`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Revised: 11/2012
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`
`
` Photosensitivity can occur with ORACEA; Patients should minimize or
`
`avoid exposure to natural or artificial sunlight (5.4)
`
`
` Tetracyclines have been associated with the development of autoimmune
`
`syndromes; if symptoms develop, discontinue ORACEA immediately
`(5.5)
`
`
` Bacterial resistance to tetracyclines may develop in patients using
`
`ORACEA. It should only be used as indicated (5.8)
`------------------------------ADVERSE REACTIONS-------------------------------
`
`Some of the most common adverse reactions (incidence >2% and more
`common than with placebo) are nasopharyngitis, sinusitis, diarrhea,
`
`hypertension and aspartate aminotransferase increase (6)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Galderma
`Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`------------------------------DRUG INTERACTIONS-------------------------------
`
`
`
` Patients on anticoagulant therapy may require downward adjustment of
`their anticoagulant dosage (7.1)
`
`
` Some bacteriostatic drugs may interfere with the bactericidal action of
`penicillin, it is advisable to avoid giving tetracycline-class drugs in
`conjunction with penicillin (7.2)
`
` The concurrent use of tetracycline and methoxyflurane has been reported
`to result in fatal renal toxicity (7.3)
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`
`
` Doxycycline like other tetracycline-class drugs, can cause fetal harm
`
`when administered to a pregnant woman (5.1, 8.1)
`
`
` The use of drugs of the tetracycline class during tooth development may
`
`cause permanent discoloration of the teeth (5.1, 8.4)
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
` ORACEA® safely and effectively. See full prescribing information for
`
` ORACEA.
`ORACEA (doxycycline) capsules for oral use
`Initial U.S. Approval: 1967
`
`----------------------------INDICATIONS AND USAGE---------------------------
`
` ORACEA is a tetracycline-class drug indicated for the treatment of only
`inflammatory lesions (papules and pustules) of rosacea in adult patients
`(1.1)
`Limitations of Use
`
` This formulation of doxycycline has not been evaluated in the treatment
`
`or prevention of infections (1.2)
`
` Efficacy of ORACEA beyond 16 weeks and safety beyond 9 months have
`
`not been established (1.2)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
` 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 (2.1)
`
`
` 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 (2.2, 5.5)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
` 40 mg capsule (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`
` ORACEA is contraindicated in persons who have shown hypersensitivity
`
`
`to doxycycline or other tetracyclines (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
`
` The use of ORACEA 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) (5.1)
`If pseudomembranous colitis occurs, discontinue ORACEA (5.2)
`If renal impairment exists, ORACEA doses may need to be adjusted to
`avoid excessive systemic accumulations of the drug and possible liver
`injury. (5.3)
`_______________________________________________________________________________________________________________________________________
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`INDICATIONS AND USAGE
`
`1.1
`Indication
`
`1.2 Limitations of Use
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`
`2.2
`Important Considerations for Dosing Regimen
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Teratogenic Effects
`
`5.2 Pseudomembranous Colitis
`
`5.3 Metabolic Effects
`
`5.4 Photosensitivity
`
`5.5 Autoimmune Syndromes
`
`5.6 Tissue Hyperpigmentation
`
`5.7 Pseudotumor Cerebri
`
`5.8 Development of Drug Resistant Bacteria
`
`5.9 Superinfection
`
`5.10 Laboratory Monitoring
`
`6 ADVERSE REACTIONS
`
`7 DRUG INTERACTIONS
`
`7.1 Anticoagulants
`
`7.2 Penicillin
`
`7.3 Methoxyflurane
`
`
`7.4 Antacids and Iron Preparations
`
`7.5 Low Dose Oral Contraceptives
`
`7.6 Oral Retinoids
`
`7.7 Barbiturates and Anti-epileptics
`
`7.8 Drug/Laboratory Test Interactions
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`10 OVERDOSAGE
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`12.4 Microbiology
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`Reference ID: 3214183
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`
`
`2
`
`3
`
`4
`
`5
`
`INDICATIONS AND USAGE
`1.1 Indication
`
`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.
`
`1.2 Limitations of Use
`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.
`
`
`Efficacy of ORACEA beyond 16 weeks and safety beyond 9 months have not been established.
`
`
`ORACEA has not been evaluated for the treatment of the erythematous, telangiectatic, or ocular components of rosacea.
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 General Dosing Information
`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.
`
`
`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 (6)].
`
`
`
`2.2 Important Considerations for Dosing Regimen
`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 organisms.
`
`
`DOSAGE FORMS AND STRENGTHS
`40 mg beige opaque capsule imprinted with “GLD 40”
`
`CONTRAINDICATIONS
`This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any of the other tetracyclines.
`
`WARNINGS AND PRECAUTIONS
`5.1 Teratogenic Effects
`ORACEA should not be used during pregnancy.
`
`
`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.
`
`
`
`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.
`
`
`
`All tetracyclines form a stable calcium complex in any bone-forming 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.
`
`
`5.2 Pseudomembranous Colitis
`Clostridium difficile associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including doxycycline, and may range in severity
`
`
`from mild to fatal colitis.
`
`
`
`Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
`C. Difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity
`
`and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who
`present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the
`administration of antibacterial agents.
`
`
`If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte
`
`
`management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
`
`5.3 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 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.
`
`
`
`5.4 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 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.
`
`5.5 Autoimmune Syndromes
`
`Reference ID: 3214183
`
`

`

`
`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.
`
`
`5.6 Tissue Hyperpigmentation
`Tetracycline-class drugs 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.
`
`
`
`5.7 Pseudotumor cerebri
`Pseudotumor cerebri (benign intracranial hypertension) in adults has been associated with the use of tetracyclines. The usual clinical manifestations are
`headache and blurred vision. Bulging fontanels have been associated with the use of tetracyclines in infants. While both of these conditions and related
`symptoms usually resolve after discontinuation of the tetracycline, the possibility for permanent sequelae exists. Patients should be questioned for visual
`disturbances prior to initiation of treatment with tetracyclines and should be routinely checked for papiledema while on treatment.
`
`
`
`5.8 Development of Drug Resistant Bacteria
`
`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 only be used as indicated.
`
`
`5.9 Superinfection
`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 Candida
`overgrowth.
`
`5.10 Laboratory Monitoring
`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.
`
`
`ADVERSE REACTIONS
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly
`
`
`compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
`
`
`Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received
`
`ORACEA or placebo over a 16-week period. The following table summarizes selected adverse reactions that occurred in the clinical trials at a rate of ≥ 1%
`for the active arm:
`
`
`
`6
`
`
`
`Table 1. Incidence (%) of Selected Adverse Reactions in Clinical
`
`Trials of ORACEA (n=269) vs. Placebo (n=268)
`
`
`
`
`
`ORACEA
`
`Placebo
`
`Nasopharyngitis
`
`Pharyngolaryngeal Pain
`
`Sinusitis
`
`Nasal Congestion
`
`Fungal Infection
`
`Influenza
`
`Diarrhea
`
`
`Abdominal Pain Upper
`
`Abdominal Distention
`
`Abdominal Pain
`
`Stomach Discomfort
`
`Dry Mouth
`
`
`Hypertension
`
`Blood Pressure Increase
`
`Aspartate Aminotransferase
`Increase
`
`Blood Lactate
`Dehydrogenase Increase
`
`13 (5)
`
`
`3 (1)
`
`7 (3)
`
`
`4 (2)
`
`
`5 (2)
`
`5 (2)
`
`12 (5)
`
`
`5 (2)
`
`3 (1)
`
`
`
`3 (1)
`
`3 (1)
`
`3 (1)
`
`
`8 (3)
`
`4 (2)
`
`
`6 (2)
`
`4 (2)
`
`9 (3)
`
`
`2 (1)
`
`2 (1)
`
`
`2 (1)
`
`
`1 (0)
`
`3 (1)
`
`7 (3)
`
`
`1 (0)
`
`1 (0)
`
`
`
`1 (0)
`
`2 (1)
`
`0 (0)
`
`
`2 (1)
`
`1 (0)
`
`
`2 (1)
`
`1 (0)
`
`Reference ID: 3214183
`
`

`

`Blood Glucose Increase
`
`Anxiety
`
`
`Pain
`
`Back Pain
`
`
`Sinus Headache
`
`
`
` 3 (1)
`
`4 (2)
`
`4 (2)
`
`3 (1)
`
`3 (1)
`
`
`
`
`
` 0 (0)
`
`0 (0)
`
`1 (0)
`
`0 (0)
`
`0 (0)
`
`7
`
`8
`
`
`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 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 (2)].
`
`
`Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above [see Warnings
`
`and Precautions (5.4)].
`
`
`Renal toxicity: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.3)].
`
`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.
`
`
`
`DRUG INTERACTIONS
`
`7.1 Anticoagulants
`Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment
`of their anticoagulant dosage.
`
`
`7.2 Penicillin
`Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with
`penicillin.
`
`7.3 Methoxyflurane
`The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.
`
`
`7.4 Antacids and Iron Preparations
`Absorption of tetracyclines is impaired by bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron-
`containing preparations.
`
`
`7.5 Low Dose Oral Contraceptives
`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.
`
`7.6 Oral Retinoids
`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.
`
`
`7.7 Barbiturates and Anti-epileptics
`Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
`
`
`
`7.8 Drug/Laboratory Test Interactions
`False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Teratogenic Effects: Pregnancy Category D [see Warnings and Precautions (5.1)].
`
`Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues.
`
`
`
`8.3 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.
`
`8.4 Pediatric Use
`ORACEA should not be used in infants and children less than 8 years of age [see Warnings and Precautions (5.1)]. ORACEA has not been studied in
`
`children of any age with regard to safety or efficacy, therefore use in children is not recommended.
`
`8.5 Geriatric Use
`
`Clinical studies of ORACEA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger
`
`
`
`subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for
`
`
`an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or
`
`
`cardiac function, and concomitant disease or other drug therapy.
`
`
`Reference ID: 3214183
`
`

`

`
`
`10
`
`11
`
`
`
`
`
`12
`
`
`
`
`
`
`
`
`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.
`
`
`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 (C22H24N2O8).
`
`The structural formula of doxycycline, USP is:
`
`
`
`
`with an empirical formula of C22H24N2O8•H2O and a molecular weight of 462.46. The chemical designation for doxycycline is 2-Naphthacenecar­
`boxamide,4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-, [4S-(4α, 4aα, 5α, 5aα, 6α,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.
`
`
`
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`The mechanism of action of ORACEA in the treatment of inflammatory lesions of rosacea is unknown.
`
`
`12.3 Pharmacokinetics
`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 2.
`
`Table 2. Pharmacokinetic Parameters [Mean (±SD)] for ORACEA
`
`
`
`
`Single Dose 40
`mg capsules
`
`Steady-State#
`40 mg capsules
`
`N
`
`30
`
`31
`
`Cmax*
`(ng/mL)
`
`
`510 ± 220.7
`
`600 ± 194.2
`
`Tmax+ (hr)
`
`AUC0-oo *
`(ng•hr/mL)
`
`
`3.00
`(1.0-4.1)
`
`2.00
`(1.0-4.0)
`
`9227±
`3212.8
`
`7543 ±
`2443.9
`
`t1/2* (hr)
`
`21.2 ± 7.6
`
`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 and Precautions (5.1)].
`
`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 Drug Interactions (7)].
`
`
`12.4 Microbiology
`Doxycycline is a member of the tetracycline-class of drugs. The plasma concentrations of doxycycline achieved with ORACEA during administration [see
`Clinical Pharmacology (12.3) and Dosage and Administration (2.2)] are less than the concentration required to treat bacterial diseases. ORACEA should not
`
`be used for treating bacterial infections, providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated with any
`
`Reference ID: 3214183
`
`

`

`13
`
`14
`
`
`
`
`
`
`
`16
`
`
` bacterial disease [see Indications and Usage (1.2)]. In vivo microbiological studies utilizing a similar 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.
`
` NONCLINICAL TOXICOLOGY
`13.1 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 up to at 200 mg/kg/day, or in
`females at the lower dosages studied.
`
`
`
`Doxycyline was assessed for potential to induce carcinogenesis in CD-1 mice by gavage at dosages 20, 75, and 150 mg/kg/day in males and at dosages of
`20, 100, and 300 mg/kg/day in females. No impact upon tumor incidence was observed in male and females mice at systemic exposures approximately 4.2
`
`and 8.3 times that observed in humans, respectively.
`
`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 mammalian chromosomal aberration assay conducted
`
`
`
`
`
`with CHO cells 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 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.
`
` 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 trials involving 537 subjects (total of 269 subjects on ORACEA from the two trials) with
`rosacea (10 to 40 papules and pustules and two or fewer nodules). Pregnant and nursing women, subjects <18 years of age, and subjects with ocular rosacea
`
`
`and/or blepharitis/meibomianitis who require ophthalmologic treatment were excluded from trial. Mean baseline lesion counts were 20 and 21 for ORACEA
`
`and placebo subject groups respectively.
`
`
`At Week 16, subjects 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
`trials.
`
`Table 3: Clinical Results of ORACEA versus Placebo
`
`
`
`
`
`
`
`
`Mean Change in
`Lesion Count
`from Baseline
`
`No. (%) of
`
`Subjects Clear or
`
`Almost Clear in
`the IGA*
`
`Study 1
`
`Study 2
`
`ORACEA
`
`Placebo
`
`ORACEA
`
`Placebo
`
`40 mg
`N=127
`
`-11.8
`
`
`N=124
`
`-5.9
`
`
`40 mg
`
`N=142
`
`-9.5
`
`
`N=144
`
`-4.3
`
`
`39 (30.7%)
`
`
`24
`(19.4%)
`
`
`21
`(14.8%)
`
`
`9 (6.3%)
`
`
`*Investigator’s Global Assessment
`
`Subjects treated with ORACEA did not demonstrate significant improvement in erythema when compared to those treated with placebo.
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`ORACEA (beige opaque capsule imprinted 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
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`See FDA-approved patient labeling (Patient Information)
`
`
`Patients taking ORACEA Capsules 40 mg should receive the following information and instructions:
`
`
`It is recommended that ORACEA not be used by individuals of either gender who are attempting to conceive a child
`
`
`It is recommended that ORACEA not be used by pregnant or breast feeding women
`
`
`Patients should be advised that pseudomembranous colitis can occur with doxycycline therapy. If patients develop watery or bloody stools, they
`
`
`
`
`should seek medical attention.
`
`Patients should be advised that pseudotumor cerebri can occur with doxycycline therapy. If patients experience headache or blurred vision they should
`
`
`seek medical attention.
`
`
`
`
`Reference ID: 3214183
`
`

`

`
`
`
`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.
`
`Autoimmune syndromes, including drug-induced lupus-like syndrome, autoimmune hepatitis, vasculitis and serum sickness have been observed with
`
`
`tetracycline-class drugs, 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3214183
`
`

`

`
`
`
`PATIENT INFORMATION
`
`ORACEA (Or-RAY-sha)
`
`(doxycycline)
`
`capsules
`
`
`
`Read this Patient Information before you start taking ORACEA and each time you get a refill. There may be new
`information. This information does not take the place of talking to your doctor about your medical condition or treatment.
`
`What is ORACEA?
` ORACEA is a tetracycline class medicine. ORACEA is a prescription medicine used in adults to treat only pimples or
`
`
`bumps (papules and pustules) caused by a condition called rosacea. ORACEA does not lessen redness caused by rosacea.
`
`ORACEA should not be used for the treatment or prevention of infections.
`
`It is not known if ORACEA is:
`
`
`effective fo