CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TI0N NUMBER:
`
`50—805
`
`LABELING
`
`

`

`NDA 50-805
`
`Page 4
`
`ORACEATM
`
`(doxycycline, USP) Capsules 40 mg*
`
`*30 mg Immediate Release & 10 mg Delayed Release beads
`
`Rx Only
`KEEP OUT OF REACH OF CHILDREN
`
`The dosage of ORACEA differs from that of doxycycline used to treat infections. To reduce the
`development of resistant bacteria as well as to maintain the effectiveness of other antibacterial drugs,
`ORACEA should be used only as indicated.
`
`ORACEA is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea
`in adult patients.
`
`'
`
`This formulation of doxycycline has not been evaluated as an antibacterial in the treatment of
`infections.
`
`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 (C22H24N208).
`
`The structural formula Of doxycycline, USP is:
`
`CH3
`
`DH
`
`1'3ng
`
`CH3
`
`33/
`
` I.
`
`11
`
`D
`
`\
`U \
`
`_
`
`_,/ ‘\\
`[/4
`5
`\-
`
`4
`
`\\
`3
`
`{/OH
`k ,
`
`2
`
`l
`
`28.
`
`\12 i\ I
`UH
`.l
`
`UH
`
`o
`
`COME
`'
`
`.HZO
`
`with an empirical formula of C22H24NzOg-HZO and a molecular weight of 462.46. The chemical
`designation for doxycycline is 2—Naphthacenecarboxamide, 4—(dimethylamino)—
`
`

`

`NDA 50—805
`
`Page 5
`
`l,4,4a,5,5a,6,1 1,l2a—octahydro—3,5,10,l2,12a-pentahydroxy—6-methyl—1,1l—dioxo—, [4S—(4aa, 4aoL, 50L,
`5a0t, 6a,12a0t)]—, monohydrate. It is very slightly soluble in water.
`
`Inert ingredients in the formulation are: hypromellos'e, 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.
`V
`
`CLINICAL PHARMACOLOGY
`
`Pharmacokineties
`
`ORACEA capsules are not bioequivalent to other doxycycline products. The pharmacokinetics of
`doxycycline following oral administration of ORACEA was investigated in 2 volunteer studies
`involving 61 adults. Pharmacokinetic parameters for ORACEA following single oral doses and at
`steady-state in healthy subjects are presented in Table 1.
`
`
`Table 1. Pharmacokinetic Parameters [Mean i SD for ORACEA
`Cmax *
`
`_- (n/mL
`
`Single Dose 40 mg capsules
`
`
`__
`
`+
`
`Tm (hr)
`
`-
`3.00
`
`
`
`air/mt
`
`AUCO-uo*
`
`
`9227 ::
`
`2.00
`_
`1.0 4 0
`
`7543 i
`2443.9
`
`t1/2 *
`
`21.2 i
`
`
`23.2 ::
`6.2
`
`
`
`
`
`
`
`
`
`
`Steady-State# 40 mg capsules
`
`
`
`31
`600 i 1942
`
`* Mean
`+ Median
`# Day 7
`
`
`
`
`
`Absorption: In a single—dose food—effect study involving administration of ORACEA to healthy
`volunteers, concomitant administration with a 1000 calorie, high—fat, high—protein meal that included
`dairy products, resulted in a decrease in the rate and extent of absorption (Cmax and AUC) by about 45
`% and 22 %, respectively, compared to dosing under fasted conditions. This decrease in systemic
`exposure can be clinically significant, and therefore if ORACEA‘is taken close to meal times, it is
`recommended that it be taken at least one hour prior to or two hours after meals
`
`Distribution: Doxycycline is greater than 90% bound to plasma proteins.
`
`Metabolism: Major metabolites of doxycycline have not been identified. However, enzyme inducers
`such as barbiturates, carbamazepine, and phenytoin decrease the half—life of doxycycline.
`
`Excretion: Doxycycline is excreted in the urine and feces as unchanged drug. It is reported that
`between 29% and 55.4% of an administered dose can be accounted for in the urine by 72 hours.
`Terminal half-life averaged 21.2 hours in subjects receiving a single dose of ORACEA.
`
`Special Populations
`
`Geriatric: Doxycycline pharmacokinetics have not been evaluated in geriatric patients.
`
`Pediatric: Doxycycline pharmacokinetics have not been evaluated in pediatric patients (See
`WARNINGS section).
`
`

`

`NDA 50—805
`
`Page 6
`
`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 pharrnacokinetics among racial groups have not been evaluated.
`
`Renal Insufi‘iciency: Studies have shoWn no significant difference in serum half—life of doxycycline in
`patients with normal and severely impaired renal function. Hemodialysis does not alter the serum half—
`life of doxycycline.
`
`Hepatic Insufficiency: Doxycycline pharmacokinetics have not been evaluated in patients with hepatic
`insufficiency.
`
`Gastric Insufficiency: In a study in healthy volunteers (N=24) the bioavailability of doxycycline is
`reported to be reduced at high pH. This reduced bioavailability may be clinically significant in patients
`with gastrectomy, gastric bypass surgery or who are otherwise deemed achlorhydric.
`
`Drug Interactions: (See PRECAUTIONS section)
`
`MICROBIOLOGY
`Doxycycline is a member of the tetracycline class of antibacterial drugs. The plasma concentrations of
`doxycycline achieved with ORACEA during administration (see CLINICAL PHARMACOLOGY
`AND DOSAGE AND ADMINISTRATION) are less than the concentration required to treat bacterial
`diseases. In vivo microbiological studies utilizing a similar drug exposure for up to .l 8 months
`demonstrated no detectable long—term effects on bacterial flora of the oral cavity, skin, intestinal tract,
`and vagina.
`
`ORACEA should not be'used for treating bacterial infections, providing antibacterial prophylaxis, or
`reducing the numbers or eliminating microorganisms associated with any bacterial disease.
`
`CLINICAL STUDIES
`
`The safety and efficacy of ORACEA in the treatment of only inflammatory lesions (papules and
`pustules) of rosacea was evaluated in two randomized, placebo—controlled, multi—centered, double—
`blind, 16—week Phase 3 studies involving 537 patients (total of 269 patients on ORACEA from the two
`studies) with rosacea (10 to 40 papules and pustules and two or fewer nodules). Pregnant and nursing
`women, patients <18 years of age, and patients with ocular rosacea and/or blepharitis/meibomianitis
`who require ophthalmologic treatment were excluded from study. Mean baseline lesion counts were 20
`and 21 for ORACEA and placebo patient groups respectively.
`
`At Week 16, patients in the ORACEA group were evaluated using co—primary endpoints of mean
`reduction in lesion counts and a dichotomized static Investigator's Global Assessment of Clear or
`Almost Clear (defined as l 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
`
`
`
`Stud 1
`Study 2
`
`ORACEA
`Placebo
`40 mg
`
`
`
` N = 142 N = 144
`
`
`
`Mean Change in Lesion
`
` —9.5 -4.3
`
`Count from Baseline
`
`
`
`
`
` 39 (30.7%)
`
`
`21 (14.8%)24 (19.4%) 9 (6.3%)
`
`
`* Investigator’s Global Assessment
`
`
`
`
`
`NDA 50—805
`
`Page 7
`
`
`
`No. (%) of Subjects
`Clear or Almost Clear
`in the IGA*
`
`Patients treated with ORACEA did not demonstrate significant improvement in erythema when
`compared to those treated with placebo.
`
`INDICATIONS AND USAGE
`
`ORACEA is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea
`in adult patients. No meaningful effect was demonstrated for generalized erythema (redness) of
`rosacea. ORACEA has not been evaluated for the treatment of the erythematous, telangiectatic, or
`ocular components of rosacea. Efficacy of ORACEA beyond 16 weeks and safety beyond 9 months
`have not been established.
`
`This formulation of doxycycline has not been evaluated in the treatment or prevention of infections.
`ORACEA should not be used for treating bacterial infections, providing antibacterial prophylaxis, or
`reducing the numbers or eliminating microorganisms associated with any bacterial disease.
`
`To reduce the development of drug—resistant bacteria as well as to maintain the effectiveness of other
`antibacterial drugs, ORACEA should be used only as indicated.
`
`CONTRAINDICATIONS
`
`This drug is contraindicated in persons who have shown hypersensitivity to doxycycline 01' any of the
`other tetracyclines.
`
`WARNINGS
`
`Teratogenic effects
`1) Doxycycline, like other tetracycline-class antibiotics, can cause fetal harm when administered
`to a pregnant woman. If any tetracycline is used during pregnancy or if the patient becomes
`pregnant while taking these drugs, the patient should be informed of the potential hazard to the
`fetus and treatment stopped immediately.
`‘
`
`ORACEA should not be used during pregnancy (see PRECAUTIONS: Pregnancy).
`
`

`

`NDA 50—805
`Page 8
`
`2) The use of drugs of the tetracycline class during tooth development (last half of pregnancy,
`infancy, and childhood up to the age of 8 years) may cause permanent discoloration of the teeth
`(yellow-gray-brown). This adverse reaction is more common during long—term use of the drug but
`has been observed following repeated short—term courses. Enamel hypoplasia has also been reported.
`Tetracycline drugs, therefore, should not be used during tooth development unless other drugs
`are not likely to be effective or are contraindicated.
`
`3) All tetracyclines form a stable calcium complex in any bone—forming tissue. A decrease in 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
`PRECAUTIONS: Pregnancy section).
`
`Gastrointestinal effects
`
`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.
`
`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 livertoxicity.
`Under such conditions, lower than usual total doses are indicated, and if therapy is prolonged, serum
`level determinations of the drug may be advisable.
`
`.
`Photosensitivity
`Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals
`taking tetracyclines. Although this was not observed during the duration of the clinical studies with
`ORACEA, patients should minimize or avoid exposure to natural or 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.
`
`

`

`NDA 50—805
`
`Page 9
`
`PRECAUTIONS
`General
`
`Safety of ORACEA beyond 9 months has not been established.
`
`As with other antibiotic preparations, use of ORACEA may result in overgrowth of non-susceptible
`microorganisms, including fungi. If superinfection occurs, ORACEA should be discontinued and
`appropriate therapy instituted. Although not observed in clinical trials with ORACEA, the use of
`tetracyclines may increase the incidence of vaginal candidiasis.
`
`ORACEA should be used with caution in patients with a history of or predisposition to candidiasis
`overgrowth.
`
`Bacterial resistance to tetracyclines may develop in patients using ORACEA. Because of the potential
`for drug-resistant bacteria to develop during the use of ORACEA, it should be used only as indicated.
`
`Autoimmune Syndromes
`Tetracyclines have been associated with the development of autoimmune syndromes. Symptoms may
`be manifested by fever, rash, arthralgia, and malaise. In symptomatic patients, liver function tests,
`ANA, CBC, and other appropriate tests should be performed to evaluate the patients. Use of all
`tetracycline-class drugs should be discontinued immediately.
`
`.
`Tissue Hyperpigmentation
`Tetracycline class antibiotics are known to cause hyperpigmentation. Tetracycline therapy may induce
`hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral
`cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation has been
`reported. to occur independently of time or amount of drug administration, whereas other pigmentation
`has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse
`pigmentation as well as over sites of scars or injury.
`
`Pseudotumor cerebri
`
`Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in
`individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.
`
`Information for Patients
`
`See Patient Package Insert that accompanies this Package Insert for additional information to
`give patients.
`
`1. 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.
`
`2. Concurrent use of doxycycline may render oral contraceptives less effective (See Drug
`Interactions).
`
`

`

`NDA 50-805
`
`Page 10
`
`3. Autoimmune syndromes, including drug—induced lupus—like syndrome, autoimmune hepatitis,
`vasculitis and serum sickness have been observed with tetracycline—class antibiotics, including
`doxycycline. Symptoms may be manifested by arthralgia, fever, rash and malaise. Patients who
`experience such symptoms should be cautioned to stop the drug immediately and seek medical
`help.
`
`4. Patients should be counseled about discoloration of skin, scars, teeth or gums that can arise
`from doxycycline therapy.
`
`5. 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.
`
`6. It is recommended that ORACEA not be used by pregnant or breast feeding women.(See
`Carcinogenesis, Mutagenesis, Impairment of Fertility, Pregnancy and Nursing Mothers
`sections).
`'
`
`7. It is recommended that ORACEA not be used by individuals of either gender who are
`attempting to conceive a child ( See Carcinogenesis, Mutagenesis, Impairment of Fertility,
`and Pregnancy sections).
`
`Laboratory Tests
`Periodic laboratory evaluations of organ systems, including hematopoietic, renal and hepatic studies
`should be performed. Appropriate tests for autoimmune syndromes should be performed as indicated.
`
`Drug Interactions
`1. Because tetracyclines have been shown to depress plasma prothrombin activity, patients
`who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
`
`2. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to
`avoid giving tetracycline—class drugs in conjunction with penicillin.
`
`3. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal
`toxicity.
`
`4. Absorption of tetracyclines is impaired by bismuth subsalicylate, proton pump inhibitors, antacids
`containing aluminum, calcium or magnesium and iron-containing preparations.
`
`5. Doxycycline may interfere with the effectiveness of low dose oral contraceptives. To avoid
`contraceptive failure, females are advised to use a second form of contraceptive during treatment with
`doxycycline.
`
`6. There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated with
`the concomitant use of isotretinoin and tetracyclines. Since both oral
`retinoids, including isotretinoin and acitretin, and the tetracyclines, primarily minocycline, can cause
`increased intracranial pressure, the concurrent use of an oral retinoid and a tetracycline should be
`avoided.
`
`

`

`NDA 50—805
`
`Page 11
`
`Drug/Laboratory Test Interactions: False elevations of urinary catecholamine levels may occur due
`to interference with the fluorescence test.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Doxycycline was assessed for potential to
`induce carcinogenesis in a study in which the compound was administered to Sprague-Dawley rats by
`gavage at dosages of 20, 75, and 200 mg/kg/day for two years. An increased incidence of uterine
`polyps was observed in female rats that received 200
`mg/kg/day, a dosage that resulted in a systemic exposure to doxycycline approximately 12.2 times that
`observed in female humans who use ORACEA (exposure comparison based upon area under the curve
`(AUC) values). No impact upon tumor incidence was observed in male rats at 200 mg/kg/day, or in
`either gender at the other. dosages studied. Evidence of oncogenic activity was obtained in studies with
`related compounds, i.e., oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid
`tumors).
`
`Doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study
`with mammalian cells (CHO/HGPRT forward mutation assay) or in an in viva micronucleus assay
`conducted in CD—l mice. However, data from an in vitro assay with CHO cells for potential to cause
`chromosomal aberrations suggest that doxycycline is a weak clastogen.
`
`Oral administration of doxycycline to male and female Sprague—Dawley rats adversely affected fertility
`and reproductive performance, as evidenced by increased time for mating to occur, reduced sperm
`motility, velocity, and concentration, abnormal sperm morphology, and increased pre—and post—
`implantation losses. Doxycycline induced reproductive toxicity at all dosages that were examined in
`this study, as even the lowest dosage tested (50 mg/kg/day) induced a statistically significant reduction
`in sperm velocity. Note that 50 mg/kg/day is approximately 3.6 times the amount of doxycycline
`contained in the recommended daily dose of ORACEA for a 60—kg human when compared on the basis
`of AUC estimates. Although doxycycline impairs the fertility of rats when administered at sufficient
`dosage, the effect of ORACEA on human fertility is unknown.
`
`'
`
`Pregnancy: Teratogenic Effects: Pregnancy Category D. (See WARNINGS Section). Results from
`animal studies indicate that doxycycline crosses the placenta and is found in
`fetal tissues.
`
`Nonteratogenic effects: (See WARNINGS Section).
`
`Labor and Delivery: The effect of tetracyclines on labor and delivery is unknown.
`
`Nursing Mothers: Tetracyclines are excreted in human milk. Because of the potential for
`serious adverse reactions in infants from doxycycline, ORACEA should not be used in mothers who
`breastfeed.(See WARNINGS Section).
`
`Pediatric Use: ORACEA should not be used in infants and children less than 8 years of age (See
`WARNINGS section). ORACEA has not been studied in children of any age with regard to safety or
`efficacy, therefore use in children is not recommended.
`
`

`

`NDA 50—805
`
`Page 12
`
`ADVERSE REACTIONS
`
`Adverse Reactions in Clinical Trials of ORACEA: In controlled clinical trials of adult patients With
`mild to moderate rosacea, 537 patients received ORACEA or placebo over a 16—week period. The
`most frequent adverse reactions occurring in these studies are listed in Table 3
`
`

`

`NDA 50—805
`
`Page 13
`
`
`Table 3. Incidence (%) of Selected Adverse Reactions in Clinical Trials of
`ORACEA (n=269) vs. Placebo (n=268)
`
`
`
`
`
`
`
`
`
`
`Fungal Infection
`
`Influenza
`
`Diarrhea
`
`Abdominal Pain Upper
`
`Abdominal Distention
`
`Abdominal Pain
`Stomach Discomfort
`
`Dry Mouth
`
`Hypertension
`
`Blood Pressure Increase
`
`Aspartate Aminotransferase Increase
`
`Blood Lactate Deh dro enase Increase
`
`Blood Glucose Increase
`
`Anxiet
`
`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 Section).
`
`Skin: maculopapular and erythematous rashes. Exfoliative dermatitis has been reported, but is
`uncommon. Photosensitivity is discussed above. (See WARNINGS Section).
`
`Renal toxicity: Rise in BUN has been reported and is apparently dose—related.(See WARNINGS
`Section).
`
`Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum
`sickness, pericarditis, and exacerbation of systemic lupus erythematosus.
`
`Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.
`
`

`

`NDA 50-805
`
`Page 14
`
`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.
`
`DOSAGE AND ADMINISTRATION
`
`THE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE
`USED TO TREAT INFECTIONS. EXCEEDIN G THE RECOMMENDED DOSAGE
`MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS INCLUDING THE
`DEVELOPMENT OF RESISTANT MICROORGANISMS.
`
`One ORACEA Capsule (40 mg) should be taken once daily in the morning on an empty stomach,
`preferably at least one hour prior to or two hours after meals.
`
`Efficacy beyond 16 weeks and safety beyond 9 months have not been established.
`
`Administration of adequate amounts of fluid along with the capsules is recommended to wash down
`the capsule to reduce the risk of esophageal irritation and ulceration. (See
`ADVERSE REACTIONS Section).
`
`HOW SUPPLED
`
`ORACEA (beige opaque capsule printed with CGPI 40) containing doxycycline, USP in an amount
`equivalent to 40 mg of anhydrous doxycycline. Bottle of 30 (NDC XXXXX-XXX-XX).
`
`Storage: All products are to be stored at controlled room temperatures of 15°C —30°C (59°F
`—86°F) and dispensed in tight, light—resistant containers (USP). Keep out of reach of children.
`
`Patent Information: patent No. xxxxxxxxxx
`
`ORACEA is a trademark of CollaGenex Pharmaceuticals, Inc., Newtown, PA, 18940 Manufactured
`by:
`CardinalHealth
`
`Winchester, KY 40391
`
`Marketed by:
`CollaGenex Pharmaceuticals, Inc.
`Newtown, PA, 18940
`
`May 26, 2006
`
`

`

`NDA 50-805
`
`Page 15
`
`Patient Information
`ORACEATM (Or-RAY—sha) (doxycycline, USP) Capsules 40 mg*
`*30 mg Immediate ReleaSe & 10 mg Delayed Release beads
`
`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 may not lessen the facial
`redness caused by rosacea.
`
`It may cause stained teeth
`ORACEA should not be given to infants and children 8 years or younger.
`in infants and children. The yellow, gray, brown colored staining will not go away.
`
`ORACEA should not be used for the treatment of infections.
`
`ORACEA has not been studied for use longer than 9 months.
`
`Who should not take ORACEA?
`
`Do not take ORACEA if you are allergicto any medicine known as a
`tetracycline, including doxycycline and minocycline. If you are not sure, talk to your
`doctor or pharmacist.
`
`What should I tell my doctor before taking ORACEA?
`Tell your doctor about all your health conditions. Be sure to tell your doctor if
`you
`
`0
`o
`0
`0
`0
`0
`0
`
`0
`
`have had an allergic reaction to doxycycline or other medicines known as tetracyclines
`are pregnant or planning to become pregnant. ORACEA may harm your unborn baby.
`are breastfeeding. ORACEA passes into your breast milk and may harm your baby.
`have kidney problems
`have liver problems
`have had surgery on your stomach
`have or had a yeast or fungus infection in your mouth or vagina.
`
`spend time in sunlight or artificial sunlight, such as a tanning booth or sunlamp. ORACEA may
`cause you to get severe sunburns photosensitivity).
`
`Tell your doctor about all of the medicines you take, including prescription and non-prescription
`medicines, vitamins, and herbal supplements.
`
`ORACEA and other medicines can affect each other causing serious side effects. Especially tell your
`doctor if you take
`
`

`

`NDA 50-805
`
`Page 16
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`blood thinners (anticoagulants), such as warfarin or Coumadin®. Your doctor may need to
`change your anticoagulant dose.
`any medicine to treat pimples (acne) or psoriasis
`
`ORACEA may affect the way other medicines work, and other medicines may affect how ORACEA
`works. Especially tell your doctor if you take
`.
`
`o
`
`birth control pills. Talk to your doctor about other methods of birth control because birth
`control pills may not work as well when you are taking ORACEA.
`antacid medicines containing calcium, magnesium or aluminum,
`products containing iron
`
`any medicine to treat an infection
`any medicine to treat seizures, such as barbiturates, Phenobarbital, carbamazepine, Tegretol®,
`phenytoin or Dilantin®
`Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist
`when you get a new medicine.
`
`How should I take ORACEA?
`
`0 Take ORACEA exactly as prescribed by your doctor. Do not change your dose unless told to
`do so by your doctor. Taking more than the prescribed dose may increase your chance of
`having side effects.
`0 The usual dose of ORACEAis one capsulein the morning.
`0 Do not take ORACEA with or right after a meal. It may not work as well. If you take
`ORACEA close to meal times, you should take it at least one hour before your meal or two
`hours after your meal.
`0 Take ORACEA with a full glass of water while sitting or standing. To prevent irritation to your
`throat, do not lay down right after taking ORACEA.
`0 Do not take ORACEA with or right after taking antacids or products that contain calcium,
`aluminum, magnesium, or iron. ORACEA may not work as well.
`If you take too much ORACEA, or overdose, stop taking ORACEA and talk to your doctor.
`0
`If you miss a dose of ORACEA, skip that dose and take the next dose at your regular time.
`0
`0 Do not take ORACEA to treat infections caused by bacteria germs or viruses.
`0 Your doctor may do blood tests from time to time to check for side effects of ORACEA.
`
`What should I avoid while taking ORACEA?
`- Do not spend time in sunlight or artificial sunlight, such as a tanning booth or sunlamp. You
`could get a severe sunburn. Use sunscreen and wear clothes that cover your skin if you have to
`be in sunlight.
`0 You should not take ORACEA if you are pregnant or breast feeding.
`0 You should not take ORACEA if you are a man or a woman trying to have a baby.
`4
`
`What are the possible side effects of ORACEA?
`ORACEA may cause serious side effects. Stop taking ORACEA and talk to your doctor right
`away if you
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`NDA 50-805
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`Page 17
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`have any skin rash, redness, orunusual or severe sunburn
`have an allergic reaction, which may cause a skin rash, swelling, difficulty swallowing, or a
`feeling of tightness in your throat
`become pregnant
`have stomach cramps, high fever, and bloody diarrhea (pseudomembranous colitis)
`have fever, rash, joint pain, and feel tired. These may be symptoms of a problem where your
`body is attacking itself (autoimmune syndrome).
`
`ORACEA may also cause
`-
`darkening of your skin, scars, teeth, or gums
`0
`severe headaches, dizziness, or double vision from high pressure in the fluid around the brain
`
`Some common side effects of ORACEA are soreness in the nose and throat, diarrhea, and sinus
`infection.
`
`These are not all the possible side effects of ORACEA. For more information, ask your doctor or
`pharmacist.
`
`Tell your doctor if you have aside effect that bothers you or that does not go away.
`
`How should I store ORACEA?
`
`Store ORACEA at room temperature at 59°F to 86°F (15°C to 30°C).
`0
`0 Keep ORACEA in a tightly closed container.
`0 Keep ORACEA inside container and out of light.
`0 Keep ORACEA and all medicine out of the reach of children.
`
`General Information about ORACEA
`
`Do not take ORACEA for a condition for which it was not prescribed. Do not
`give ORACEA to other people, even if they have the same symptoms you have. It may harm them.
`
`This leaflet gives the most important information about ORACEA. For more
`information, talk with your doctor or health care provider. You can also ask your
`doctor or pharmacist for information that is written for health professionals. More
`Information about ORACEA is available by contacting CollaGenex Pharmaceuticals Inc. at l—xxx—xxx-
`xxxx
`
`What are the ingredients in ORACEA?
`Active ingredient: doxycycline
`
`Inactive ingredients: hypromellose, iron oxide red, iron oxide yellow, methacrylic acid copolymer,
`polyethylene glycol, Polysorbate 80, sugar spheres, talc, titanium dioxide, and triethyl citrate.
`
`ORACEA is a registered trademark of CollaGenex Pharmaceuticals, Inc.,
`Newtown, PA 18940.
`
`

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`NDA 50-805
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`Page 18
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`Spheres, Talc. Titanium Dioxide, and Triethyl Citrate
`Dosage: One capsule per day.
`Store at controlled room temperature of 15°C - 30°C (59°F - 86°F).
`Patient Sample—NOT FOR SALE
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`Each capsule contains
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`THE DOSAGE OF ORACEA DIFFERS FROM THAT OF DOXYCYCLINE USED TO
`TREAT INFECTIONS. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT
`IN AN INCREASED INCIDENCE 0F SIDE EFFECTS, INCLUDING THE
`
`DEVELOPMENTOFRESISTANTMICROORGANISMS.
`
`Oracea should be taken once daily in the morning. If Oracea is taken close to
`mealtimes. it is recommended that it be taken at least one hour prior to or two
`hours alter meals. Efficacy beyond 16 weeks and safety beyond 12 months
`have not been established.
`
`l
`
`Administration of adequate amounts of fluid along with the capsules is
`recommended to wash down the drug to reduce the risk of esophageal
`irritation and ulceration. (Se