DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 208462 NDA APPROVAL Millennium Pharmaceuticals, Inc. Attention: Melissa Anderson, RAC Director Global Regulatory Affairs 40 Landsdowne Street Cambridge, MA 02139 Dear Ms. Anderson: Please refer to your New Drug Application (NDA) dated July 10, 2015, received July 10, 2015, and your amendments submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Ninlaro® (ixazomib) capsules, 2.3, 3, and 4 mg. This new drug application provides for the use of Ninlaro® (ixazomib) capsule in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. 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. A 36 month shelf life is granted for Ninlaro (ixazomib) capsules stored at room temperature not to exceed 30oC (86o F). 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/For Industry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert and patient package insert). 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/UCM072392.pdf. The SPL will be accessible via publicly available labeling repositories. Reference ID: 3849755 NDA 208462 Page 2 CARTON AND IMMEDIATE CONTAINER LABELS Submit final printed carton and immediate container labels that are identical to the enclosed carton and immediate container labels 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 208462.” Approval of this submission by FDA is not required before the labeling is used. Marketing the products with FPL that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug. ADVISORY COMMITTEE Your application for Ninlaro® (ixazomib) was not referred to an FDA advisory committee because the application did not raise significant public health questions on the role of the drug in the diagnosis, cure, mitigation, treatment, or prevention of a disease. 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. Because this drug product for this indication has an orphan drug designation, you are exempt from this requirement. 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, Medication Guide, and patient PI (as applicable) to: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266 Reference ID: 3849755 NDA 208462 Page 3 Alternatively, you may submit a request for advisory comments electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft Guidance for Industry (available at: http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM443702.pdf ). 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. Form FDA 2253 is available at http://www.fda.gov/downloads/AboutFDA/Reports ManualsForms/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. REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). MEDWATCH-TO-MANUFACTURER PROGRAM The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event reports that are received directly by the FDA. New molecular entities and important new biologics qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for this product. To participate in the program, please see the enrollment instructions and program description details at http://www.fda.gov/Safety/MedWatch/HowTo Report/ucm166910.htm. POST APPROVAL FEEDBACK MEETING New molecular entities and new biologics qualify for a post approval feedback meeting. Such meetings are used to discuss the quality of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, call the Regulatory Project Manager for this application. PDUFA V APPLICANT INTERVIEW FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program. For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing. The purpose of the interview is to better Reference ID: 3849755 NDA 208462 Page 4 understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review. ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about the interview process. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final assessments. Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to these assessments. If you have any questions, please contact Jacquin Jones, Regulatory Project Manager, at (240) 402-4590. Sincerely, {See appended electronic signature page} Richard Pazdur, MD Director Office of Hematology and Oncology Products Center for Drug Evaluation and Research Enclosures: Content of Labeling Carton and Container Labeling Reference ID: 3849755 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RICHARD PAZDUR 11/20/2015 Reference ID: 3849755