CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TI0N NUMBER:
`
`50-805
`
`MEDICAL REVIEW
`
`

`

`CLINICAL REVIEW
`
`Application Type
`Submission Number
`
`NDA 5.05(b)(1)
`50-805
`
`Submission Code
`
`N000
`
`Letter Date
`
`Stamp Date
`PDUFA Goal Date
`
`July 29,- 2005
`August 3, 2005
`June 1, 2006
`
`Reviewer Name
`
`Review Completion Date
`
`Patricia Brown, MD
`May 26, 2006
`
`Established Name
`
`(Proposed) Trade Name
`Therapeutic Class
`Applicant
`
`Doxycycline
`7 (OraceaTM)
`Rosacea product
`CollaGeneX Pharmaceuticals
`
`Priority Designation
`
`S
`
`Formulation
`
`Dosing Regimen
`Indication -
`
`Intended Population
`
`Capsule 40mg
`Once Daily in morning
`
`, f
`_ Inflammatory Lesions
`(Papules and Pustules) of Rosacea
`in Adult Patients
`
`Men and Women 18 years and
`older
`
`

`

`Clinical Review
`
`Patricia C. Brown, MD
`NDA 50-805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`Table of Contents
`
`1
`
`EXECUTIVE SUMMARY ................................................................................................................................5
`
`1.1
`1.2
`
`RECOMMENDATION ON REGULATORY ACTION ........................................................................................... 6
`RECOMMENDATION ON POST—MARKETING ACTIONS .................................................................................. 6
`
`1.2.1 Risk Management Activity ........................................................................................................................ 6
`1.2.2 Required Phase 4 Commitments ............................................................................................................... 6
`1.2.3 Other Phase 4 Requests ............................................................................................................................. 7
`SUMMARY OF CLINICAL FINDINGS .............................................................................................................. 7
`
`1 .3
`
`1.3.1 Brief Overview of Clinical Program ......................................................................................................... 7
`1.3.2 Efficacy ..................................................................................................................................................... 8
`1.3.3
`Safety ....................................................................................................................................................... 9
`1.3.4 Dosing Regimen and Administration ........................................................................................................ 9
`1.3.5 Drug-Drug Interactions ........................................................................................................................... 10
`1.3 .6 Special Populations ................................................................................................................................. 10
`INTRODUCTION AND BACKGROUND .................................................................................................... 11
`
`PRODUCT INFORMATION ........................................................................................................................... 1 1
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS .......................................................................... 1 1
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES .............................................. 12
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ................................................... 12
`PRE-SUBMISSION REGULATORY ACTIVITY ............................................................................................... 14
`OTHER RELEVANT BACKGROUND INFORMATION ...................................................................................... 18
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES .................................................... 18
`
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ............................'............................................... 18
`ANIMAL PHARMACOLOGY/TOXICOLOGY .................................................................................................. 19
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY.....................................................20
`
`SOURCES OF CLINICAL DATA .................................................................................................................... 20
`TABLES OF CLINICAL STUDIES .................................................................................................................. 20
`REVIEW STRATEGY ................................................................................................................................... 23
`
`DATA QUALITY AND INTEGRITY23
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ....................................................................................... 23
`FINANCIAL DISCLOSURES .......................................................................................................................... 23
`
`CLINICAL PHARMACOLOGY ...................................................................................................................24
`
`
`PHARMACOKINETICS ....................................................................................................................... 24
`PHARMACODYNAMICS ............................................................................................................................... 26
`EXPOSURE-RESPONSE RELATIONSHIPS ..................................................................................................... 27
`
`INTEGRATED REVIEW OF EFFICACY ................................................................................................... 27
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`3.1
`3.2
`
`4.1
`4.2
`4.3
`
`4.4
`4.5
`4.6
`
`5.1
`
`5.2
`5.3
`
`2
`
`3
`
`4
`
`5
`
`‘6
`
`6.1
`
`INDICATION ................................................................................................................................................ 27
`6.1.1 Methods ................................................................................................................................................... 28
`
`6.1.2 General Discussion of Endpoints ............................................................................................................ 28
`6.1.3 Study Design ........................................................................................................................................... 29
`Concomitant Medications: ................................................................................................................................. 31
`The following medications were prohibited during the studies: ........................................................................ 31
`6.1.4 Efficacy Findings .................................................................................................................................... 35
`6.1.5 Clinical Microbiology ............................................................................................................................. 50
`6.1.6 Efficacy Conclusions .............................................................................................................................. 51
`
`INTEGRATED REVIEW OF SAFETY ........................................................................................................ 52
`
`

`

`Clinical Review
`
`Patricia C. Brown, MD
`NDA 50—805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`7.]
`
`METHODS AND FINDINGS .......................................................................................................................... 52
`Deaths .......................................................................................................................................................... 52
`
`Other Serious Adverse Events ........................................................................................................................... 53
`
`Dropouts and Other Significant Adverse Events ............................................................................................... 54
`7.1.4 Other Search Strategies ........................................................................................................................... 61
`7.1.5 Common Adverse Events ........................................................................................................................ 63
`Less Common Adverse Events
`.......................................................................................................... 68
`
`7.2
`
`7.1.7 Laboratory Findings ................................................................................................................................ 69
`7.1.8 Vital Signs ............................................................................................................................................... 75
`7.1.9 Electrocardiograms (ECGS) .................................................................................................................... 77
`7.1.10 Immunogenicity .................................................................................................................................... 77
`7.1.11 Human Carcinogenicity .......................................................................................................................... 78
`7.1.12 Special Safety Studies ....................................................................................................................... 78
`
`7.1.14 Human Reproduction and Pregnancy Data ................................................................................. 78
`
`7.1.15 Assessment of Effect on Growth ....................................................................................................... 79
`7.1.16 Overdose Experience .............................................................................................................................. 79
`7.1.17 Post-Marketing Experience ..................................................................................................................... 79
`ADEQUACY OF PATIENT EXPOSURE AND SAFETY ASSESSMENTS .............................................................. 80
`Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to Evaluate
`Safety ................................................................................................................................................................. 80
`Description of Secondary Clinical Data Sources Used to Evaluate Safety ........................................................ 82
`Adequacy of Overall Clinical Experience .......................................................................................................... 83
`7.2.4 Adequacy of Special Animal and/or In Vitro Testing ............................................................................... 84
`7.2.5 Adequacy of Routine Clinical Testing ...................................................................................................... 84
`7.2.6 Adequacy of Metabolic, Clearance, and Interaction Workup ................................................................... 85
`7.2.7 Adequacy of Evaluation for Potential Adverse Events for Any New Drug and
`Particularly for
`Drugs in the Class Represented by the New Drug; Recommendations for Further Study85
`7.2.8 Assessment of Quality and Completeness of Data .................................................................................... 85-
`7.2.9 Additional Submissions, Including Safety Update .................................................................................... 85
`SUMMARY OF SELECTED DRUG-RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF DATA, AND
`7.3
`CONCLUSIONS ......................................................................................................................................................... 87
`7.4
`GENERAL METHODOLOGY ......
`
`Pooling Data Across Studies to Estimate and Compare Incidence .................................................................... 88
`7.4.2 Explorations for Predictive Factors .......' .................................................................................................. 8 8
`7.4.3 Causality Determination .......................................................................................................................... 89
`
`8
`
`ADDITIONAL CLINICAL ISSUES .............................................................................................................. 89
`
`8.]
`8.2
`8.3
`8.4
`
`8.5
`8.6
`8.7
`
`8.8
`
`DOSING REGIMEN AND ADMINISTRATION ................................................................................................. 89
`DRUG-DRUG INTERACTIONS ..................................................................................................................... 90
`SPECIAL POPULATIONS .............................................................................................................................. 90
`PEDIATRICS ............................................................................................................................................... 91
`
`ADVISORY COMMITTEE MEETING ..............................................................................,............................ 91
`
`LITERATURE REVIEW ................................................................................................................................ 9]
`POST—MARKETING RISK MANAGEMENT PLAN .......................................................................................... 91
`
`OTHER RELEVANT MATERIALS .................................................................................................................. 9 1
`
`9
`
`OVERALL ASSESSMENT............................................................................................................................. 92
`
`9.1
`
`9.2
`9.3
`
`CONCLUSIONS ........................................................................................................................................... 92
`
`RECOMMENDATION ON REGULATORYACTION .......... 93
`RECOMMENDATION ON POST-MARKETING ACTIONS ................................................................................ 93
`
`9.3.1 Risk Management Activity...................................................................................................................... 93
`9.3.2 Required Phase 4 Commitments .......................................................................................................... 93
`
`9.3.3 Other Phase 4Requests ....................... 94
`LABELING REVIEW .................................................................................................................................... 94
`
`9.4
`
`

`

`Clinical Review
`Patricia C. Brown, MD
`NDA 50-805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`10 APPENDICES .................................................................................................................................................. 96
`
`10.1
`10.2
`
`REVIEW OF INDIVIDUAL STUDY REPORTS ................................................................................................. 96
`LABEL ....................................................................................................................................................... 96
`
`

`

`Clinical Review
`Patricia C. Brown, MD
`NDA 50-805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`1 EXECUTIVE SUMMARY
`
`For this application, the sponsor has studied OraceaTM (doxycycline, USP) 40 mg capsules in
`four pharmacokinetic Phase 2 trials and 2 pivotal Phase 3 trials. Dose was selected by the
`sponsor to be putatively sub-antimicrobial and to be equivalent to Periostat®, a previously
`approved product held by the same sponsor. In comparison with other doxycycline products, no
`new safety issues were identified in clinical studies with OraceaTM (doxycycline, USP) 40 mg
`capsules. No deaths occurred in healthy patients during the development program. Serious
`adverse events were limited and appeared not related to study drug. The most common side
`effects attributable to study drug use were nasopharyngitis, diarrhea, hypertension, and sinusitis.
`
`The sponsor’s original proposed indication is to vM ‘
`_ —"" . This has been since modified to treatment of only the inflammatory lesions (papules and
`pustules) of rosacea in adult patients. The sponsor has stated that at the systemic concentration
`provided by OraceaTM, doxycycline is not effective as an antimicrobial agent and appears to exert
`its actions On inflammatory lesions of rosacea by mechanisms independent of antibacterial
`activity.lThe sponsor has not submitted data supporting this mechanism of action. Furthermore
`there are seen some possible indicators of antibacterial action in the form of an increase in
`diarrhea in the active treatment arms of the pivotal trials.
`
`The change in total inflammatory lesion count from baseline to Week 16 was the primary
`endpoint specified in the protocols. Endpoints, however, were the subject of ongoing, repeated
`Agency comment during development of this drug product. The agency requested that a co-
`primary endpoint be a static Investigator Global Assessment that included clinical descriptors of
`rosacea.
`
`Efficacy was evaluated in two randomized, placebo—controlled, multi-centered, double-blind
`Phase 3 trials. These trials extended for 16 weeks and involved 537 patients, 269 on OraceaTM
`doxycycline 40 mg capsules and 268 on placebo. At Week 16, patients in'the OraceaTM
`doxycycline 40 mg capsule group were evaluated using co-primary endpoints of mean reduction
`in lesion counts and a dichotomized static Investigator's Global Assessment. Patients in the
`OraceaTM group exhibited a mean reduction in lesion count that exceeded that of the patients in
`the placebo group by 5.9 lesions in Study 301 and 5.2 lesions in Study 302. Using a static
`Investigator's Global Assessment score at Week 16 more patients in the OraceaTM group had
`improved into the lesser disease categories when compared to the placebo group in both Phase 3
`studies. When success was dichotomized to Clear or Almost Clear (defined as 1 to 2 small
`papules or pustules), patients in the OraceaTM group exhibited success that exceeded that of
`patients in the placebo group by 11.3% in Study 301 and by 8.5% in Study 302.
`
`The magnitude of the efficacy shown by the OraceaTM doxycycline product is clinically
`somewhat limited and modest for an oral medication. However, as compared with other
`products approved for rosacea, the efficacy demonstrated is in a similar range.
`
`

`

`Clinical Review
`
`Patricia C. Brown, MD
`NDA 50—805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`While the sponsor did demonstrate efficacy in the co—primary endpoints, reduction in
`inflammatOry lesion counts at Week 16 and in improvement in the sponsor defined IGA, these
`findings do not address the totality of the clinical signs of rosacea. In reference to erythema, this
`descriptor was removed from the Investigator’s Global Assessment after the meeting of May 3,
`2004. Using change from baseline in Clinician’s Erythema Assessment Total Score, patients
`treated with OraceaTM (doxycycline, USP) 40 mg capsules did not demonstrate significant
`improvement in erythema when compared to those treated with placebo for the combined Studies
`301 and 302.
`
`It is the opinion of this reviewer that the endpoints as selected by the sponsor are not optimal;
`however, they are sufficient for approval. The efficacy demonstrated for this drug product is
`also sufficient for approval. This is stated in View of a relatively benign product safety profile
`and provided that labeling adequately informs the user/prescriber regarding what can be expected
`for benefit.
`
`1.1 Recommendation on Regulatory Action
`
`This reviewer recommends that OraceaTM (doxycycline, USP) 40 mg capsules be approved for
`treatment of only inflammatory lesions (papules and pustules) of rosacea in patients 18 years of
`age and older.
`
`1.2 Recommendation on Post-Marketing Actions
`
`1.2.1 Risk Management Activity
`
`The standard risk management measures of prescription status, professional labeling and
`spontaneous adverse event reporting are sufficient risk management activities for this drug
`at this time.
`
`1.2.2 Required Phase 4 Commitments
`
`The required Phase 4 commitments will involve fiirther safety evaluation of OraceaTM
`(doxycycline, USP) 40 mg capsules.
`1
`A) Conduct a properly designed human sperm motility and morphology study to evaluate the
`effects of long—term use of OraceaTM (doxycycline, USP) 40mg capsules on human sperm in
`male patients with rosacea.
`
`The sponsor has agreed and will: 1) Submit study protocol September 2006. 2) Start study
`February 2007. 3) Submit study report June 2008.
`
`B) Submission of carcinogenicity study protocol and dose finding data: June 2007.
`Carcinogenicity study start date: August 2007.- Submission of final carcinogenicity study
`report: February 2010..
`
`

`

`Clinical Review
`
`Patricia C. Brown, MD
`_NDA 50—805
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`The Sponsor agrees to this Phase 4 commitment as follows: 1) Submit carcinogenicity study
`protocol: June 2007. 2) Study start date: August 2007. 3) Final report submission:
`February 2010.
`
`-
`
`C) Conduct a study to examine longer term safety in at least 300 rosacea patients treated with
`OraceaTM (doxycycline, USP) 40mg capsules for at least 1 year. Study report submission
`within 2 years from date of approval.
`
`The Sponsor contends that it has already fulfilled the requirements for study of long-term
`safety based on data from other studies extending as long as 12 to 18 months with another
`formulation of doxycycline.
`
`Because this is a systemic drug and not topical, exposure is similar between OraceaTM and
`the other formulation of doxycycline. This response is acceptable.
`
`D) A post-approval Medication Error Monitoring Program for the proprietary name,
`OraceaTM. This program should consist of:
`0
`15-Day Reporting of all Medication Errors;
`0 Root Cause Analysis; and
`'
`o Trigger requiring a proprietary name change.
`
`.
`
`CollaGenex Pharmaceuticals agrees to a Medication Error Monitoring Program for the
`proprietary name, OraceaTM, consisting of the above three components.
`
`This Phase 4 commitment appears sufficient to address any concerns regarding the
`proprietary name, OraceaTM, at this time.
`
`1.2.3 Other Phase 4 Requests
`
`No other phase 4 requests are made.
`
`1.3 Summary of Clinical Findings
`
`1.3.1 Brief Overview of Clinical Program
`
`TRADENAME (OraceaTM) doxycycline 40mg capsules is an oral product intended for once
`daily administration for the treatment of inflammatory lesions in patients with rosacea. The
`sponsor has submitted a 505(b)(1) application. The sponsor has performed two pivotal Phase 3
`trials, each having two arms and enrolling a total of 537 patients. Of these 269 were randomized
`to OraceaTM and 268 Were randomized to placebo. The Phase 2 program included two pilot
`pharrnacokinetic studies, a multiple-dose steady—state bioequivalence study comparing OraceaTM
`with Periostat®, and a food effect study. These studies enrolled a total of 94 patients, of these 47
`were exposed to one daily dose of OraceaTM and 46 were exposed to OraceaTM once daily for a
`
`7
`
`

`

`Clinical Review
`Patricia C. Brown, MD
`NDA 50-805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`total of seven days. The safety database involves 362 patients exposed to OraceaTM in Phases 2
`and 3. OraceaTM (doxycycline'
`.M, capsules) is not marketed in any
`country at this time.
`
`1.3.2 Efficacy
`
`Pivotal trials, COL—101-ROSE—301 and COL—101-ROSE-302, were nearly identical Phase 3,
`multi—center, randomized, placebo—controlled against the active drug, and double—blind. These
`' trials were of adequate design and sufficiently powered to ‘study the safety and efficacy of
`OraceaTM at a dose of 40mg once daily in patients 18 years and older.
`
`In the pivotal trials COL—101—ROSE—301 (Study 301) and COL-101-ROSE-302 (Study 302)
`OraceaTM was statistically superior to placebo in producing a change from baseline in
`inflammatory lesion count at Week 16. For Study 301, ITT-LOCF population, the Week 16
`changes from baseline lesion count were —11.8 and —5.9 for OraceaTM and placebo, respectively.
`For Study 302, ITT-LOCF population, the Week, 16 changes from baseline lesion count were —
`9.5 and -4.3, respectively. These changes were statistically significant using an ANOVA model,
`p 5 0.0002 and p 5 0.0001 for studies 301 and 302.
`
`The change in total inflammatory lesion count from baseline to Week 16 was the primary
`endpoint specified in the protocols; however, endpoints were the subject of ongoing, repeated
`Agency comment during development of this drug product. The agency had requested a co—
`primary endpoint to be a static Investigator Global Assessment that included clinical descriptors
`of rosacea.
`
`As identified in the protocols a secondary endpoint was change from baseline in IGA at Week
`16. This IGA largely reflects a grouping of lesion counts. The Division recommended
`dichotomizing this endpoint to define treatment responders as those having an IGA score of 0
`(Clear) or 1 (Near Clear) at endpoint (Week 16). This endpoint, as dichotomized, was employed
`by the Division as a co-primary endpoint. The proportion of patients responding in the OraceaTM
`group was significantly greater than in the placebo group in both studies 301 and 302 (p 5
`0.0361 and p 5 0.0120). More specifically, at Week 16, in Study 301, 30.7 % of the OraceaTM
`patients versus 19.4 % of the placebo patients were scored as successes on this endpoint. In
`Study 302, 14.8% of the OraceaTM patients versus 6.3% of the placebo patients were scored as
`successes on this endpoint.
`
`Results for an erythema endpoint, change from baseline in the Clinician’s Erythema Score, were
`only marginally clinically meaningful. Treatment differences were statistically significant in
`Study 301 (p 5 0.0164) but not in Study 302 (p 5 0.4278). For the combined studies, 301 and
`302, treatment differences were not statistically significant (p 5 0.024). Of note, erythema was
`removed from the Investigator’s Global Assessment after the meeting of May 3, 2004.
`Attempting to provide a static overall IGA, the Clinical team defined a post hoc extended IGA
`that incorporated erythema. On this endpoint, there were no statistically significant treatment
`differences.
`
`

`

`Clinical Review
`Patricia C. Brown, MD
`NDA 50-805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`Therefore, the sponsor has demonstrated efficacy of OraceaTM 40mg capsules for the treatment
`of only inflammatory lesions (papules and pustules) of rosacea in patients 18 years and older.
`
`1.3.3 , Safety
`
`Six hundred thirty one patients were enrolled in the phase 2 and 3 studies. Of these 362 were
`exposed to OraceaTM.
`In the phase 3 studies the mean exposure was 102 days with a median of
`30 days. The 4 month safety update report was reviewed and did not reveal new safety issues.
`
`No deaths in healthy patients have occurred during the clinical development program for
`OraceaTM. In addition no deaths have occurred in healthy patients while participating in clinical
`studies with Periostat®, a related product. No serious adverse events (SAEs) occurred in the
`pivotal study COL-101—ROSE-301. During study COL—101-ROSE—302, five patients
`experienced serious adverse effects. Three patients in the OraceaTM treatment group experienced
`8 SAEs which were not considered related to study drug.
`'
`
`Thirty two patients discontinued study drug due to AEs: 20/269 in the OraceaTM treatment group
`and 12/268 in the placebo group. Of the 20 patients in the OraceaTM treatment group who
`discontinued 13 were withdrawn due to AE’s considered probably or possibly related to study
`medication. Four patients withdrew solely due to gastrointestinal disorders and four patients
`withdrew due to gastrointestinal disorders in addition to AE’s in at least one other system organ
`class.
`
`For the combined phase 3 studies, 55.4% of patients treated with OraceaTM and 45.5% of patients
`treated with placebo experienced adverse events. AE’s reported by more than 1% of treated
`patients occurred at a higher rate in the OraceaTM than the placebo group, however between
`group differences were generally 4 or fewer patients. The largest between group differences
`were seen for diarrhea, hypertension, sinusitis, and upper respiratory tract infection. Diarrhea
`was noted in 12 patients in the OraceaTM group and 7 patients in the placebo group. Most of
`_
`these AE’s were considered possibly related to the study medication. (It is possible that the
`presence of an excess of diarrhea in the OraceaTM treatment group could suggest an antimicrobial
`effect.) HOwever, an analysis was performed by the statistician of those AE’s occurring in more
`than 1% of the OraceaTM subjects. Twenty five AEs were evaluated and only two showed
`statistical significance before adjusting for multiplicity and none after adjustment. It is noted
`that the studies are not powered to test for adverse events.
`
`’
`
`1.3.4 Dosing Regimen and Administration
`
`OraceaTM capsules, 40 mg are intended for once daily oral administration. This is the dosage
`regimen studied in the Phase 2 pharmacokinetic studies and in the Phase 3 pivotal trials.
`
`To select the optimal dose duration, and frequency of treatment, the Agency had recommended
`that Phase 2 dose-ranging studies be performed. The selection of the 40mg/day dose of
`OraceaTM was based on a previous study by the sponsor in which Periostat® tablets 20 mg twice
`
`

`

`Clinical Review
`Patricia C. Brown, MD
`NDA 50-805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`daily given to patients with moderate rosacea over a 16 week period resulted in a significant
`reduction in the total inflammatory lesion count as compared with placebo.
`Also pilot pharmacokinetic studies showed that plasma doxycycline concentrations with
`OraceaTM 40mg/day were maintained below the antimicrobial threshold, a plasma level (Cmax)
`below 1.0 ug/mL. The sponsor states this antimicrobial threshold was defined based on previous
`experience with the approved drug Periostat®. A higher dose did not appear, according to the
`sponsor, to be necessary for efficacy and would expose patients to antimicrobial concentrations
`of doxycycline that might increase the risk of developing resistant organisms.
`
`At steady state OraceaTM 40mg/day and Periostat® 20 mg twice a day have demonstrated similar
`drug exposure (AUC) in pharmacokinetic trials. According to the sponsor, this would indicate
`that the safety profile of Periostat® is similar to that of OraceaTM. Since the safety profile of
`Periostat® has been shown to be similar to that of placebo, the sponsor asserts that there is no
`potential safety benefit expected with a lower dose of OraceaTM.
`
`1.3.5 Drug-Drug Interactions
`
`The proposed labeling for OraceaTM will follow that of tetracycline class antibiotics.
`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.
`
`1.3.6 Special Populations
`
`OraceaTM was studied in patients 18 years and older. This is appropriate for a disease that has its
`onset between the ages of 30 and 50 years. With respect to age, sex, and race the pivotal trial
`population studied was reflective of those most at risk for rosacea and not the US. population as
`
`10
`
`

`

`Clinical Review
`
`Patricia C. Brown, MD
`NDA 50-805
`
`OraceaTM (doxycycline, USP) 40 mg capsules
`
`a whole. Those studied on OraceaTM had a, median age of 46.0 years, were predominantly
`female (69%), and were primarily Caucasian (90%).
`
`In general OraceaTM was more effective than placebo across gender and age groups when
`analyzed for lesion counts and Week 16 IGA. In study 301 OraceaTM wa