Document
DailyMed Label: ORACEA
Title
DailyMed Label: Oracea
Date
2009
Document type
DailyMed Prescription
Name
Oracea
Generic name
doxycycline
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-5676
Product information
NDC: 54868-5676
Description
ORACEA (doxycycline, USP) capsules 40 mg are hard gelatin capsule
shells filled with two types of doxycycline beads (30 mg immediate release and
10 mg delayed release) that together provide a dose of 40 mg of anhydrous
doxycycline (C 22 H 24 N 2 O 8 ).
The structural formula of doxycycline, USP is:
with an empirical formula of C 22 H 24 N 2 O 8 •H 2 O and a molecular weight of 462.46. The chemical designation
for doxycycline is 2-Naphthacenecarboxamide,
4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-,
[4S-(4aα, 4aα, 5α, 5aα, 6a,12aα)]-, monohydrate. It is very slightly soluble in
water.
Inert ingredients in the formulation are: hypromellose, iron oxide red, iron
oxide yellow, methacrylic acid copolymer, polyethylene glycol, Polysorbate 80,
sugar spheres, talc, titanium dioxide, and triethyl citrate. Active ingredients:
Each capsule contains doxycycline, USP in an amount equivalent to 40 mg of
anhydrous doxycycline.
image of Oracea chemical structure
Indications
ORACEA is indicated for the treatment of only inflammatory
lesions (papules and pustules) of rosacea in adult patients. No meaningful
effect was demonstrated for generalized erythema (redness) of rosacea. ORACEA
has not been evaluated for the treatment of the erythematous, telangiectatic, or
ocular components of rosacea. Efficacy of ORACEA beyond 16 weeks and safety
beyond 9 months have not been established.
This formulation of doxycycline has not been evaluated in the treatment or
prevention of infections. ORACEA should not be used for treating bacterial
infections, providing antibacterial prophylaxis, or reducing the numbers or
eliminating microorganisms associated with any bacterial disease.
To reduce the development of drug-resistant bacteria as well as to maintain
the effectiveness of other antibacterial drugs, ORACEA should be used only as
indicated.
Dosage
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.
Administration 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).
Contraindications
This drug is contraindicated in persons who have shown hypersensitivity to
doxycycline or any of the other tetracyclines.
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 microorganisms, 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.
Information for Patients
See Patient Package Insert that accompanies this
Package Insert for additional information to give patients.
Photosensitivity manifested by an exaggerated sunburn reaction has been
observed in some individuals taking tetracyclines, including doxycycline.
Patients should minimize or avoid exposure to natural or artificial sunlight
(tanning beds or UVA/B treatment) while using doxycycline. If patients need to
be outdoors while using doxycycline, they should wear loose-fitting clothes that
protect skin from sun exposure and discuss other sun protection measures with
their physician. Treatment should be discontinued at the first evidence of
sunburn.
Concurrent use of doxycycline may render oral contraceptives less effective
(see
Drug Interactions
).
Autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune
hepatitis, vasculitis and serum sickness have been observed with
tetracycline-class antibiotics, including doxycycline. Symptoms may be
manifested by arthralgia, fever, rash and malaise. Patients who experience such
symptoms should be cautioned to stop the drug immediately and seek medical help.
Patients should be counseled about discoloration of skin, scars, teeth or
gums that can arise from doxycycline therapy.
Take ORACEA exactly as directed. Increasing doses beyond 40 mg every morning
may increase the likelihood that bacteria will develop resistance and will not
be treatable by other antibacterial drugs in the future.
It is recommended that ORACEA not be used by pregnant or breast feeding
women. (see
Carcinogenesis,
Mutagenesis, Impairment of Fertility , Pregnancy
and
Nursing Mothers
sections).
It is recommended that ORACEA not be used by individuals of either gender
who are attempting to conceive a child (see
Carcinogenesis, Mutagenesis, Impairment of
Fertility , and
Pregnancy
sections).
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
Because tetracyclines have been shown to depress plasma prothrombin
activity, patients who are on anticoagulant therapy may require downward
adjustment of their anticoagulant dosage.
Since bacteriostatic drugs may interfere with the bactericidal action of
penicillin, it is advisable to avoid giving tetracycline-class drugs in
conjunction with penicillin.
The concurrent use of tetracycline and methoxyflurane has been reported to
result in fatal renal toxicity.
Absorption of tetracyclines is impaired by bismuth subsalicylate, proton
pump inhibitors, antacids containing aluminum, calcium or magnesium and
iron-containing preparations.
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.
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.
Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to
interference with the fluorescence test.
Carcinogenesis, Mutagenesis, Impairment 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 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
administered 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 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 efficacy, therefore use in children is not recommended.
Adverse reactions
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
Table 3.
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 54868-5676-0 ).
Storage All products are to be stored at controlled room temperatures of
l5°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 and patents
pending.
Manufactured by: CardinalHealth Winchester, KY 40391
Marketed by: CollaGenex Pharmaceuticals, Inc. Newtown, PA 18940
May 26, 2006
Clinical pharmacology
ORACEA capsules are not bioequivalent to other doxycycline products. The
pharmacokinetics of doxycycline following oral administration of ORACEA was
investigated in 2 volunteer studies involving 61 adults. Pharmacokinetic
parameters for ORACEA following single oral doses and at steady-state in healthy
subjects are presented in Table 1.
Table 1. Pharmacokinetic Parameters [Mean (± SD)] for ORACEA
N
C max
* (ng/mL)
Tmax **
(hr)
AUC0-∞ * (ng∙hr/mL)
t1/2 (hr) *
Single Dose 40 mg capsules
30
510 ± 220.7
3.00 (1.0-4.1)
9227 ± 3212.8
21.2 ± 7.6
Steady-State *** 40 mg capsules
31
600 ± 194.2
2.00 (1.0-4.0)
7543 ± 2443.9
23.2 ± 6.2
* Mean ** Median *** Day 7
Absorption In a single-dose food-effect study involving administration of
ORACEA to healthy volunteers, concomitant administration with a 1000 calorie,
high-fat, high-protein meal that included dairy products, resulted in a decrease
in the rate and extent of absorption (Cmax and AUC) by about 45% and 22%,
respectively, compared to dosing under fasted conditions. This decrease in
systemic exposure can be clinically significant, and therefore if ORACEA is
taken close to meal times, it is recommended that it be taken at least one hour
prior to or two hours after meals.
Distribution Doxycycline is greater than 90% bound to plasma proteins.
Metabolism Major metabolites of doxycycline have not been identified.
However, enzyme inducers such as barbiturates, carbamazepine, and phenytoin
decrease the half-life of doxycycline.
Excretion Doxycycline is excreted in the urine and feces as unchanged drug.
It is reported that between 29% and 55.4% of an administered dose can be
accounted for in the urine by 72 hours. Terminal half-life averaged 21.2 hours
in subjects receiving a single dose of ORACEA.
Special Populations
Geriatric Doxycycline pharmacokinetics have not been evaluated in geriatric
patients.
Pediatric Doxycycline pharmacokinetics have not been evaluated in pediatric
patients (see
WARNINGS
section).
Gender The pharmacokinetics of ORACEA were compared in 16 male and 14
female subjects under fed and fasted conditions. While female subjects had a
higher Cmax and AUC than male subjects, these differences were thought to be due
to differences in body weight/lean body mass.
Race Differences in doxycycline pharmacokinetics among racial groups
have not been evaluated.
Renal Insufficiency Studies have shown no significant difference in serum half-life
of doxycycline in patients with normal and severely impaired renal function.
Hemodialysis does not alter the serum half-life of doxycycline.
Hepatic Insufficiency Doxycycline pharmacokinetics have not been evaluated in patients
with hepatic insufficiency.
Gastric Insufficiency In a study in healthy volunteers (N=24) the bioavailability of
doxycycline is reported to be reduced at high pH. This reduced bioavailability
may be clinically significant in patients with gastrectomy, gastric bypass
surgery or who are otherwise deemed achlorhydric.
Drug Interactions (see
PRECAUTIONS
section)
Clinical studies
The safety and efficacy of ORACEA in the treatment of only
inflammatory lesions (papules and pustules) of rosacea was evaluated in two
randomized, placebo-controlled, multi-centered, double-blind, 16-week Phase 3
studies involving 537 patients (total of 269 patients on ORACEA from the two
studies) with rosacea (10 to 40 papules and pustules and two or fewer nodules).
Pregnant and nursing women, patients less than 18 years of age, and patients with
ocular rosacea and/or blepharitis/meibomianitis who require ophthalmologic
treatment were excluded from study. Mean baseline lesion counts were 20 and 21
for ORACEA and placebo patient groups respectively.
At Week 16, patients in the ORACEA group were evaluated using co-primary
endpoints of mean reduction in lesion counts and a dichotomized static
Investigator's Global Assessment of Clear or Almost Clear (defined as 1 to 2
small papules or pustules) when compared to the placebo group in both Phase 3
studies.
Table 2: Clinical Results of ORACEA versus Placebo
Study 1
Study 2
ORACEA 40 mg N = 127
Placebo N = 124
ORACEA 40 mg N = 142
Placebo N = 144
Mean Change in Lesion Count from Baseline
-11.8
-5.9
-9.5
-4.3
No (%) of Subjects Clear or Almost Clear in the IGA *
39 (30.7%)
24 (19.4%)
21 (14.8%)
9 (6.3%)
* Investigator's Global Assessment
Patients treated with ORACEA did not demonstrate significant improvement in
erythema when compared to those treated with placebo.
Package label
ORACEA Capsule, 40 mg
image of Oracea 40 mg package label
2 organizations
1 product
Product
Doxycycline MonohydrateOrganization
Galderma Laboratories, L.P.Organization
Physicians Total Care, Inc.