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

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`50-805
`
`000
`
`8/3/05
`
`Oracea
`
`INTENDED CLINICAL POPULATION:
`
`Patients with Inflammatory Lesions from Rosacea
`
`SPONSOR:
`
`CollaGenex Pharmaceuticals
`
`DOCUMENTS REVIEWED:
`
`Vols. 1, 2 and 4
`
`REVIEW DIVISION:
`
`Division
`
`of Dermatology
`
`and Dental Drug
`
`PHARM/TOX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`Products (HFD-540)
`
`Carmen Booker, Ph.D.
`
`Paul Brown, Ph.D.
`
`Stanka Kukich, M.D.
`
`Shalini Jain
`
`Date ofreview submission to Division File System (DFS): May 1, 2006
`
`*2“,
`
`

`

`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY .............................................................................................. 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW ................................................... 5
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY................................................................... 5
`
`2.6.2 PHARMACOLOGY ......................................................................................................... 6
`2.6.2.1
`Brief summary ........................................................................................................................ 6
`2.6.2.2
`Primary pharmacodynamics ................................................................................................... 6
`2.6.2.3
`Secondary pharmacodynamics ............................................................................................... 7
`2.6.2.4
`Safety pharmacology .............................................................................................................. 7
`2.6.2.5
`Pharmacodynamic drug interactions ....................................................................................... 7
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY......................................................... 7
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS ............................................................ 7
`2.6.4.1
`Brief summary ........................................................................................................................ 7
`2.6.4.2
`Methods of Analysis ............................................................................................................... 7
`2.6.4.3
`Absorption .............................................................................................................................. 7
`2.6.4.4
`Distribution ............................................................................................................................. 7
`2.6.4.5
`Metabolism ............................................................................................................................. 8
`2.6.4.6
`Excretion ................................................................................................................................. 8
`2.6.4.7
`Pharmacokinetic drug interactions .......................................................................................... 8
`2.6.4.8
`Other Pharmacokinetic Studies ............................................................................................... 8
`2.6.4.9
`Discussion and Conclusions ................................................................................................... 8
`2.6.4.10
`Tables and figures to include comparative TK summary ................................................... 8
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY ................................................. 8
`
`2.6.6 TOXICOLOGY................................................................................................................. 8
`2.6.6.1
`Overall toxicology summary .................................................................................................. 8
`2.6.6.2
`Single-dose toxicity ................................................................................................................ 9
`2.6.6.3
`Repeat—dose toxicity ............................................................................................................... 9
`2.6.6.4
`Genetic toxicology .................................................................................................................. 9
`2.6.6.5
`Carcinogenicity ....................................................................................................................... 9
`2.6.6.6
`Reproductive and developmental toxicology ........................................................................ 10
`2.6.6.7
`Local tolerance ..................................................................................................................... 10
`2.6.6.8
`Special toxicology studies .................................................................................................... 10
`2.6.6.9
`Discussion and Conclusions ................................................................................................. 10
`2.6.6.10
`Tables and Figures ............................................................................................................ 11
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY .............................................................. 11
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS ............................................... 11
`
`APPENDIX/ATTACHMENTS ................................................................................................. 12
`
`

`

`
`
`Reviewer: Carmen D. Booker PhD. NDA No. 50-805
`
`EXECUTIVE SUMMARY
`
`Recommendations
`
`A. Recommendation on approvability: The product is approvable with respect to
`nonclinical concerns.
`
`B. Recommendation for nonclinical studies: The sponsor has committed to
`conduct a necessary second carcinogenicity study in mice during Phase 4.
`
`C. Recommendations on labeling: None.
`
`II.
`
`Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings
`
`Doxycycline did not elicit signs of toxicity when administered to Crl:CD(SD)BR
`rats by gavage on a single occasion at a dose of 500 mg/kg. Of two males and two
`females that received single doses of 750 mg/kg, only one death occurred (a
`male). In a 13—week study in which doxycycline was administered to ratsat
`dosages of 25, 100, 400 and 600 mg/kg/day, toxicity was observed at 400
`mg/kg/day and above, including adverse clinical signs, a trend toward reduced
`weight gain, suppressed erythrocytic parameters, reduced plasma protein, reduced
`weight and hematopoietic activity of the spleen, and mild inflammation of the GI
`tract, including moderate to marked focal erosions of the stomach. The NOAEL
`was determined to be 100 mg/kg/day. Daily administration of doxycycline to
`cynomolgus monkeys at doses of 5, 15 or 30 mg/kg/day for 12 months was
`generally well tolerated and produced minimal signs of toxicity.
`
`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. Data from an
`in vitro assay with CHO cells for potential to cause chromosomal aberrations
`suggest that doxycycline is a weak clastogen.
`
`A two-year bioassay was conducted in rats to assess the carcinogenicity of
`doxycycline. The only remarkable, statistically significant, treatment-related
`observation in the study was an increased incidence of uterine polyps in females
`in the high-dose group (200 mg/kg/day). The sponsor has committed to conduct a
`second carcinogenicity study in mice during Phase 4.
`
`Doxycycline, as a tetracycline, is likely to induce tooth staining in children when
`administered to children or pregnant women. Doxycycline adversely affected
`fertility and reproductive performance of rats. Doxycycline is in pregnancy
`category D.
`
`

`

`
`
`Reviewer: Carmen D. Booker Ph.D. NDA No. 50-805
`
`B. Pharmacologic activity
`
`Doxycycline isl'an antibiotic compound as well as an inhibitor of collagenase.
`However, the speculative mechanism of action in treatment of rosaCea is Via the
`inhibition of neutrophil activity and several neutrophil-associated pro—
`inflammatory processes. No adverse pharmacological activity has been observed
`in the cardiovascular, respiratory and central nervous systems following
`doxycycline treatment.
`
`C. Nonclinical safety issues relevant to clinical use
`
`There are no nonclinical safety issues relevant to the clinical use of OraceaTM.
`
`

`

`
`
` Reviewer: Carmen D. Booker Ph.D. NDA No. 50-805
`
`2.6 PHARMACOLOGY/TOXICOLOGYREVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number: 50-805
`Review number: 1
`
`Sequence number/date/type of submission: N—000/3—Aug—2004
`Information to sponsor: Yes ( ) No (X)
`Sponsor and/0r agent: CollaGenex Pharmaceuticals
`
`Reviewer name: Carmen D. Booker, PhD.
`Division name: Division of Dermatology and Dental Drug Products
`HFD #2 540
`
`-
`
`Review completion date:
`
`Drug:
`
`Trade name: Oracea
`
`Generic name: Doxycycline monohydrate
`Code name: COL- 101
`
`Chemical name: 4—(dimethylamino)— l ,4,4a,5,5a,6,l 1,12a—octahydro—
`3 ,5 , 10, 12, 12a—pentahydroxy—6—methyl— 1 , 1 1-dioxo-2—naphthacenecarboxamide
`monohydrate
`CAS registry number: 17086-28—1
`Molecular formula/molecular weight: C22H24N208‘H20 / 462.46
`Structure:
`
`CH3
`
`H3C
`OH
`
`\ /
`N
`
`CH3
`
`OH
`
`\
`
`OH
`
`CONH2
`
`OH
`
`O
`
`OH
`
`O
`
`Relevant INDs/NDAs/DMFs: IND 67,833;____._,_ 1:; NDA 50—744; NDA 50-783;
`IND :7
`
`Drug class: Antibiotic/collagenase inhibitor
`
`Intended clinical population: To (/5 inflammatory lesions in patients with rosacea '
`
`

`

`
`
`Reviewer: Carmen D. Booker Ph.D. NDA No. 50-805
`
`Clinical formulation: Quantitative Composition (mg/capsule)
`
`Doxycycline Monohydrate, USP/NF
`
`Hypromellose,
`‘
`USP/NF
`Methacrylic Acid Copolymer, “W: USP/NF
`Triethyl Citrate, USP/NF
`Talc, USP/NF
`
`
`
`‘ USP/NF
`Sugar Spheres, 'er
`Hard Gelatin Capsule ‘,... Beige Opaque
`
`Route of administration: oral
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`'cited otherwise.
`
`Studies reviewed within this submission: None. Please see the Pharmacology review of
`NDA 50—744 for evaluation of applicable data. NDA 50—744 is held by the same sponsor
`(CollaGenex) as the current NDA and contains the applicable study reports.
`
`Studies not reviewed Within this submission: None.
`
`2.6.2 PHARMACOLOGY
`
`2.6.2.1 Brief summary
`
`DoxycyclineIS an antibiotic compound as well as an inhibitor of collagenase However
`the speculative mechanism of action in treatment of rosacea is via the inhibition of
`neutrophil activity and several neutrophil-associated pro-inflammatory processes. No
`adverse pharmacological activity has been observed in the cardiovascular, respiratory and
`central nervous systems following doxycycline treatment.
`
`2.6.2.2 Primary pharmacodynamics
`
`Mechanism of action: The speculative mechanism of action is via anti—inflammation.
`Neutrophil-mediated processes contribute, in part to the development of inflammatory
`lesions1n patients with rosacea. Doxycycline has been shown to inhibit neutrophils
`activity and several neutrophil-associated pro—inflammatory processes.
`
`
`Drug activity related to proposed indication: The inhibition of pro-inflammatory
`processes, such as those associated with nitric oxide production or interleukin-6, caused
`by doxycycline decreases the inflammatory response associated with rosacea.
`
`

`

`Reviewer: Carmen D. Booker, Ph.D.
`
`NDA No. 50-805
`
`2.6.2.3 Secondary pharmacodynamics
`
`Doxycycline is an antibiotic compound with activity against many species of bacteria
`when administered at sufficient doses. Tetracyclines, such as doxycycline, are primarily
`bacteriostatic and have antimicrobial activity against a wide range of gram—positive and
`gram—negative organisms. It is believed that tetracyclines exert their antimicrobial effect
`Via the inhibition of protein synthesis.
`
`2.6.2.4 Safety pharmacology
`
`The literature and previous clinical experience with Periostat® and Vibramycin suggest
`that there are no safety pharmacology concerns associated with doxycycline.
`
`2.6.2.5 Pharmacodynamic drug interactions
`
`The labeling for OraceaTM will include the same information on precautions regarding
`drug interactions as the approved product labeling for Periostat®.
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY
`
`No new pharmacology or safety pharmacology studies have been conducted on doxycycline. See
`summaries above.
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS
`
`2.6.4.1 Brief summary
`
`No new nonclinical pharmacokinetic studies on doxycycline have been conducted. The
`pharmacokinetics of doxycycline has been discussed extensively in scientific literature.
`Doxycycline is well-absorbed from the GI tract. Protein binding is extremely variable.
`Published values for the serum half-life and renal clearance of doxycycline are 14.5—22
`hours and 16 mL/minute, respectively. Doxycycline is excreted in the urine and feces as
`unchanged drug.
`’
`V
`\
`
`2.6.4.2 Methods of Analysis
`
`Methods of analysis are discussed within individual study reviews. Please see reviews
`associated with NDA 50—744.
`
`2.6.4.3 Absorption
`
`Doxycycline is well absorbed after oral administration.
`
`2.6.4.4 Distribution
`
`As stated in the approved labeling for Periostat®, doxycycline is greater than 90% bound
`to plasma proteins.
`
`

`

`Reviewer: Carmen D. Booker, Ph.D.
`
`NDA No. 50-805
`
`2.6.4.5 Metabolism
`
`Major metabolites of doxycycline have not been identified.
`
`2.6.4.6 Excretion
`
`Doxycycline is excreted in the urine and feces as unchanged drug.
`
`2.6.4.7 Pharmacokinetic drug interactions
`
`Enzyme inducers such as barbiturates, carbamazepine and phenytoin decrease the half-
`life of doxycycline. Bismuth subsalicylate, proton pump inhibitors, antacids and
`nutritional supplements containing aluminum, calcium, magnesium or iron impair the
`absorption of doxycycline.
`
`2.6.4.8 Other Pharmacokinetic Studies
`
`No new nonclinical pharmacokinetic studies on doxycycline have been conducted.
`
`2.6.4.9 Discussion and Conclusions
`
`No new nonclinical pharmacokinetic studies on doxycycline have been conducted.
`
`2.6.4.10
`
`Tables and figures to include comparative TK summary
`
`No new nonclinical pharmacokinetic studies on doxycycline have been conducted.
`
`2.6.5 PHARMACOKINETICS TABULATED SUMIVIARY
`
`No new nonclinical pharmacokinetic studies on doxycycline have been conducted. See
`summaries above.
`
`2.6.6 TOXICOLOGY
`
`Note: All nonclinical studies were conducted using doxycycline hyclate (Periostat®). In
`humans, OraceaTM,40 mg QD has been shown to be equivalent (using least squares mean
`Cmax and AUCSS values) to the approved product Periostat® tablets, 20 mg BID
`(according to the sponsor).
`
`2.6.6.1 Overall toxicology summary
`
`General toxicology: Please see the reviews associated with NDA 50-744. Briefly,
`doxycycline did not elicit signs of toxicity when administered to Crl:CD(SD)BR rats by
`gavage on a single occasion at a dose of 500 mg/kg. Of two males and two females that
`received single doses of 750 mg/kg, only one death occurred (a male). In a 13-week study
`
`

`

`
`
`Reviewer: Carmen D. Booker Ph.D. NDA No. 50—805 .
`
`
`
`in which doxycycline was administered to rats at dosages of 25, 100, 400 and 600
`mg/kg/day, toxicity was observed-at 400 mg/kg/day and above, including adverse clinical
`signs, a trend toWard reduced weight gain, suppressed erythrocytic parameters, reduced
`plasma protein, reduced weight and hematopoietic activity of the spleen, and mild
`inflammation of the GI tract, including moderate to marked focal erosions of the
`stomach. The NOAEL was determined to be 100 mg/kg/day. Daily administration of
`doxycycline to cynomolgus monkeys at doses of 5, 15 or 30 mg/kg/day for 12 months
`was generally well tolerated and produced minimal signs of toxicity.
`
`Genetic toxicology: Please see the reviews associated with NDA 50—744. Briefly,
`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—1 mice. Data from an in vitro assay with CHO
`cells for potential to cause chromosomal aberrations suggest that doxycycline is a Weak
`clastogen.
`
`Carcinogenicity: A two—year bioassay was conducted in rats to assess the carcinogenicity
`of doxycycline. The only remarkable, statistically significant, treatrnent—related
`observation in the study was an increased incidence of uterine polyps in females in the
`high-dose group (200 mg/kg/day). The sponsor has committed to conduct a second
`carcinogenicity study in mice during Phase 4.
`
`Reproductive toxicology: Doxycycline, as a tetracycline, is likely to induce tooth staining
`in children when administered to children or pregnant women. Doxycycline adversely
`affected fertility and reproductive performance of rats. Doxycycline is in pregnancy
`category D.
`
`2.6.6.2 Single-dose toxicity
`
`Please see the reviews associated with NDA 50—744. No new toxicity studies on
`doxycycline have been submitted.
`
`2.6.6.3 Repeat-dose toxicity
`
`Please see the reviews associated with NDA 50—744. No new toxicity studies on
`doxycycline have been submitted.
`
`2.6.6.4 Genetic toxicology
`
`Please see the reviews associated with NDA 50—744. No new genetic toxicology studies
`on doxycycline have been submitted.
`
`2.6.6.5 Carcinogenicity
`
`Please see the reviews associated with NDA 50—744. No new carcinogenicity studies on
`doxycycline have been submitted.
`
`

`

`Reviewer: Carmen D. Booker, Ph.D.
`
`NDA No. 50—805
`
`The sponsor has submitted a protocol for a carcinogenicity study in mice-to be conducted
`as a Phase 4 commitment. The sponsor intends to conduct a 7-day dose range finding
`study in July 2006. A subsequent 4-week toxicology study will be conducted in
`September 2006. The sponsor anticipates that a 13—week toxicology study will begin in'
`January 2007. During June 2007, the sponsor will file the proposed doses for use in the
`104—week carcinogenicity study with the Agency for review by the CAC. The 104-week
`carcinogenicity study will begin in August of 2007. The sponsor anticipates having a
`final report for the carcinogenicity study available in February 2010.
`
`2.6.6.6 Reproductive and developmental toxicology
`
`Please see the reviews associated with NDA 50-744. No new reproductive and
`developmental toxicology studies on doxycycline have been submitted.
`
`2.6.6.7 Local tolerance
`
`OraceaTM is orally ingested; therefore, local tolerance is not a safety concern.
`
`2.6.6.8 Special toxicology studies
`
`Please see the reviews associated with NDA 50-744. No new special toxicology studies
`on doxycycline have been submitted.
`
`2.6.6.9 Discussion and Conclusions
`
`Doxycycline did not elicit signs of toxicity when administered to Crl:CD(SD)BR rats by
`gavage on a single occasion at a dose of 500 mg/kg. Of two males and two females that
`received single doses of 750 mg/kg, only one death occurred (a male). In a 13—week study
`in which doxycycline was administered to rats at dosages of 25, 100, 400 and 600
`mg/kg/day, toxicity was observed at 400 mg/kg/day and above, including adverse clinical
`signs, a trend toward reduced weight gain, suppressed erythrocytic parameters, reduced
`plasma protein, reduced weight and hematopoietic activity of the spleen, and mild
`inflammation of the GI tract, including moderate to marked focal erosions of the
`stomach. The NOAEL was determined to be 100 mg/kg/day. Daily administration of
`- doxycycline to cynomolgus monkeys at doses of 5, 15 or 30 mg/kg/day for 12 months
`was generally well tolerated and produced minimal signs of toxicity.
`
`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-1 mice. Data from an in vitro assay with CHO
`cells for potential to cause chromosomal aberrations suggest that doxycycline is a weak
`clastogen.
`
`A tvvo—year bioassay was conducted in rats to assess the carcinogenicity of doxycycline.
`The only remarkable, statistically significant, treatment—related observation in the study
`was an increased incidence of uterine polyps in females in the high—dose group (200
`
`10
`
`

`

`
`
`Reviewer: Carmen D. Booker Ph.D. NDA No. 50-805
`
`mg/kg/day). The sponsor has committed to conduct a second carcinogenicity study1n
`mice during Phase 4.
`
`Doxycycline, as a tetracycline, is likely to induce tooth staining in children when
`administered to children or pregnant women. Doxycycline adversely affected fertility and
`reproductive performance of rats. Doxycycline is in pregnancy category D.
`
`2.6.6.10
`
`Tables and Figures
`
`Please see the reviews associated with NDA 50—744. No new toxicity studies on
`doxycycline have been submitted.
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY
`
`No new toxicology studies on doxycycline have been submitted. See summaries above.
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS
`
`Conclusions. There are no nonclinical safety1ssues relevant to the clinical use of
`OraceaTM.
`
`Unresolved toxicology issues: Sponsor has committed to conduct a 2-year
`carcinogenicity study with doxycycline monohydrate in mice.
`
`Recommendations: NDA 50—805 is approvable in regard to pharrnacologic and
`toxicologic concerns.
`
`Suggested labeling: The labeling for OraceaTM with regard to nonclinical safety will be
`the same as that approved for Periostat®, with the exception of the section entitled
`“Carcinogenesis, Mutagenesis, Impairment of Fertility”. In this section, the sponsor was
`asked (in an information request sent April 7, 2006) to use AUC values for exposure
`comparisons. In a response sent to the Agency on April 19 2006, the sponsor adjusted
`the label using AUC data collected1n preclinical studies (see attached table). The label13
`acceptable to this reviewer.
`
`Signatures (optional):
`
`Reviewer Signature
`
`Supervisor Signature
`
`
`
`Concurrence Yes
`
`No
`
`ll
`
`

`

`
`
`Reviewer: Carmen D. Booker Ph.D. NDA No. 50-805 I
`
`
`
`APPENDIX/ATTACHMENTS
`
`Table 2. Comparison of Preclinical Versus Human Exposure
`
`- Study
`
`(mg/kg/daY)
`
`Dose
`
` 2 year
`
`carcinogenicity
`in rats
`
`
`
`
`
`
`
`mom»
`
`W.
`
`-
`
`600.5 -n
`
`20 m
`75 m
`200 mg/kg
`
`130 mg/m2
`487.5 mgm2
`1300 mg/m2
`
`10,968“ -
`40,981a -
`91,925b -
`
`AUG
`increase
`
`(factor)
`
`3.05
`
`0.91
`
`Reproductive
`
`toxicoloy, rat
`
`50 mg/kg
`
`2
`
`325 mg/m
`
`a
`
`27.321 -
`
`Human Exposure
`
`0.5 rug/kg
`
`22.2 mgm2
`
`7543*
`
`Carcinogenicity
`200 mg/kg
`, multiple vs.
`human dose
`
`400
`
`,
`
`v
`
`58.6
`
`12.2
`
`
`
`. Reproductive 50
`mg/kg multiple
`vs. human dose
`
`100
`
`'
`
`5.6
`
`‘ interpolation calculated assuming doselinearity
`b interpolation calculated as Y = 372.83): + 17359
`* data from study COL-lOl-SSPK-106
`
`12
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Carmen Booker
`
`5/1/2006 01:42:11 PM
`PHARMACOLOGIST
`
`Paul Brown
`
`5/1/2006 07:40:59 PM
`PHARMACOLOGIST
`
`