`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`Public Health Service
`
`Food and Drug Administration
`
`Rockville, MD 20857
`
`
`
`
`
`
`NDA 21-926
`
`
`
`
`POZEN, Inc.
`Attention: Paul A. Ossi
` Sr. Vice President, Regulatory Affairs
`1414 Raleigh Road, Suite 400
`Chapel Hill, NC 27517
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` NDA APPROVAL
`
`
`
`
`
`
`
`
`Dear Mr. Ossi:
`
`
`Please refer to your new drug application (NDA) dated August 5, 2005, received August 8, 2005,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Treximet™ (sumatriptan and naproxen sodium) Tablets. Each tablet contains sumatriptan
`(85 mg as the succinate) and naproxen sodium (500 mg).
`
`We acknowledge receipt of your submissions dated October 11, 2007, January 11, 2008, January
`14, 2008, and April 7, 2008.
`
`Your October 11, 2007 submission constituted a complete response to our June 8, 2006 action
`letter.
`
`This new drug application provides for the use of Treximet™ (sumatriptan and naproxen
`sodium) Tablets for the acute treatment of migraine attacks with or without aura in adults.
`
`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.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`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.
`
`We are waiving the pediatric requirement for ages 0 months to up to 6 years because necessary
`studies are impossible or highly impracticable in that age group. In addition, we are deferring
`submission of your pediatric studies for ages 6 years to 17 years because this product is ready for
`approval for use in adults and the pediatric studies have not been completed.
`
`
`

`

`NDA 21-926
`Page 2
`
`The findings in adults, and on which the current approval is based, demonstrate sufficient safety
`to proceed with pediatric studies in children ages 12 years to 17 years. Pediatric studies in
`children ages 6 years to up to 11 years should be delayed until additional safety and effectiveness
`data have been collected in older children and we make a determination whether pediatric studies
`are practicable for children ages 6 years to 11 years.
`
`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) are required pediatric postmarketing studies. The status of this required
`pediatric postmarketing studies must be reported annually according to 21 CFR 314.81 and
`section 505B(a)(3)(B) of the FDCA. This requirement is listed below.
`
`
`
`1. 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.
`
`
`
`2. Conduct a long-term open label safety study in pediatric patients with migraine ages 12
`years to 17 years.
`
`
`
`Final Report Submission:
`
` Within 3 years of the date of approval
`
`
`As noted above, we will determine if you must perform studies in pediatric patients ages 6 years
`to 11 years after we have reviewed the above required studies.
`
`Submit final reports to this NDA 21-926. For administrative purposes, all submissions related to
`these required pediatric postmarketing studies must be clearly designated “Required Pediatric
`
`Assessment”.
`
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the FDCA to authorize FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C.
`355(o)(3)(A)). This provision took effect on March 25, 2008.
`
`We have determined that you are required, pursuant to section 505(o)(3) of the FDCA, to
`conduct a postmarketing clinical trial to assess the known serious risk of hypertension associated
`with exposure to sumatriptan succinate and naproxen sodium. We have determined that an
`analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the
`FDCA will not be sufficient to assess the known serious risk of hypertension. Furthermore, the
`new pharmacovigilance system that FDA is required to establish under section 505(k)(3) has not
`yet been established and is therefore not sufficient to assess the known serious risk of
`hypertension. Finally, we have determined that only a clinical trial (rather than a nonclinical or
`observational study) will be sufficient to assess this known serious risk. Therefore, based on
`appropriate scientific data, FDA has determined that you are required, pursuant to section
`505(o)(3) of the FDCA, to conduct the following clinical trial:
`
`3. A randomized, double-blind, active comparator clinical trial of Treximet™ in adults with
`
`episodic migraine dosed with either Treximet™, naproxen sodium 500 mg, or sumatriptan 85 mg
`
`

`

`NDA 21-926
`Page 3
`
`to further assess the hypertensive effects of Treximet™ relative to each of its two active
`ingredients. The timetable you have submitted states that you will conduct this clinical trial
`according to the following schedule:
`
`
`Final Report Submission: Within 24 months of the date of approval
`
`
`
`Submit protocols to your IND 68,436, with a cross-reference letter to this new drug application
`(NDA) 21-926. Submit final reports to your NDA 21-926. Please use the following designators
`to label prominently all submissions, including supplements, relating to this postmarketing
`clinical trial as appropriate:
`
`
`• Required Postmarketing Protocol under 505(o)
`
`• Required Postmarketing Final Report under 505(o)
`
`• Required Postmarketing Correspondence under 505(o)
`
`You are required to report periodically to FDA on the status of this clinical trial pursuant to
`sections 505(o)(3)(E)(ii) and 506B of the FDCA, as well as 21 CFR 314.81. Under section
`505(o)(3)(E)(ii), you are also required to periodically report to FDA on the status of any study or
`
`trial otherwise undertaken to investigate a safety issue associated with Treximet™.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENT
`
`
`Title IX, Subtitle A, Section 901 of FDAAA amends the FDCA to authorize FDA to require the
`submission of a Risk Evaluation and Mitigation Strategy (REMS) if the Secretary determines
`
` that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks (section
`505-1(a)(2)). This provision took effect on March 25, 2008.
`
`In accordance with section 505-1 of FDCA, as one element of a REMS, FDA may require the
`development of a Medication Guide as provided for under 21 CFR Part 208. Pursuant to 21 CFR
`Part 208, FDA has determined that Treximet™ poses a serious and significant public health
`concern requiring the distribution of a Medication Guide. The Medication Guide is necessary for
`patients’ safe and effective use of Treximet™. FDA has determined that Treximet™ is a product
`that has serious risks of which patients should be made aware because information concerning
`the risks could affect patients’ decisions to use Treximet™. Nonsteroidal anti-inflammatory
`drugs, including naproxen sodium, are associated with numerous safety risks, including an
`increased risk of cardiovascular events and gastrointestinal toxicity. Under 21 CFR 208, you are
`responsible for ensuring that the Medication Guide is available for distribution to patients who
`are dispensed Treximet™.
`
`
`Your proposed REMS, submitted on April 15, 2008 in an electronic communication, is
`approved. The REMS consists of the Medication Guide included with this letter and the
`timetable for submission of assessments of the REMS included in your April 15, 2008
`submission. The timetable you submitted is as follows:
`
`
`1st FDAAA assessment: November 2009 (18 months from approval)
`2nd FDAAA assessment: May 2011 (3 years from approval)
`3rd FDAAA assessment: May 2015 (7 years from approval)
`
`

`

`NDA 21-926
`Page 4
`
`
`
`Information needed for assessment of the REMS should include but may not be limited to:
`
`
`a. Survey of patients’ understanding of the serious risks of Treximet™
`
`b. Report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24
`
`c. Report on failures to adhere to distribution and dispensing requirements, and corrective
`actions taken to address noncompliance
`
`
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described
`at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for
`the package insert, text for the patient package insert, Medication Guide). Upon receipt, we will
`transmit that version to the National Library of Medicine for public dissemination. For
`administrative purposes, please designate this submission, “SPL for approved NDA 21-926.”
`
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Please submit final printed carton and container labels that are identical to your January 14, 2008
`carton and container labels, and also include the minor editorial revisions indicated below, as
`soon as they are available, but no more than 30 days after they are printed.
`
`On April 15, 2008, we note that you agreed to the following revisions to the Treximet carton and
`container labels submitted on January 14, 2008:
`
`General Comments:
`
`
`1. Relocate the dosage form statement so that it is to the right of and adjacent to the established
`name or, alternatively, relocate the statement of strength so that it is below the dosage form
`
`statement (see examples below).
`
`
`
`
`
`
`Treximet
`
`(sumitriptan and naproxen sodium) Tablets
`
`85 mg/500 mg
`
`
`
`
`
`2. Increase the size and prominence of the statement of strength.
`
`3. Remove the “New” callout from the labels and labeling.
`
`

`

`NDA 21-926
`Page 5
`
` Container Labels - Sides, Top, and Bottom
`
`
`1. See General Comment #1 above.
`
`
`2. Delete the wording
`
`3. Add the drug administration precautionary statement “Tablets should not be split, crushed,
`
`or chewed” or similar verbiage.
`
`
`
`Carton Labeling - Outside
`
`1. Add the drug administration precautionary statement “Tablets should not be split, crushed,
`
`or chewed” or similar verbiage.
`
`
`2. Add the wording “Provide a Medication Guide to each patient to whom this drug product is
`dispensed” or similar verbiage.
`
`
`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 (October 2005). 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.” 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.
`
`
`PROMOTIONAL MATERIALS
`
`
`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(s)
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`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(s), 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 Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see www.fda.gov/cder/ddmac.
`
`
`
`
`
`
`
`
`

`

`
`
`NDA 21-926
`Page 6
`
` LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`
` the letter to both this NDA and to the following address:
`
`
`MedWatch
`Food and Drug Administration
`HFD-001, Suite 5100
`5515 Security Lane
`Rockville, MD 20852
`
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21
`CFR 314.80 and 314.81).
`
`If you have any questions, call Jacqueline H. Ware, Pharm.D., Regulatory Project Manager, at
`(301) 796-1160.
`
`
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Katz,
`Russell
`
`
`Director
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`
` M.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Enclosure
`
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`/s/
`
`---------------------
`Russell Katz
`
`4/15/2008 07:06:40 PM
`
`
`