CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 2057180rig15000 CHEMISTRY MEMORANDUM PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DATE: September 16, 2014 FROM: Raymond P. Frankewich, Review Chemist, Branch IV, DNDQA THROUGH: Moo-Jhong Rhee, Branch Chief, Blanch N, DNDQA TO: CMC Review #1 for NDA 205718 SUBJECT: Clari?cation of CMC Review #1 of NDA 205718 In CMC Review dated 5-29-2014, Table 3 on pg. 49 needs to be revised. In the table, three substances, oleate and Sodium Stearyl Fumarate NF are noted as not being nresent in the Inactive Ingredient Database (IIG): However, in fact, all three of these substances are listed in the 116. and oleate are listed under different names as shown in the following tables. Substances Listed in 11G Consistent with Substances Listed in HG Consistent with ce 1 oleate? Reference ID: 3629251 Addendum to CMC Review #1 NDA 205718 Page 2 of 2 It is noted that the amounts of these substances listed in the 11G are greater than the amounts that are used in the drug product, AKYNZEOO (netupitant and palonosetron) capsules. A revised Table 3 is provided below. Revisions to the table are highlighted. In CMC Review it was concluded that the levels of and oleate used in the drug product was not considered a safety issue, because these were also used in the previously approved drug, AloxiD (NDA 22-23 3), and that conclusion remains valid. is identi?ed The The speci?c oleate used in this drug product on the website of its supplier maximum amount in the table below is the maximum for Table 3 Excipients in the NPCC, Daily Intake, and Current Levels of Intake from Inactive Ingredient Database Exdplelt Reference Function Amount per Daub-sol Micr talline cellulose Eur Sucrbid esters Internal Povidone K-30 Eur. Croscarmellose sodium NF Ph. Eur. Silicon dioxide NF Ph. Eur. Sodium steaiyl ?nnarate NF Ph. Eur. Magnesium stearate NF Ph. Eur. Ph. Eur. Glycerin Eur. oleate Internal Butylated hydroxyanisole NF Ph. Eur. (BHA) 1 - FDA Inactive Ingredient Search for Approved Drug Products, at 2 - Maximum amount of this material in any dosage form recognized in the Database with a name be? ii with ?oral: caisule?. Reference ID: 3629251 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAYMOND P FRANKEWICH 09/17/2014 MOO JHONG RHEE 09/17/2014 Chief, Branch IV Reference ID: 3629251 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DATE: August 15, 2014 FROM: Raymond P. Frankewich, Ph.D., Review Chemist, Branch IV, DNDQA II/ONDQA THROUGH: Moo-Jhong Rhee, Ph.D., Branch Chief, Branch IV, DNDQA II/ONDQA TO: NDA 205718 SUBJECT: Final Recommendation The previous CMC Review #1, dated 5-29-2014, made a recommendation of not approval of this NDA because of the following unresolved issues: 1. Final recommendation from the Office of Compliance has not been received. 2. Label/labeling issues were not satisfactorily resolved from the CMC perspective. The Office of compliance has issued an overall “Acceptable” recommendation on July 23, 2014 (Attachment 1). Labels/labeling were revised according to our recommendations in CMC Review #1 (Attachment 2). Updated container labels were submitted on April 25, 2014 and July 16, 2014. Updated package insert was submitted on August 8, 2014. In CMC Review #1 under II.C (Basis for Approvability or Not-Approval Recommendation), it is noted “(see the List of Deficiencies, p. 171)”. This is a typographical error. The List of Deficiencies in CMC Review #1 begins on pg. 168. Recommendation: From the ONDQA perspective, this NDA is now recommended for APPROVAL with expiration dating period of 24 months. 9 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 3611040 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAYMOND P FRANKEWICH 08/15/2014 MOO JHONG RHEE 08/15/2014 Chief, Branch IV Reference ID: 3611040 CMC REVIEW OF NDA 205718 NDA 205718 Akynzeo? (netupitant and palonosetron) Capsules 300mg/0.5mg Helsinn Healthcare SA Raymond P. Frankewich, Hitesh Shroff, Nina Ni, Review Team Of?ce of New Drug Quality Assessment Division of New Drug Quality Assessment II Branch IV CMC REVIEW For the Division of Gastroenterology and Inborn Errors Products CMC Review #1 Page 1 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 Table of Contents Table of Contents 2 CMC Review Data Sheet 4 The Executive Summary 10 I. Recommendations 10 A. Recommendation and Conclusion 011 Approvability 10 B. Recommendation 011 Phase 4 (Post-Marketing) Commitments, Agreements. and/or Risk Management Steps. if Approvable 10 II. Slunmary of MC Assessments 10 A. Description of the Drug Product(s) and Drug Substance(s) 10 B. Description of How the Drug Product is Intended to be Used 12 C. Basis for Approvability or Not-Approval Recommendation 12 Administrative 12 CMC Assessment 13 I. Review Of ommon Technical Document-Quality (C td?Q) Module 3.2: Body Of Data 13 DRUG SUBSTANCE l3 31 8.1 General Information 13 31 82 Manufacture 16 32 8.3 Characterization 22 37 8.4 Control of Drug Substance 24 39 8.5 Reference Standards or Materials 28 42 8.6 Container Closure System 29 43 8.7 Stability 3O 43 DRUG PRODUCT 45 RI Description and Composition of the Drug Product 45 P2 Pharmaceutical Development 54 P3 Manufacture 83 R4 Control of Excipients 96 P5 Control of Drug Product 105 R6 Reference Standards or Materials 137 R7 Container Closure System 138 P8 Stability 140 A APPENDICES 153 Al Facilities and Equipment (biotech only) 153 A2 Adventitious Agents Safety Evaluation 153 A. 3 Novel Excipients 1 5 3 REGIONAL INFORMATION 153 R1 Executed Batch Records 153 CMC Review #1 Page 2 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 R2 Comparability Protocols 154 R3 Methods Validation Package 154 II. Review Of ommon Technical Document-Quality (C td-Q) Module 1 156 A. Labeling Package Insert 156 B. Enviromnental Assessment Or Claim Of Categorical Exclusion 168 HI. List Of De?ciencies to be Communicated 168 IV. Attachment 1 70 CMC Review #1 Page 3 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 CMC Review Data Sheet CMC Review Data Sheet 1. NDA 205718 2. REVIEW #2 1 3. REVIEW DATE: 29-May - 2014 4. REVIEWERS: Raymond P. Frankewich, Hitesh Shroff, Nina Ni, 5. PREVIOUS DOCUMENTS: None 6. BEING REVIEWED: Submission(s) Reviewed Document Date Original Submission September 27, 20 1 3 November 14, Amendment 2 0 1 3 Amendment (labeling) December 20? 20 3 February 5 Amendment 2 0 1 4 February 14, Amendment 2014 Amendment March 27, 2014 Amendment May 16, 2014 Amendment May 2 7, 2014 7. NAME ADDRESS OF APPLICANT: Name: Helsinn Healthcare SA Address: Via Pian Scairolo 9 Pazzallo Lugano Switzerland 69 12 CMC Review #1 Page 4 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 MC Review Data Sheet Representative: Dr. Craig Lehmann August Consulting, Inc. 515 Capital of Texas Highway, Suite 150 Austin, Texas 78746 Telephone: 512-347-1755 8. DRUG PRODUCT TYPE: a) Proprietary Name: Akynzeo b) Non-Proprietary Name (Per salt policy): Netupitant-palonosetron hydrochloride c) Code Name/# (ONDQA only): None (1) Chem. Type/ Submission Priority (ONDQA only): 0 Chem. Type: 1, 4 0 Submission Priority: (Imder PDUFA Program) 9. LEGAL BASIS FOR SUBMISSION: 505(b)(1) 10. PHARMACOL. CATEGORY: Antiemetic (netupitant) Antiemetic; antinauseant (palonosetron) 11. DOSAGE FORM: Capsule 12. 300 mg (netupitant) 0.5 mg (palonosetron) l3. ROUTE OF ADMINISTRATION: Oral 14. DISPENSED: \l Rx _orc 15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACK1NG SYSTEM): SPOTS product Form Completed Not a SPOTS product 16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA, MOLECULAR WEIGHT: Netupitant CMC Review #1 Page 5 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 MC Review Data Sheet Chemical name (IUPAC name): 2- dimethyl-N? 1 -yl)pyridin-3 -yl] propanamide Structural formula: Molecular formula: 30H32F6N4O Relative molecular mass: 578.61 g/mol Palonosetron hydrochloride Chemical name (IUPAC name): 2,3 ,3a,4,5 hydrochloride Structural formula: Molecular formula: C19H24N20 CMC Review #1 Page 6 of 174 Reference ID: 3516115 4- CMC Review Data Sheet Relative molecular mass: 332.87 g/mol CMC Review #1 Page 7 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 CMC Review Data Sheet 17. SUPPORTING DOCUMENTS: A. DMFs: ITEM DATE DMF TYPE HOLDER REFEREN CED STATUS2 REVIEW CONHVIENTS OMPLETED Helsinn Advanced Netupitant drug Reviewed by 26715 SA substance 1 Adequate March 21' 2014 Hitesh Shroff Helsinn Advanced Palonosetron February 27. Reviewed by 16063 SA Hydrochloride 1 Adequate 2014 Hitesh Shroff (10(4) 1 Ad ember 26. equa 201 3 1 Adequate October 29. 1997 oRreaE'iewedwfg Renewed for? Adequate August 30. 2013 oral IV 1 Adequate May 15. 2014 1 Action codes for DMF Table: 1 DMF Reviewed. Other codes indicate why the DMF was not reviewed. as follows: 2 ?Type 1 DMF 3 Reviewed previously and no revision since last review 4 Suf?cient infonnation in application 5 Authority to reference not granted 6 DMF not available 7 Other (explain tmder 2 Adequate. Inadequate. or (There is enough data in the application. therefore the DMF did not need to be reviewed) B. Other Documents: DOCUNIENT APPLICATION NUNIBER DESCRIPTION Aloxiw (palonosetron NDA 21-372 hydrochloride injection) Aloxi? (palonosetron NDA 22-233 hydrochloride capsules) CMC Review #1 Page 8 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 CMC Review Data Sheet 18. STATUS: 0NDQA: CMC . RELATED REVIEWS RECOMMENDATION DATE REVIEWER Biometrics NA EES Pending 2/7/2014 Phann/Tox NA Biophann NA LNC NA Methods Validation Acceptable with 4/29/2014 modi?cations (see review) DMETS NA EA Categorical exclusion (see review) Microbiology NA CMC Review #1 Page 9 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 Executive Surmnary Section The CMC Review for NDA 205718 The Executive Summary 1. Recommendations A. Recommendation and Conclusion on Approvability The applicant has provided suf?cient MC information to assm?e the identity, strength, purity, and quality of the drug product. However, a ?nal ?Acceptable? recommendation from Of?ce of Compliance for the manufacturing facilities has not been made. Also the information on the label/labeling currently is not acceptable from the MC perspective. Therefore, ??om the MC perspective, this NDA is not ready for approval at this time in its present form per B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable NA 11. Summary of CMC Assessments A. Description of the Drug Product(s) and Drug Substance(s) (1) Drug Substance *Throughout this review, the USAN name, palonosetron hydrochloride, is being used. However, per salt name policy, the established name will be presented as palonosetron. So when palonosetron is expressed for some reason, it actually represents palonosetron hydrochloride. This diug product contains two drug substances, netupitant and palonosetron hydrochloride. Netupitant is a New Molecular Entity (NME). Both drug substances are antiemetics, and are intended to treat nausea and vomiting associated with chemotherapy. CMC Review #1 Page 10 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 Executive Summary Section Palonosetron hydrochloride and netupitant are designed to together treat acute nausea and vomiting (emesis) and delayed emesis. Palonosetron hydrochloride is described as a well-known potent and selective 5- HT3 receptor antagonist. Palonosetron hydrochloride has been marketed in the U. S. since 2003. An oral formulation of palonosetron hydrochloride (Aloxi? capsules 0.50 mg, NDA 22-233) was approved in 2008. Netupitant is described as a novel, potent, and selective receptor antagonist. Netupitant was discovered by Roche who performed early development studies on netupitant on its own. Roche subsequently licensed netupitant to this NDA applicant (Helsirm) who then developed the netupitant palonosetron hydrochloride combination drug product. Information from DMF 26715, held by Helsinn Advanced SA, was reviewed for this NDA. Information ??om DMF 16063, also held by Helsinn Advanced SA, was also reviewed for this NDA. Both reviews were performed by Hitesh Shroff, (2) Drug Product The drug product consists of a Size 0 hard gelatin capsule containing three 100 mg immediate-release tablets containing 100 mg netupitant, and one soft gelatin capsule (softgel) containing mm 0.50 mg of palonosetron (0.56 mg of palonosetron hydrochloride). Thus the dosage delivered by one capsule of the drug product is 300 mg netupitant and 0.5 mg palonosetron. The design intent was to develop an oral ?xed dose combination to allow administration of two (hug substances in a single dosage form prior to each chemotherapy cycle. The 100 mg netupitant tablet and the 0.50 mg palonosetron softgel are produced as intermediate drug products. They are referred to by the applicant as Intermediate Netupitant Tablet and Intermediate Palonosetron Softgel. The softgel is produced by (W) In this review, the Intermediate Netupitant Tablet is often referred to as INT, and the Intermediate Palonosetron So?gel is often referred to as (law The ?nal combination capsule is referred to by the applicant as Netupitant Palonosetron CMC Review #1 Page 11 of 174 Reference ID: 3516115 CMC REVIEW OF NDA 205718 Executive Summary Section Combination Capsule. In this review, the combination capsule is often referred to as NPC . The proposed container closure system for the NPC is a l-unit blister package. The secondary package is an outer carton, containing the one-1mit blister. Proposed shelf life for the NPC is 24 months. B. Description of How the Drug Product is Intended to be Used According to the draft labeling, the adult dosage of the drug product is one capsule administered approximately one hour prior to the start of chemotherapy. The capsule can be taken with or without food. C. Basis for Approvability or Not-Approval Recommendation 21 CFR No ?Acceptable? recommendation from the Of?ce of Compliance has been made for the compliance of the facilities involved. 21 CFR 0 Labels and labeling issues have not been fully resolved (see the List of Deficiencies, p. 171) Administrative A. Reviewer?s Signature: (See appended electronic signature page) Raymond P. Frankewich, Branch IV, ONDQA, DNDQA II. B. Endorsement Block: (See appended electronic signature page) Moo Jhong Rhee, Branch Chief, Branch IV, ONDQA, DNDQA II C. CC Block: entered electronically in DFS 162 Page(s) has been Withheld in Full as b4 immediately following this page CMC Review #1 Page 12 of 174 Reference ID: 3516115 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAYMOND P FRANKEWICH 05/30/2014 MOO JHONG RHEE 05/30/2014 Chief, Branch IV Reference ID: 3516115 DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Food and Drug Administration Center for Drug Evaluation and Research METHODS VALIDATION REPORT SUMMARY TO: Raymond P. Frankewich, CMC Reviewer Office of New Drug Quality Assessment (ONDQA) E-mail Address: raymond.frankewich@fda.hhs.gov Phone: (301)-796-1354 Fax: (301)-796-9749 FROM: FDA Division of Pharmaceutical Analysis Michael Trehy, MVP Coordinator 645 S Newstead Avenue St. Louis, MO 63110 Phone: (314) 539-3815 Through: John Kauffman, Deputy Director Phone: (314) 539-2168 SUBJECT: Methods Validation Report Summary Application Number: 205718 Name of Product: Akynzeo® (netupitant-palonosetron hydrochloride) capsule Applicant: Helsinn Healthcare SA Applicant’s Contact Person: Dr. Craig Lehmann Address: August Consulting, Inc. 515 Capital of Texas Highway, Suite 150 Austin, TX 78746 Telephone: (512) 347-1755 Fax: (512) 347-9375 Date Methods Validation Consult Request Form Received by DPA: 10/11/2013 Date Methods Validation Package Received by DPA: 10/11/2013 Date Samples Received by DPA: 11/18/2013 Date Analytical Completed by DPA: 4/28/2014 Laboratory Classification: 1. Methods are acceptable for control and regulatory purposes. 2. Methods are acceptable with modifications (as stated in accompanying report). 3. Methods are unacceptable for regulatory purposes. Comments: Analyst’s comments and link to analyst’s work sheets are attached. DPATR-FY14-045 Reference ID: 3497181 Page 1 of 5 Version: 2/6/2013 DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Center for Drug Evaluation and Research Division of Pharmaceutical Analysis 645 S. Newstead Ave. St. Louis, Missouri 63110 Telephone (314) 539-3858 FAX (314) 539-2113 Date: April 25, 2014 To: Raymond P. Frankewich, Ph. D., CMC Reviewer, ONDQA Marie Kowblansky, Ph. D., CMC Lead, ONDQA Through: John Kauffman, Ph. D., Deputy Director, Division of Pharmaceutical Analysis From: Anjanette Smith, Chemist, Division of Pharmaceutical Analysis Subject: Method Validation for NDA 205718 Akynzeo ® (netupitant-palonosetron hydrochloride) Capsule Helsinn Healthcare SA The following methods were evaluated and are acceptable for quality control and regulatory purposes:      Related Substances and Identification by HPLC, drug substance (ALC/146) Assay by HPLC, drug substance (ALC/147) Netupitant Impurities, drug product (32P25-7) Assay of Netupitant, drug product (32P52-5) Dissolution - Netupitant, drug product (32P52-11) The following method was evaluated and is acceptable for quality control and regulatory purposes with modification:  (b) (4) - Netupitant, drug substance (AGC/166) (b) (4) Analyst’s work sheets and data are available at http://ecmsweb.fda.gov:8080/webtop/drl/objectId/090026f88068cb0c 3 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page DPATR-FY14-045 Reference ID: 3497181 Page 2 of 5 Version: 2/6/2013 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MICHAEL L TREHY 04/28/2014 JOHN F KAUFFMAN 04/29/2014 Reference ID: 3497181