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Brief Summary of Full Prescribing Information
INDICATIONS AND USAGE
ORACEA is indicated only tor the treatment of inf I ammatory 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
administered to a pregnant woman. If any tetracycline is used during pregnancy or if the patient becomes
pregnant while taking these drags, 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) All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in f Ibula 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 neariy 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 f I ora of the colon and may permit overgrowth of
clostridia. Studies indicate that a toxin produced by Clostridium diff Idle is a primary cause of “antibiotic-
associated colitis.”
If a diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated.
Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate
to severe cases, consideration should be given to management with fl uids and electrolytes, protein
supplementation, and treatment with 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 with normal renal function, in patients with signif I cantly impaired function, higher
serum levels of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and acidosis. If renal
impairment exists, even usual oral or parenteral doses may lead to excessive systemic 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 determinations 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 minimize or avoid exposure to natural or artif icial 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 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 administration, whereas other pigmentation
has been reported to occur upon prolonged administration. 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 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 penicillin, it is advisable to avoid
giving tetracycline-class drugs in conjunction with penicillin. 3. The concurrent use of tetracycline and
methoxyf lurane has been reported to result in fatal renal toxicity. 4. Absorption of tetracyclines is impaired by
bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, 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 concomitant use of isotretinoin and tetracyclines. Since both oral retinoids,
including isotretinoin and acitretin, and the tetracyclines, primarily minocycline, 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 with ORACEA during administration (see DOSAGE AND
ADMINISTRATION) are less than the concentrations required to treat bacterial diseases.
In vivo
microbiological
studies utilizing a similar drug exposure for up to 18 months demonstrated no detectable long-term effects
on bacterial f I ora of the oral cavity, skin, intestinal tract, and vagina.
Carcinogenesis, Mutagenesis, Impaiiment of Fertility: Doxycycline was assessed for potential to induce
carcinogenesis in a study in which the compound was administered 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 systemic 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 minocycline (thyroid tumors).
Doxycycline demonstrated no potential to cause genetic toxicity in an
in vitro
point mutation study with
mammalian cells (CHO/HGPRT forward mutation assay) or in an
in vivo
micronucleus assay conducted in
CD-1 mice. However, data from an
in vitro
assay with CHO cells for potential to cause chromosomal
aberrations suggest that doxycycline is a weak clastogen.
Oral administration 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 examined in this study, as even the lowest
dosage tested (50 mg/kg/day) induced a statistically signif Icant 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 administered at suff Icient 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 milk. 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 eff Icacy, therefore use
in children is not recommended.
ADVERSE REACTIONS
Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients with mild 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.
1 Incidence (%) of Selected Adverse Reactions in Clinical Trials of ORACEA <n=2B9) vs. Placebo (n=2G8)
ORACEA
Placebo
Nasopharyngitis
13 (4.8)
9 (3.4)
Pharyngolaryngeal Pain
3 (1.1)
2 00.7)
Sinusitis
7 (2.6)
2 (0.7)
Nasal Congestion
4 (1.5)
2 (0.7)
Fungal Infection
5 (1.9)
1 (0.4)
Inf 1
uenza
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, antimicrobial doses:
Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inf I ammatory
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: 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 systemic lupus erythematosus.
Blood: Hemolytic anemia, 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 benef it 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.
Eff Icacy beyond 16 weeks and safety beyond 9 months have not been established.
Administration of adequate amounts of f luid 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 GLD 40) containing doxycycline, USP in an amount equivalent
to 40 mg of anhydrous doxycycline. Bottle of 30 (NDC 0299-3822-30).
Storage: All 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
Winchester, Kentucky 40391 USA
www.oracea.com
GALDERMA
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itted
to the future
of dermatology
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