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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 21-926/S-012/S-011
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`FULFILLMENT OF POSTMARKETING
`REQUIREMENTS
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`NEW POSTMARKETING REQUIREMENTS
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`Pernix Therapeutics
`Attention: Leslie Sands, MS, RAC
`10 North Park Place, Suite 201
`Morristown, NJ 07960
`
`Dear Ms. Sands:
`
`Please refer to your supplemental New Drug Application (sNDA) dated and received November
`14, 2014, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act
`(FDCA), for Treximet (sumatriptan/naproxen)10mg/60mg.
`
`We acknowledge receipt of your amendments dated the following:
`
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`March 25, 2015 April 24, 2015 May 8, 2015
`December 19, 2014 March 6, 2015
`February 13, 2015 March 19, 2015 (2) April 16, 2015 May 6, 2015
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`February 24, 2015 March 24, 2015
`April 23, 2015 May 7, 2015
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`
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`This Prior Approval supplemental new drug application proposes sumatriptan/naproxen for the
`acute treatment of migraine with or without aura in adolescents 12 to 17 years old.
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`APPROVAL & LABELING
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`We have completed our review of this supplemental 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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`Additionally, we note that the Prior Approval labeling supplement (S-011) dated April 22, 2014
`proposed labeling in Physician Labeling Rule (PLR) format. This labeling was incorporated into
`our review of this supplemental application.
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`CONTENT OF LABELING
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`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
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`Reference ID: 3756007
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`

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`NDA 21-926/S-012/S-011
`Page 2
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`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 package insert, Medication Guide), with the addition of any labeling changes in pending
`“Changes Being Effected” (CBE) supplements, as well as annual reportable changes not
`included in the enclosed labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and immediate container labels that are identical to carton and
`immediate-container labels submitted on March 19, 2015, 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 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 21-926/S-012.”
`Approval of this submission by FDA is not required before the labeling is used.
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`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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`MARKET PACKAGE
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`Please submit one market package of the drug product when it is available to the following
`address:
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`Reference ID: 3756007
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`NDA 21-926/S-012/S-011
`Page 3
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`Lana Chen
`Food and Drug Administration
`Center for Drug Evaluation and Research
`White Oak Building 22, Room: 4352
`10903 New Hampshire Avenue
`Silver Spring, Maryland 20993
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`FULFILLMENT OF POSTMARKETING REQUIREMENTS
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`We refer to the deferred pediatric studies noted in our original approval letter dated April 15,
`2008:
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`1277-1
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`Conduct a controlled effectiveness study of Treximet for the acute treatment of
`migraine attacks with or without aura in pediatric patients ages 12 years to 17
`years.
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`1277-2
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`Conduct a long-term open label safety study in pediatric patients with migraine
`ages 12 years to 17 years.
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`We have reviewed your supplemental application and conclude that the above requirements were
`fulfilled.
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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.
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`We have waived the pediatric requirement for ages 0 months to up to 6 years because necessary
`studies are impossible or highly impracticable in that age group.
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`In our April 15, 2008, approval letter, we stated that pediatric studies in children ages 6 years to
`up to 11 years should be deferred until additional safety and effectiveness data have been
`collected in older children and we make a determination as to whether pediatric studies are
`practicable for children ages 6 years to 11 years. You have submitted safety and efficacy data of
`Treximet for the treatment of migraine in in children ages 12 years to 17 years. Based on our
`review of these data, and of other information, we have determined that pediatric studies to
`evaluate the safety and efficacy of Treximet in children ages 6 years to 11 years with migraine
`are practicable and will be required, as described below.
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`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act are required postmarketing studies. The status of these postmarketing studies must
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`Reference ID: 3756007
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`NDA 21-926/S-012/S-011
`Page 4
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`be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These
`required studies are listed below.
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`2910-1 Conduct a juvenile rat toxicology study to identify the unexpected serious risk of
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` adverse effects of sumatriptan/naproxen on postnatal growth and development. The
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` study should utilize animals of an age range and stage(s) of development that are
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` comparable to the intended pediatric population; the duration of dosing should cover
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` the intended length of treatment in the pediatric population. In addition to the usual
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` toxicological parameters, this study must evaluate effects of sumatriptan/naproxen on
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` growth, reproductive development, and neurological and neurobehavioral development.
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` Final Protocol Submission: November 2016
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` Study Completion: November 2017
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` Final Report Submission: May 2018
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`2910-2 Conduct a pharmacokinetics (PK) study in children ages ≥6 years to 11 years with
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` migraine. Using information from this PK study, conduct a controlled efficacy study in
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` children ages ≥6 years to 11 years with migraine. Conduct a long-term open-label
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` safety study in pediatric patients with migraine ages ≥6 years to 11 years. The long-
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` term safety study must provide a descriptive analysis of safety data in at least 50
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` pediatric patients treated with Treximet for a duration of at least 6 months, treating on
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` average at least one migraine attack per month, at doses evaluated in the efficacy study.
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`Submit the protocol(s) to your IND 68,436, with a cross-reference letter to this NDA.
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`Reports of these required pediatric postmarketing studies must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
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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 the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
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` Final Protocol Submission: November 2016
` Study Completion: November 2020
` Final Report Submission: May 2021
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`Reference ID: 3756007
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`NDA 21-926/S-012/S-011
`Page 5
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`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`You must submit final promotional materials and package insert(s), accompanied by a Form
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. 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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`If you have any questions, call Lana Chen, Regulatory Project Manager, at (301) 796-1056.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Eric Bastings, M.D.
`Deputy Director
`Division of Neurology Products
`Office of Drug Evaluation 1
`Center for Drug Evaluation and Research
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`ENCLOSURE:
`Content of Labeling
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`Reference ID: 3756007
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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/
`----------------------------------------------------
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`ERIC P BASTINGS
`05/14/2015
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`Reference ID: 3756007
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