CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 021879Orig1s000 PHARMACOLOGY REVIEW(S) MEMORANDUM DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration ________________________________________________________________________ Division of Neurology Products (HFD-120) Center for Drug Evaluation and Research Date: October 29, 2010 From: Lois M. Freed, Ph.D. Supervisory Pharmacologist Subject: NDA 21-879 (Nuedexta; dextromethorphan plus quinidine); SDN 38, dated April 23, 2010 (received April 30, 2010). ________________________________________________________________________ Nuedexta™ (formerly Neurodex™, Zenvia™) is a combination drug product intended for the treatment of pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis or multiple sclerosis. Nuedexta contains dextromethorphan hydrobromide and quinidine sulfate, two marketed drugs. NDA 21-879 was originally submitted by the sponsor (Avanir Pharmaceuticals) on January 27, 2006 (received January 30, 2006). The nonclinical data provided in support of that application were reviewed by Dr. Kathleen Young (Pharmacology/Toxicology Review and Evaluation, NDA 21-879, Kathleen Young, Ph.D., October 30, 2006). An Approvable letter was sent to the sponsor on October 30, 2006, without draft labeling. Deficiencies precluding approval were clinical (both safety and efficacy); however, a number of nonclinical comments were communicated to the sponsor: • Potential deficiencies (e.g., lack of adequate high dose) in the fertility and early embryonic development, embryofetal development, and pre-and post-natal development studies in rat and the embryofetal development study in rabbit. • The lack of a chronic toxicology study in non-rodent. • The need to conduct a juvenile neurotoxicology study in an appropriate animal species to assess the potential for [Nuedexta] to induce apoptotic neurodegeneration during development. • The ongoing 2-year carcinogenicity study in rat should be submitted as soon as possible. The sponsor submitted nonclinical data to IND 56954 (dextromethorphan/quinidine for PBA) in response to these comments. These data were reviewed by Dr. D. Charles Thompson (Preliminary Pharmacology/Toxicology IND Safety Evaluation, IND 56,954, D. Charles Thompson, R.Ph, Ph.D., 5/7/2009) and comments were sent to the sponsor on 7/22/2009: Reference ID: 2856942 1 • The new nonclinical data adequately justified the high dose used in the original rat fertility and early embryonic development (to implantation) and embryofetal development studies, so those studies would not need to be repeated. However, the pre- and post-natal development study, conducted using a lower high-dose, will need to be repeated using the same high dose used in the original fertility and embryofetal studies. In addition, due to differences in the degree of maternal toxicity between studies, the pre- and post-natal study should include a teratology examination. • The embryofetal development study in rabbit will need to be repeated. The sponsor was informed in preliminary responses to a Type C meeting request (sent 11/9/2009; meeting cancelled by the sponsor) that a pre- and post-natal development study in rat and an embryofetal development study in rabbit would be needed, but may be submitted post-approval. However, based on additional information submitted by the sponsor, the repeat pre- and post-natal evaluation would not need to include a teratology evaluation. In the Complete Response, the sponsor submitted the following nonclinical studies: • In vitro hERG assay of AVP-923 (dextromethorphan [DM]/quinidine [Q]) in HEK293 cells. • In vitro effects of quinidine sulfate on ECG parameters in the rabbit left ventricular wedge preparation. • In vivo 7-day PK study of DM/Q in Beagle dog • In vitro metabolism studies in human liver preparations • Toxicology o 5-week dose-ranging study of DM/Q in Beagle dog o 39-week oral toxicity study of DM/Q in Beagle dog o 24-month carcinogenicity study of DM/Q in rat All of these studies, with the exception of the in vitro metabolism studies (to be reviewed by the Clinical Pharmacology team), were reviewed by Dr. Thompson (Pharmacology/Toxicology NDA Review and Evaluation, NDA 21-879, D. Charles Thompson, R.Ph, Ph.D., 10/1/2010). Based on his review, Dr. Thompson has concluded that the nonclinical studies submitted are adequate to support approval of Nuedexta for the intended indication, with the following nonclinical studies to be conducted as postmarketing requirements (PMRs): • Juvenile neurotoxicology study in rat. • Pre- and post-natal development study in rat • Embryo-fetal development study in rabbits. Dr. Thompson notes that the sponsor has committed to conducting these studies post- approval, and has suggested time lines for the conduct and submission of these studies. Reference ID: 2856942 2 Comments: I concur with Dr. Thompson’s conclusion and recommendations. I would also recommend, as a postmarketing requirement (PMR), a juvenile animal toxicology study in one species (rat) to support the PMR for a pediatric study. One additional issue needs to be addressed. According to a recent published study (Huang X-P et al. Mole Pharm 76(4):710-722, 2009, discussed in Elangbam CS Tox Path 000:1-12, 2010 online), quinidine has been identified as a 5HT2B agonist. According to Huang et al. (2009), these are the first data to demonstrate this effect of quinidine. (Huang et al. (2009) did not identify dextromethorphan as a 5HT2B agonist; the sponsor did not assess either quinidine or dextromethorphan for binding or activity at the 5HT2B receptor.) 5HT2B agonist activity is considered a potential cause of drug-induced cardiac valvulopathy. A number of drugs reported to induce valvular heart disease (VHD) in humans, including some that have been removed from the market due to a documented association with VHD (pergolide, fenfluramine, and dexfenfluramine), have been demonstrated to be potent 5HT2B agonists (cf. Frachon I et al. PLoS One 5(4):1-5, 2010; Roth BL NEJM 356(1):6-9, 2007; Zanettini R et al. NEJM 356(1):39-46, 2007). To my knowledge, there have been no published reports of VHD in humans caused by quinidine, although quinidine has been marketed for many years as a Class 1a antiarrhythmic at substantially higher doses. It is possible, however, that treatment may be longer in duration in patients with PBA, and duration of treatment is reported to be an important risk factor for drug-induced VHD (cf. Roth, 2007; Shade et al. NEJM 356(1):29-38, 2007). No effects on cardiac valves were observed in the toxicity studies of DM/Q; however, at least in the rodent, histopathological evaluation of cardiac valves is commonly absent. Therefore, the lack of reported valvular effects in the toxicity studies of DM/Q does not rule out the potential for quinidine to induce valvulopathy. Since 5HT2B agonist activity has been reported only in a single published study, the sponsor should be given the opportunity to confirm this pharmacodynamic effect, i.e., by conducting studies to assess the in vitro binding affinity and functional activity of quinidine at the 5HT2B receptor. If these studies confirm that quinine is a 5HT2B agonist, an investigative study should be conducted to assess the potential for quinidine to induce cardiac valvulopathy. Depending on the results of these studies, it may also be necessary for a focused examination of cardiac valves to be incorporated into the juvenile animal toxicology study to be conducted post-approval. This issue can be addressed when the juvenile study protocol is submitted for review. Therefore, I would recommend that studies to investigate the binding affinity and functional activity of quinidine at the 5HT2B receptor and, if necessary, a follow-up investigative study to assess the potential for quinidine to induce cardiac valvulopathy be an additional PMR. 3 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 2856942 3 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- LOIS M FREED 10/29/2010 Reference ID: 2856942 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION Application number: 21-879 Supporting document/s: 38 Applicant’s letter date: 23 April 2010 CDER stamp date: 30 April 2010 Product: Zenvia™ (Dextromethorphan/Quinidine; formerly Neurodex™) Indication: Treatment of Pseudobulbar Affect occurring in ALS, MS, stroke, and Alzheimer’s Disease Applicant: Avanir Pharmaceuticals, Inc. 101 Enterprise, Suite 300 Aliso Viejo, CA 92656 Review Division: Neurology Products, HFD-120 Reviewer: D. Charles Thompson, R.Ph., Ph.D., D.A.B.T. Supervisor/Team Leader: Lois M. Freed, Ph.D. Division Director: Russell G. Katz, M.D. Project Manager: Susan B. Daugherty, R.N., B.S.N. Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 21-879 are owned by Avanir Pharmaceuticals, Inc. or are data for which Avanir Pharmaceuticals, Inc. has obtained a written right of reference. Any information or