Blood Lactate Dehydrogenase
`Increase
`
`Blood Glucose Increase
`
`Anxiety
`
`Pain
`
`Back Pain
`
`Sinus Headache
`
`4 (2)
`
`3 (1)
`
`4 (2)
`
`4 (2)
`
`3 (1)
`
`3 (1)
`
`1 (0)
`
`0 (0)
`
`(0)
`
`1 (0)
`
`(0)
`
`(0)
`
`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 infec-
`
`tions. Exceeding the recommended dosage may result in an increased
`incidence of side effects including the development of resistant microorgan-
`
`
`isms. (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)
`• 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)
`• ORACEA may cause pesudotumor cerebri (benign intracranial hypertension).
`Discontinue ORACEA if symptoms occur. (5.7)
`• Bacterial resistance to tetracycline 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 conjunc-
`tion 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: 07/2013
`
`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
`6.1 Clinical Trials Experience
` 6.2 Postmarketing Experience
`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 Barbituates 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.
`
`
`
`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 bacte-
`rial 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.
`2 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 infec-
`tions. Exceeding the recommended dosage may result in an increased
`
`incidence of side effects including the development of resistant organisms.
`
`3 DOSAGE FORMS AND STRENGTHS
` 40 mg beige opaque capsule imprinted with “GLD 40”
`4 CONTRAINDICATIONS
`This drug is contraindicated in persons who have shown hypersensitivity
`to doxycycline or any of the other tetracyclines.
`
`5 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 treat-
` ment 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 antimi-
`crobial 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 aministration 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
`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. Tetracy-
`cline 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 adminis-
`tration, 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 ques-
`tioned for visual disturbances prior to initiation of treatment with tetracy-
`clines 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 over-
` growth of non-susceptible microorganisms, including fungi. If superinfec-
`
`tion 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 auto-
`immune syndromes should be performed as indicated.
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`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 1. Incidence (%) of Selected Adverse Reactions in Clinical Trials of
`ORACEA (n=269) vs Placebo (n=268)
`
`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
`
`ORACEA
`
`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)
`
`Placebo
`
`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)
`
`
`
`
`
`
`
`
`
`
`
`
`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, dyspha-
` gia, 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.
`6.2 Postmarketing Experience
`Because these reactions are reported voluntarily from a population of
`uncertain size, it is not always possilbe to reliably estimate their
`frequency or establish a causal relationaship to drug exposure. The
`following adverse reactions have been identified during post approval use
`of ORACEA
`• Nervous system: Pseudotumor cerebri (benign intracranial hyperten-
` sion), headache.
`
`7 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 pen-
`icillin, 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 contra-
`ceptives. 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 hyper-
`tension) associated with the concomitant use of isotretinoin and tetracy-
`clines. 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 inter-
`ference with the fluorescence test.
`
`8 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 gen-
`eral, 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.
`10 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.
` Supernus Pharms. 2011 (Substitute Exhibit)
` IPR 2013-00371
`
`000001
`
`Galderma Laboratories, Inc. Ex 2004
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01777
`
`

`
`11 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:
`O
`OH
`O
`OH OH
`
`CONH2
`
`• H2O
`
`OH
`
`H
`
`N(CH3)2
`
`H
`CH3
`OH
`H
`H
`H
`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-(4a, 4aa, 5a,
`5aa, 6a,12aa)]-, 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 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
`N
`Cmax*
`Tmax+ (hr)
`AUC0-00*
`t1/2* (hr)
`(ng/mL)
`(ng•hr/mL)
`510 ± 220.7
`9227 ±
`3212.8
`
`3.00
`(1.0-4.1)
`
` 21.2 ± 7.6
`
`30
`
`Single Dose
`40 mg
`capsules
`
`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 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 differ-
`ences 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 bioa-
`vailability 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 administr-
`ation [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 microor-
` ganisms 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.
`13 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 expo-
`sure 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 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 female 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 abberation
`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 veloc-
`ity. 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.
`14 CLINICAL STUDIES
`The safety and efficacy of ORACEA in the treatment of only inflammatory
`lesions (papules and pustules) of rosacea was evaluated in two random-
`ized, 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 respec-
`tively.
`
` 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
`Study 1
`Study 2
`ORACEA
`Placebo
`ORACEA
`Placebo
`
`
`
`
`
`
`
`
`
`40 mg
`N=127
`
`-11.8
`
`N=124
`
`-5.9
`
`40mg
`N=142
`
`-9.5
`
`N=144
`
`-4.3
`
`39 (30.7%)
`
`24 (19.4%) 21 (14.8%) 9 (6.3%)
`
`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 improve-
` ment in erythema when compared to those treated with placebo.
`16 HOW SUPPLIED/STORAGE AND HANDLING
` ORACEA (beige opaque capsule imprinted with “GLD 40”) containing doxy-
`
`cycline, 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.
`• Photosensitivity manifested by an exaggerated sunburn reaction has
`been observed in some individuals taking tetracyclines, including doxy-
`cycline. Patients should minimize or avoid exposure to natural or
`artificial sunlight (tanning beds or UVA/B treatment) while using doxycy-
`cline. 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. Treat-
`
` ment 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. Symp-
`toms 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 resis-
`tance and will not be treatable by other antibacterial drugs in the future.
`
`
`
`
`
`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 for use for longer than 16 weeks.
`• safe for use longer than 9 months.
`• safe and effective in children. ORACEA should not be used in infants
`and children less than 8 years of age because it may cause stained
`teeth in infants and children.
`Who should not take ORACEA?
`