered to Sprague-Dawley rats by gavage at
dosages of 20, 75, and 200
mg/kg/day for two years. An
increased incidence of uterine polyps was observed in
female rats that received 200 mg/kg/day, a dosage that resulted in
a system
ic exposure to doxycycline
approximately 12.2 times that observed in
female humans who use ORACEA
(exposure comparison based
upon area under the curve (AUC) values). No impact upon
tumor incidence was observed in
male rats at 200
mg/kg/day, or in
either gender at the other dosages studied. Evidence of oncogenic activity was obtained in
studies w
ith
related
compounds, i.e., oxytetracycline (adrenal and
pituitary tumors) and
m
inocycline (thyroid
tumors).
Doxycycline demonstrated no potential to cause genetic toxicity in
an
in vitro
point mutation study w
ith
mammalian cells (CHO/HGPRT
forward mutation assay) or in
an
in
vivo
m
icronucleus assay conducted in
CD-1 m
ice. However, data from
an
in vitro
assay w
ith CHO
cells for potential to cause chromosomal
aberrations suggest that doxycycline is a weak clastogen.
Oral adm
inistration of doxycycline to male and female Sprague-Dawley rats adversely affected fertility and
reproductive performance, as evidenced by increased time for mating to occur, reduced sperm
motility,
velocity, and concentration, abnormal sperm
morphology, and increased pre-and post-implantation losses.
Doxycycline induced reproductive toxicity at all dosages that were exam
ined in
this study, as even the lowest
dosage tested (50 mg/kg/day) induced a statistically significant reduction in
sperm
velocity. Note that 50 mg/
kg/day is approximately 3.6 times the amount of doxycycline contained in
the recommended daily dose of
ORACEA
for a 60-kg human when compared on the basis of AUC
estimates. Although doxycycline impairs
the fertility of rats when adm
inistered at sufficient dosage, the effect of ORACEA
on human fertility is unknown.
Pregnancy: Teratogenic Effects: Pregnancy Category D
. (see WARNINGS section). Results from
animal
studies indicate that doxycycline crosses the placenta and is found in
fetal tissues.
Nonteratogenic effects: (see WARNINGS section).
Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown.
Nursing Mothers: Tetracyclines are excreted in
human
m
ilk. Because of the potential for serious adverse reactions
in
infants from
doxycycline, ORACEA
should not be used in
mothers who breastfeed. (see WARNINGS section).
Pediatric Use: ORACEA
should not be used in
infants and children less than
8 years of age (see WARNINGS
section). ORACEA
has not been studied in
children of any age with regard to safety or efficacy, therefore use
in
children is not recommended.
ADVERSE
REACTIONS
Adverse Reactions in
Clinical Trials of ORACEA: In
controlled clinical trials of adult patients with m
ild
to
moderate rosacea, 537 patients received ORACEA
or placebo over a 16-week period. The most frequent
adverse reactions occurring in
these studies are listed in
the table below
.
Incidence (%) of Selected Adverse Reactions in
Clinical Trials of ORACEA
(n=269) vs. Placebo (n=268)
ORACEA
Placebo
Nasopharyngitis
13 (4.8)
9 (3.4)
Pharyngolaryngeal Pain
3 (1.1)
2 (0.7)
Sinusitis
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)
Diarrhea
12 (4.5)
7 (2.6)
Abdominal Pain Upper
5 (1.9)
1 (0.4)
Abdominal Pain Distention
3 (1.1)
1 (0.4)
Abdominal Pain
3 (1.1)
1 (0.4)
Stomach Discomfort
3 (1.1)
2 (0.7)
Note: Percentages based on total number of study participants in
each treatment group.
Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in
patients
receiving tetracyclines at higher, antim
icrobial doses:
Gastrointestinal: anorexia, nausea, vom
iting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory
lesions (w
ith
vaginal candidiasis) in
the anogenital region. Hepatotoxicity has been reported rarely. Rare
instances of esophagitis and esophageal ulcerations have been reported in
patients receiving the capsule
forms of the drugs in
the tetracycline class. Most of the patients experiencing esophagitis and/or esophageal
ulceration
took their medication immediately before lying down. (see DOSAGE
AND
ADMINISTRATION
section).
Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon.
Photosensitivity is discussed above. (see WARNINGS section).
Renal toxicity: Rise in
BUN
has been reported and is apparently dose-related. (see WARNINGS section).
Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum
sickness, pericarditis, and exacerbation of system
ic lupus erythematosus.
Blood: Hemolytic anem
ia, thrombocytopenia, neutropenia, and eosinophilia have been reported.
OVERDOSAGE:
In
case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures.
Dialysis does not alter serum
half-life and thus would not be of benefit in
treating cases of overdose.
DOSAGE
AND
ADMINISTRATION
THE
DOSAGE
OF
ORACEA
DIFFERS FROM
THAT
OF
DOXYCYCLINE
USED
TO
TREAT
INFECTIONS.
EXCEEDING
THE
RECOMMENDED
DOSAGE
MAY RESULT
IN
AN
INCREASED
INCIDENCE
OF SIDE
EFFECTS INCLUDING
THE
DEVELOPMENT
OF
RESISTANT
MICROORGANISMS.
One ORACEA
capsule (40
mg) should be taken once daily in
the morning on an empty stomach, preferably
at least one hour prior to or two hours after meals.
Efficacy beyond 16 weeks and safety beyond 9 months have not been established.
Adm
inistration of adequate amounts of fluid along w
ith the capsules is recommended to wash down the
capsule to reduce the risk of esophageal irritation
and ulceration. (see ADVERSE
REACTIONS section).
HOW
SUPPLIED
ORACEA
(beige opaque capsule printed
w
ith GLD
40) containing doxycycline, USP in
an
amount equivalent
to 40 mg of anhydrous doxycycline. Bottle of 30 (NDC
0299-3822-30).
Storage: A
ll products are to be stored at controlled room
temperatures of 15°C
- 30°C
(59°F
- 86°F) and
dispensed in
tight, light-resistant containers (USP). Keep out of reach of children.
Patent Information: U
.S. Patents 5,789,395; 5,919,775; 7,232,572; 7,211,267 and patents pending.
Marketed by:
GALDERMA
LABORATORIES, L
.P
.
Fort Worth, Texas 76177 USA
Galderma is a registered trademark.
20050-0908 Revised: September 2008
Manufactured by:
Catalent Pharma Solutions, LLC
W
inchester, Kentucky 40391 USA
www.oracea.com
GALDERMA
Committed to the future
of dermatology
