Rx Only
O t ^ a c e a
(doxycycline, USP)?0%'S№SX*
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 wel 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 administered 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 folowing 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) Al 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 mild to life-threatening. Therefore, it is important to consider this diagnosis
in patients who present with diarrhea subsequent to the administration 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 usualy 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 with an antibacterial drug clinicaly 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 with 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 with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible micro-
organisms, including fungi. If superinfection occurs, ORACEA should be discontinued and appropriate therapy
instituted. Although not observed in clinical trials with ORACEA, the use of tetracyclines may increase the
incidence of vaginal candidiasis.
ORACEA should be used with caution in patients with 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 with 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 al 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 wel 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 for 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 with the bactericidal action of penicilin, it is advisable to avoid
giving tetracycline-class drugs in conjunction with penicilin. 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
with 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.
QnoB-dalfy
40
mg CapaUBB
Keep out of reach of ch
ildren.
The plasma concentrations of doxycycline achieved with ORACEA during adm
inistration (see DOSAGE AND
ADMINISTRATION) are less than the concentration 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 with
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 with
mammalian cels (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 with CHO
cels 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 al dosages that were exam
ined in this study, as even the lowest dosage
tested (50 mg/kg/day) induced a statisticaly 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
M
ICROB
IOLOGY
Adverse Reactions in Clinical Trials of ORACEA: In controled 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)
Abdom
inal Pain Upper
5 (1.9)
1
(0.4)
Abdom
inal Distention
3 (1.1)
1
(0.4)
Abdom
inal 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 folowing 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 (with 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: R
ise 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 symptomaticaly, 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 M
ICROORGANISMS.
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 with 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 with CGPI 40) containing doxycycline, USP in an amount equivalent to
40 mg of anhydrous doxycycline. Bottle of 30 (NDC
64682-009-01).
Storage: Al products are to be stored at controled 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.
ORACEA is a registered trademark of ColaGenex Pharmaceuticals, Inc.
Manufactured by:
Marketed by:
GALDERMA
CardinalHealth
Galderma Laboratories, L.P.
W
inchester, KY 40391
Fort Worth, TX 76177
7961-01 BPI 01/09
Comm
itted to the future
of dermatology
