CENTER FOR DRUG EVALUATION AND RESEARCH
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`Approval Package for:
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`APPLICATION NUMBER:
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`204824Orig2s000
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`Trade Name:
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`Generic Name:
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`Sponsor:
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`Approval Date:
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`Indications:
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` Otrexup Injection (10 mg/0.4 mL, 15 mg/0.4 mL,
`20 mg/0.4 mL, and 25 mg/0.4 mL)..
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`Methotrexate
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`Antares Pharma, Inc..
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`October 11, 2013
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`Symptomatic control of severe, recalcitrant, disabling
`psoriasis in adults who are not adequately responsive to
`other forms of therapy
`
`
`Medac Exhibit 2068
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 00001
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`

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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`204824Orig2s000
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`CONTENTS
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`Reviews / Information Included in this NDA Review.
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`
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`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
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`X
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`X
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`X
`X
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`X
`X
`X
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`X
`X
`X
`X
`X
`X
`X
`X
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`Page 00002
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`204824Orig2s000
`APPROVAL LETTER
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`Page 00003
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 204824/Original 1
`NDA 204824/Original 2
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`Antares Pharma, Inc.
`100 Princeton South Corporation Center
`Suite 300
`Ewing, NJ 08628
`
`Attention: Susan Thornton
`Senior Director, Regulatory Affairs
`
`Dear Ms. Thornton:
`
`Food and Drug Administration
`Silver Spring MD 20993
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`NDA APPROVAL
`
`Please refer to your New Drug Application (NDA) dated December 14, 2012, received
`December 14, 2012, pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Otrexup (methotrexate) Injection 10 mg/0.4 mL, 15 mg/0.4 mL, 20 mg/ 0.4 mL and
`25 mg/0.4 mL.
`
`We acknowledge receipt of your amendments dated December 19, 2012, and January 25, March
`12 and 14, April 8 and 10, May 7, 17, and 23, June 4, 6, 7, 19, and 20, July 22, August 9,
`September 3 and 12, October 2, 7, 10, and October 11, 2013.
`
`NDA 204824 provides for the use of Otrexup (methotrexate) Injection for the following
`indications which, for administrative purposes, we have designated as follows:
`
`(cid:120) NDA 204824/Original 1 – Severe Rheumatoid Arthritis (RA) including polyarticular
`Juvenile Idiopathic Arthritis (pJIA)
`
`(cid:120) NDA 204824/Original 2 – Symptomatic control of severe, recalcitrant, disabling
`psoriasis in adults who are not adequately responsive to other
`forms of therapy
`
`The subject of this action letter is NDA 204824/Original 1 and NDA 204824/Original 2.
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`Reference ID: 3389733
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`Page 00004
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`NDA 204824/Original 1
`NDA 204824/Original 2
`Page 2
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`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
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`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`Patient Information Leaflet, and text for the Instructions for Use). Information on submitting
`SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of
`Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE-CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels submitted on October 11, 2013, as soon as they are available, but no
`more than 30 days after they are printed. Please submit these labels electronically according to
`the guidance for industry titled “Providing Regulatory Submissions in Electronic Format –
`Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (June 2008).” Alternatively, you may submit 12 paper copies, with 6 of the copies
`individually mounted on heavy-weight paper or similar material. For administrative purposes,
`designate this submission “Final Printed Carton and Container Labels for approved NDA
`204824.” Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`NDA 204824/Original 1
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`We are waiving the pediatric study requirement for ages 0 through 2 years because pJIA is
`extremely rare in this age group and studies would be impossible or highly impractical.
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`Reference ID: 3389733
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`Page 00005
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`NDA 204824/Original 1
`NDA 204824/Original 2
`Page 3
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`This product is appropriately labeled for use in pJIA patients ages 2 to 17 years. Therefore, no
`additional studies are needed in this pediatric group.
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`NDA 204824/Original 2
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`We are waiving the pediatric study requirement for this application for the psoriasis indication
`because there is evidence strongly suggesting that the benefit for this drug product do not
`outweigh the risk in all pediatric age groups.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`Reference ID: 3389733
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`Page 00006
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`NDA 204824/Original 1
`NDA 204824/Original 2
`Page 4
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`If you have any questions, call Sadaf Nabavian, Regulatory Project Manager, at (301) 796-2777.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`{See appended electronic signature page}
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`Badrul A. Chowdhury, M.D., Ph.D.
`Director
`Division of Pulmonary, Allergy, and
`Rheumatology Products
`Office of Drug Evaluation II
`Center of Drug Evaluation and Research
`
`Tatiana Oussova, M.D., M.P.H.
`Deputy Director for Safety
`Division of Dermatology and Dental Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
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`Enclosures:
`Content of Labeling
`Carton and Container Labeling
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`Reference ID: 3389733
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`Page 00007
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`SARAH K YIM
`10/11/2013
`Signing for Badrul Chowdhury, M.D., Ph.D.
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`TATIANA OUSSOVA
`10/11/2013
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`Reference ID: 3389733
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`Page 00008