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)
`
`
`
`•
`
`
`
`•
`
`Efficacy of ORACEA beyond 16 weeks and safety beyond 9 months
`have not been established (1.2).
`
`
`This formulation of doxycycline has not been evaluated in the treatment
`or prevention of infections (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)
`
`
`
`The dosage of ORACEA differs from that of doxycyline used to treat
`
`infections. Exceeding the recommended dosage may result in an
`increased incidence of side effects including the development of
`resistant microorganisms (2, 5.5)
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`40 mg capsule: beige opaque capsule imprinted with “GLD 40” (3)
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`This drug 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).
`
`
`
`
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`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`If pseudomembranous colitis occurs, discontinue Oracea (5.2)
`Anti-anabolic action of the tretracyclines may cause an increase in BUN
`(5.3)
`Photosensitivity (an exaggerated sunburn reaction) can occur with Oracea;
`
`Oracea should be discontinued(5.4)
`Tetracyclines have been associated with the development of autoimmune
`
`syndromes; discontinue Oracea immediately (5.5)
`Bacterial resistance to tetracycline may develop in patients using
`
`ORACEA (5.8).
`
`------------------------------ADVERSE REACTIONS-------------------------------
`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).
`
`
`
`•
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`patient labeling.
`
`
`
`
`
`
`
`
`Revised 5/2010
`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`
`7.6 Oral Retinoids
`
`7.7 and Anti-epileptics
`
`7.8 Drug/Laboratory Test Interactions
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`8.2 Labor and Delivery
`
`8.3
` Nursing Mothers
`
`8.4 Pediatric 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
`17.1
`Information for Patients
`
`17.2 FDA-Approved Patient Labeling
`
`
`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 Anticoagulant Drugs
`
`7.2 Penicillin
`
`7.3 Methoxyflurane
`
`7.4 Other Concomitant Drug Therapy
`
`
`7.5 Low Dose Oral Contraceptives
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2
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`3
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`
`4
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`5
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`
`
`
`
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`
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`
`
`
`
`
`
`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 capsule: 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 [see Use in Specific Populations (8.1)].
`
`
`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.
`
`
`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 [see Use in Specific Populations (8.1)].
`
`
`
`5.2 Pseudomembranous Colitis
`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 permit 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. 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 fluids and electrolytes, protein
`
`
`
`supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
`
`
`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
`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 candidiasis overgrowth
`
`
`
`
`
`6
`
`7
`
`5.10 Laboratory Monitoring
`Periodic laboratory evaluations of organ systems, including hematopoetic, 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:
`
`
`
`Table 3. Incidence (%) of Selected Adverse Reactions in Clinical Trails of ORACEA (n=269) vs. Placebo (n=268)
`
`
`ORACEA
`Placebo
`13 (5)
`9 (3)
`3 (1)
`2 (1)
`
`
`7 (3)
`2 (1)
`4 (2)
`2 (1)
`
`
`5 (2)
`1 (0)
`
`
`5 (2)
`3 (1)
`12 (5)
`7 (3)
`5 (2)
`1 (0)
`
`
`3 (1)
`1 (0.)
`
`
`3 (1)
`1 (0)
`
`
`3 (1)
`2 (1)
`3 (1)
`0 (0)
`
`
`8 (3)
`2 (1)
`4 (2)
`1 (0)
`
`
`6 (2)
`2 (1)
`4 (2)
`1 (0)
`
`
`3 (1)
`0 (0)
`
`
`4 (2)
`0 (0)
`4 (2)
`1 (0)
`3 (1)
`0 (0)
`3 (1)
`0 (0)
`
`
`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
`Blood Glucose Increase
`Anxiety
`
`Pain
`
`Back Pain
`Sinus Headache
`
`
`
`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 decrese 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.
`
`8.2 Labor and Delivery
`
`The effect of tetracyclines on labor and delivery is unknown.
`
`
`
`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.
`
`
`
`
`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:
`
`
`
`
`
`
`
`
`
`
`
`8
`
`
`
`
`
`
`
`
`10
`
`
`
`11
`
`
`
`
`
`
`
`
`
`with an empirical formula of C22H24N2O8•H2O 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-(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.
`
`
`

`

`12
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`13
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`14
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`
`
`
` *Mean +Median
`
`
`
`#Day 7
`
` 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 1.
`
`Single Dose 40 mg capsules
`
`Steady-State# 40 mg capsules
`
`30
`
`31
`
`600 + 194.2
`
`7543 + 2443.9
`
`t1/2* (hr)
`
`21.2 + 7.6
`
`23.2 + 6.2
`
`Table 1. Pharmacokinetic Parameters [Mean (+ SD)] for ORACEA
`+
`N
`Cmax* (ng/mL)
`Tmax
`AUC0 -∞ *
`
`ng.hr/mL)
`
`
`(hr)
`510 + 220.7
`9227 + 3212.8
`3.00
` (1.0-4.1)
`2.00
`(1.0-4.0)
`
`
`
`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 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 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.
`
`
` 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 subjects (total of 269 subjects on ORACEA from the two studies) 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 study. 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
`
`studies.
`
`
`
`
`Table 2: Clinical Results of ORACEA versus Placebo
`Study 1
`
`ORACEA
`
`40 mg
`
`
`Placebo
`N=124
`
`Study 2
`
`ORACEA
`40 mg
`
`
`Placebo
`N=144
`
`

`

`N=127
`-11.8
`
`
`39 (30.7%)
`
`-5.9
`
`
`
`24 (19.4%)
`
`N=142
`-9.5
`
`
`
`21 (14.8%)
`
`Mean Change in Lesion Count from Baseline
`
`
`
`No. (%) of Subjects Clear or Almost Clear in
`the IGA*
`*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).
`
`-4.3
`
`
`
`9 (6.3%)
`
`16
`
`
`
`
`
`
`17
`17.1
`
`
`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
`
`PATIENT COUNSELING INFORMATION
`
`Information for Patients
`
`Patients taking ORACEA® (doxycycline, USP) 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 [see Nonclinical Pharmacology (13.1),
`
`
`and Use in Specific Populations (8.1)].
`
`
`
`
`• It is recommended that ORACEA not be used by pregnant or breast feeding women [see Nonclinical Toxicology (13.1), Use in Specific Populations (8.1) and
`
`(8.3)].
`
` 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.
`
`
`• 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 (7.5)].
`
`
`• 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.
`
`
`
`17.2 FDA-Approved Patient Labeling
`
`
`
`
`ORACEA® (Or-RAY-sha) (doxycycline, USP) Capsules 40 mg
`
`
`
`Read the Patient Information that comes with ORACEA before you start taking it and each time you get a refill. There may be new information. This
`
`
`information does not take the place of talking with your doctor about your treatment or your medical condition. If you have any questions about ORACEA, ask
`
`your doctor or pharmacist.
`
`
`What is ORACEA?
`ORACEA is a prescription medicine to treat only the pimples or bumps on the face caused by a condition called rosacea. ORACEA did not lessen the facial
`
`redness