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Other Review(S) &(17(5 )25 '58* (9$/8$7,21 $1' 5(6($5&+ APPLICATION NUMBER: 2ULJV 27+(5 5(9,(: 6 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information**** Memorandum Date: July 25, 2019 To: Jennifer Lee, PharmD, Senior Regulatory Health Project Manager, Division of Hematology Products (DHP) Virginia Kwitkowski, Associate Director for Labeling, DHP From: Robert Nguyen, PharmD, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) CC: Susannah O’Donnell, MPH, RAC, Team Leader, OPDP Subject: OPDP Labeling Comments for INREBIC (fedratinib) capsules, for oral use NDA: 212327 In response to DHP’s consult request dated February 20, 2019, OPDP has reviewed the proposed product labeling (PI) and Medication Guide for the original NDA submission for Inrebic. PI: OPDP’s comments on the proposed labeling are based on the draft PI received by electronic mail from DHP (Jennifer Lee) on July 10, 2019, and are provided below. Medication Guide: A combined OPDP and Division of Medical Policy Programs (DMPP) review was completed, and comments on the proposed Medication Guide were sent under separate cover on July 18, 2019. Thank you for your consult. If you have any questions, please contact Robert Nguyen at (301) 796-0171 or [email protected]. 30 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this pageollowing this page 1 Reference ID: 4467737 Signature Page 1 of 1 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ ROBERT L NGUYEN 07/25/2019 11:59:39 AM Reference ID: 4467737 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy PATIENT LABELING REVIEW Date: July 18, 2019 To: Ann Farrell, MD Director Division of Hematology Products (DHP) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) From: Shawna Hutchins, MPH, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Robert Nguyen, PharmD Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Medication Guide (MG) Drug Name (established INREBIC (fedratinib) name): Dosage Form and Route: Capsules, for oral use Application NDA 212327 Type/Number: Applicant: Celgene Corporation Reference ID: 4464318 1 INTRODUCTION On January 3, 2019, Celgene Corporation, submitted for the Agency’s review an original New Drug Application (NDA 212327) for INREBIC (fedratinib) capsules, for oral use, a New Molecular Entity (NME), for the proposed indication of the treatment of intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (b) (4) . This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Hematology Products (DHP) on February 20, 2019 for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for INREBIC (fedratinib) capsules, for oral use. 2 MATERIAL REVIEWED • Draft INREBIC (fedratinib) MG received on January 3, 2019 and received by DMPP and OPDP on July 10, 2019. • Draft INREBIC (fedratinib) Prescribing Information (PI) received on January 3, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on July 10, 2019. • Approved JAKAFI (ruxolitinib) comparator labeling dated May 24, 2019. 3 REVIEW METHODS In our collaborative review of the MG we: • simplified wording and clarified concepts where possible • ensured that the MG is consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the MG is free of promotional language or suggested revisions to ensure that it is free of promotional language • ensured that the MG meets the Regulations as specified in 21 CFR 208.20 • ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006) • ensured that the MG is consistent with the approved comparator labeling where applicable 4 CONCLUSIONS The MG is acceptable with our recommended changes. 5 RECOMMENDATIONS Reference ID: 4464318 • Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. • Our collaborative review of the MG is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the MG. Please let us know if you have any questions. 5 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 4464318 Signature Page 1 of 1 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ SHAWNA L HUTCHINS 07/18/2019 01:59:42 PM ROBERT L NGUYEN 07/18/2019 02:03:15 PM LASHAWN M GRIFFITHS 07/18/2019 02:07:07 PM Reference ID: 4464318 Neuro-oncology Consult Reviewer: Joohee Sul, MD Requesting Division: Division of Hematology Products (DHP) Product: Fedratinib RE: Analysis of encephalopathy cases associated with fedratinib NDA 212327 IND 078286 The Division of Hematology Products (DHP) has requested a review of multiple reported cases of possible Wernicke’s encephalopathy associated with fedratinib administration. WERNICKE’S ENCEPHALOPATHY Wernicke’s encephalopathy (WE) is clinically important syndrome of acute delirium caused by thiamine (vitamin B1) deficiency. The classic triad of symptoms includes confusion, oculomotor dysfunction and ataxia. Although patients can improve rapidly with thiamine administration, if left untreated progression to coma and death can occur. A chronic amnestic dementia characterized by severe memory loss with confabulation and lack of insight (Korsakoff’s psychosis) may also develop. Therefore, rapid recognition of the condition and urgent thiamine replacement is critical to preventing neurologic morbidity. Although WE is most commonly associated with alcohol use, the condition may also occur in the setting of poor nutritional status a myriad of conditions including hyperemesis, bariatric surgery, anorexia, and cancer. Based on autopsy studies, the clinical diagnosis of WE appears to be lower compared with the post­ mortem diagnosis determined by neuropathological features, suggesting that the condition is underdiagnosed.1-3 Pathophysiology Thiamine is essential to the function of multiple cellular processes, including metabolic pathways, maintenance of cell membrane osmotic gradients, and production of neurotransmitters. The body’s thiamine reserves are generally sufficient to support metabolic functions for 10-20 days. High-calorie and high-carbohydrate diets increase metabolic thiamine requirements. Thiamine deficiency is purported to lead to neuronal damage secondary to oxidative stress, impaired glucose metabolism, and NMDA excitotoxicity. As sites of high thiamine consumption, neurons in the periaqueductal gray matter, colliculi, medial thalami and 4 mamillary bodies are especially susceptible to deficits, accounting for the imaging changes found in these anatomic locations. Nutritional deficiency alone may not lead to WE, suggesting 5 that multiple factors may be involved. For example, abnormalities in transketolase, an enzyme 6,7 that processes thiamine, may be abnormal in individuals who develop WE, and genetic factors 8-10 have been implicated as well. Clinical Diagnosis of WE is generally based on clinical features, and can be supported by imaging findings and thiamine levels. The hallmark of WE are oculomotor signs, especially nystagmus and gaze palsies, which generally predate confusion or ataxia. The mental status changes of WE are characterized by disorientation and abulia (i.e., as seen with bithalamic strokes). Ataxia is generally appreciated when evaluating the gait and does not typically involve the extremities. Peripheral neuropathy can also occur, most often involving the lower extremities and Reference ID: 4464296 contributing to ataxia. Other clinical findings include vestibular dysfunction and autonomic dysfunction. When these symptoms occur in the alcohol users, WE is readily identified; however, the syndrome rarely presents with the classic triad and as such is generally underdiagnosed. Chronic or subclinical thiamine deficiency may lead to symptoms of WE appearing sooner; therefore, it is essential to interrogate the past medical history for weight loss and alcohol use. Moreover, glucose metabolism is a thiamine-intensive process, and a large glucose infusion can shuttle any available thiamine into cells, triggering WE. Hence, the recommendation is to always administer
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