RedHill Biopharma Ltd.Rizaport (rizatriptan) oral film

Dear Dr. Fathi:

Please refer to your New Drug Application (NDA) dated March 27, 2013, received April 3, 2013, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Rizaport (rizatriptan) oral film.

We acknowledge receipt of your amendments dated July 10, 2013, October 10, 2013, October 30, 2013, November 22, 2013, and December 5, 2013.

We also acknowledge receipt of your amendment dated January 15, 2014, which was not reviewed for this action. You may incorporate applicable sections of the amendment by specific reference as part of your response to the deficiencies cited in this letter.

We have completed our review of this application, as amended, and have determined that we

cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

PRODUCT QUALITY

Process Description Deficiencies:

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‘ies Regarding Impuri

12. Provide information pertaining to the characterization of impurities in the drug product (section P.5.5)

Drug Product Specification Deficiencies:

13. Update the drug product specifications to include tests and acceptance criteria for physical characteristics of the film (e.g., flexibility, tensile strength, acceptable level of bubbles, etc) or provide justification, supported by data, for not monitoring these parameters in the finished product. 14. The proposed acceptance criterion for the disintegration is overly broad. Tighten the

specification for disintegration to a limit that is justified by data and patient requirements.

17. The acceptance criterion for the dissolution in the drug product specification was revised toQ 4 in 15 minutes. Update the drug product release and stability specifications to

reflect this change and provide dissolution data for the last time point on the stability

samples with this method.

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Container Closure Deficiencies:

18. Provide a detailed description of the drug product container closure system including manufacturers, materials of construction, specifications for materials and parts, certificates of compliance, certificates of analyses, DMF references and the corresponding letters of authorization for the DMF references.

19. Provide a description of any secondary packaging used for the drug product.

Stability Deficiencies:

20. Revise the post approval stability commitment to provide for placement of the first three commercial batches of each strength on stability under long-term and accelerated conditions.

21. Your application lacks photostability data for the drug product. Provide photostability on at least one batch of the drug product as per ICH Q1A(R2) and Q1B, or a justification for the exclusion of this data.

22. Provide dissolution data using the revised dissolution method from samples at the end of their shelf life or the latest stability time point to support your expiry (See comment 17 above).

Environmental Impact Assessment: 23. Amend your application to request a categorical exclusion from preparing an environmental impact consideration, citing the specific citation under 21 CFR 25.31.

LABELING

We reserve full comment on the proposed labeling until the application is otherwise adequate. If you revise labeling, your response must include updated content of labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www. fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

Please submit draft carton and container labels and labeling revised as follows:

1. General Comments for Labels and Labelin: a.

The fext against the ickground for the 10 mg strength is difficult to read. Change the background colors or change the colored text for better contrast and to improve readability.

b. Revise the active ingredient fom to “Rizatriptan”. c. Relocate the strength to beneath the dosage form for customary placement. 2. Pouch Labels a. Itis unclear where the pouch should be folded before tearing open at the notch. Add a

dotted line to show where it should be folded. Revise the statement to read similar to “To open: Fold on the dotted line and tear

open at the notch.” for clarity. In addition, the dotted line and instructions for ing the pouch should appear on the principal display panel instead a tn

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order to accommodate this information, relocate the net quantity to the lower third of the principal display panel, away from the strength.

b. Add the statement “Keep product in pouch until ready to use.” to the back panel, similar to the carton labeling, to help maintain the integrity of the product.

3. Carton Labels a. Revise statements in all upper case to sentence case to improve readability.

FACILITY INSPECTIONS During a recent inspection of the © facility for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of

these deficiencies is required before this application may be approved.

505(b)(2) REGULATORY PATHWAY

An applicant filing a certification under 505(b)(2)(A)(iv) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.50(i)(1)()(A)(4) (i-e., a paragraph IV certification) must provide notice of such certification to each owner of the patent that is the subject to the certification or the representative designated by the patent owner to receive the notice. The contact information for the patent owner or its representative may be obtained from the U.S. Patent and Trademark Office (PTO). See 21 CFR 314.52(a)(1). You are proposing to rely on NDA 20865 as the listed drug. The only unexpired patent is Patent No. 5,457,895. According to the PTO’s website, it appears that this patent has been assigned to Catalent USA Woodstock, Inc., Catalent USA Packaging, LLC, Catalent Pharma Solutions, Inc., Catalent USA Paintball, Inc., and Catalent Pharma Solutions,

LLC. http://assignments.uspto.gov/assignments/q?db=pat&qt=pat&reel=& frame=&pat=545789 S&pub=&asnr=Kasnri=&asne=Kasnei=&asns Based on our records, you have not provided notice to the appropriate entities. This is a deficiency that must be addressed before FDA can approve your application.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in which to resubmit the application. A resubmission must fully address all the deficiencies listed. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM153222.pdf.

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The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, call Lana Chen, Regulatory Project Manager, at (301) 796-1056. Sincerely, {See appended electronic signature page} Eric Bastings, M.D. Deputy Director Division of Neurology Products

Office of Drug Evaluation I Center for Drug Evaluation and Research

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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.

ERIC P BASTINGS 01/31/2014

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