CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 022345Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) OFFICE OF CLINICAL PHARMACOLOGY REVIEW NDA: 22-345 Brand Name: Potiga™ Tablets Generic Name: Ezogabine Sponsor: Valeant Pharmaceuticals & GlaxoSmithKline Type of Dosage Form: Immediate release film-coated tablet Strengths: 50, 200, 300, and 400 mg Indication: Adjunctive treatment of partial onset seizures OCP Reviewers: Ta-Chen Wu, Ph.D. OCP Team Leader (Acting): Veneeta Tandon, Ph.D. OCP Division: DCP-1 HFD-860 OND Division: Division of Neurology Drug Products HFD-120 Submission Date: April 15, 2011 Type of Submission: Complete Response (Class 1) Resubmission BACKGROUND: The Sponsor submitted a complete response to the Agency’s Complete Response Letter, including labeling recommendation, dated November 30, 2010. The NDA 22-345 for POTIGA (ezogabine) tablets was originally submitted on October 30, 2009. The proposed indication is adjunctive treatment of partial onset seizures in patients 18 years of age and older. Noted in this complete response resubmission the Sponsor proposed to increase the maximum maintenance dose to 1200 mg/day (400 mg tid). To support the changes in labeling languages in Clinical Pharmacology sections, the Sponsor provided three supporting documents with respect to potential for digoxin interaction with ezogabine, hepatic impairment dosing guidance, and potential for antiepileptic drugs (AED) drug interaction with ezogabine. The main changes of the labeling recommendations are summarized below. 1. Potential for Digoxin Interaction with Ezogabine: Sections of digoxin interaction were added, as presented below. 7.2 Digoxin Data from an in vitro study showed that the N-acetyl metabolite of ezogabine (NAMR) inhibited P-glycoprotein–mediated transport of digoxin in a concentration- dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of POTIGA at therapeutic doses may increase digoxin serum concentrations. Serum levels of digoxin should be monitored [see Clinical Pharmacology (12.3)]. 1 Reference ID: 2956199 (b) (4) Rationale: The N-acetyl metabolite of ezogabine (NAMR) inhibited digoxin transport in a concentration-dependent manner in an in-vitro study. Efflux inhibitions on P- glycoprotein (P-gp) transport activity for digoxin (a probe substrate) were 33%, 56%, and 70% with NAMR concentrations of 1μM (264ng/mL), 10μM (2643 ng/mL), and 100μM (26430 ng/mL), respectively. The I/IC50 ratios for NAMR were estimated to be >0.1, and thus the inhibitory potential on P-gp mediated digoxin elimination via kidney exists, especially when the maximum maintenance dose is increased to 1200 mg/day. The Table below details the mean steady-state NAMR concentrations observed in the pivotal clinical Study VRX-RET-E22-301 in epileptic patients and the correlation with the in vitro results. A formal IC50 for NAMR was not calculated however the value of 2643 ng/mL could be considered close to the IC50 value. OCP Recommendation: Based on an in vitro study, NAMR metabolite was found to be an inhibitor of the efflux transporter P-gp at concentrations of NAMR expected after administration of proposed doses therapeutic levels of ezogabine. Therefore, we request that the sponsor conduct a study in humans as a Post Marking Requirement (PMR) to investigate the impact of NAMR as an inhibitor for P-gp using digoxin as a probe substrate. 2. Hepatic Impairment Dosing Guidance: The Sponsor proposes to reduce the starting dose to half (i.e., 50 mg tid) and the maximum maintenance dose to 600 mg/day for patients with moderate hepatic impairment, as oppose to the 750 mg/day recommended by the Agency based on the approximate 50% increase in systemic exposure of ezogabine. Per the Sponsor, the proposed dosing regimens are based on the pharmacokinetic simulations for different starting doses. In addition, the starting dose of 100 mg tid would results in greater variability in this patient population. ”The predicted steady state ezogabine Cmax and AUC(0-24) values for the initial starting dose of 100 mg TID were generally similar to or 2 Reference ID: 2956199 higher than those predicted for healthy subjects, whereas, a reduction in the initial starting dose to 50 mg TID showed that the individual predicted steady state Cmax and AUC(0-24) values were completely contained within the range of the values predicted for healthy subjects.” With that, the sponsor proposed to reduce both starting and maintenance doses in patients with moderate hepatic impairment to ½. Reviewer’s comment: Based on results of the dedicated hepatic impairment study, the maintenance dose of 750 mg/day as recommended for patients with moderate impairment is expected to have similar AUC to that observed in healthy subjects; whereas the 600 mg/day would result in lower exposure. However, we do not consider the Sponsor’s arguments, including the in- house PK simulation, convincing against the maximum 750 mg/day in this patient population. In addition, details of the simulation to support the Sponsor’s claim were not available for the Agency’s review. Details of the dosing instruction are presented in “Section 4. Dosing Recommendations for Specific Populations”of this review. 3. Potential for AED Drug Interaction with Ezogabine: The Sponsor does not agree with FDA suggestion to include the information regarding phenytoin and carbamezepine from Study 3065A1-202 in the Drug Interaction Section (Section 7). Specifically, citing limited numbers of subjects in Study 3065A1-202, the Sponsor proposes to rely on results of population PK analysis of pooled data to show that concomitant AEDs had no significant impact on ezogabine. The Sponsor acknowledges the inducing effect of phenytoin and carbamezepine on ezogabine clearance but proposes no dose adjustment. Reviewer’s comment: The Agency believes that the numbers of the subjects, though relatively limited, who were on concomitant phenytoin and carbamezepine from this specific study were sufficient enough to warrant dosage adjustment based on the observed inducing effects. Therefore, the recommended labeling languages for the pertinent drug-interaction sections have been revised and presented in a tabular format, as shown below. 7. DRUG INTERACTIONS 7.1 Antiepileptic Drugs The potentially significant interactions between POTIGA™ and concomitant AEDs are summarized in the following Table: AED Dose of POTIGA™ Influence of Influence of AED Dosage AED Dose POTIGA™ on POTIGA™ Adjustment (mg/day) (mg/day) on AED Carbamazepine a * 600-2400 300-1200 None 31% decrease Consider an increase in in AUC; POTIGA™ dosage b 23% decrease in Cmax; Phenytoin a * 120-600 300-1200 None 34% decrease Consider an increase in in AUC; POTIGA™ dosage b 18% decrease in Cmax; a Based on trough concentrations in a Phase 2 study 3 Reference ID: 2956199 (b) (4) * Inducers for uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs) [See Clinical Pharmacology (12.3)] 12.3 Pharmacolokinetcs Interactions with Antiepileptic Drugs: The interactions between POTIGA and concomitant AEDs are summarized in the following Table: AED a Dose of POTIGA Influence of Influence of AED Dosage AED Dose POTIGA on POTIGA Adjustment (mg/day) (mg/day) on AED Carbamazepine b * 600-2400 300-1200 None 31% decrease An increase in in AUC; POTIGA™ dosage 23% decrease in needs to be Cmax; considered c 28% increase in clearance; 5.3-hours shortening in half-life Phenytoin b * 120-600 300-1200 None 34% decrease An increase in in AUC; POTIGA™ dosage 18% decrease in needs to be Cmax; considered c 33% increase in clearance Topiramate b 250-1200 300-1200 None None None Valproate b 750-2250 300-1200 None None None Phenobarbital 90 600 None None None Lamotrigine 200 600 18% decrease in None None AUC; 22% increase in clearance; 5-hours shortening in half-life Others d None None None (b) (4) (b) (4) * Inducers for uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs) 4. Dosing Recommendations for Specific Populations: Dosing Recommendations for Specific Populations in Section 2 of the label have been revised to a tabular format, as presented below. 2. DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions 4 Reference ID: 2956199 Table 1. Dosing Recommendations Specific Population Initial Dose Titration Maximum Dose General Dosing General population 100 mg 3 times Increase by no more 400 mg 3 times (including patients daily than 50 mg 3 times daily with mild renal or (300 mg per day) daily, at weekly (1,200 mg per day) hepatic impairment) intervals Dosing in Specific Populations Geriatrics (patients >65 years) 50 mg 3 times daily 250 mg 3 times (150 mg per day) daily (750 mg per day) Renal impairment (patients with CrCL <50 mL per min or 50 mg 3 times daily 200 mg 3 times end-stage renal (150 mg per day) daily disease on dialysis) Increase by no more (600 mg per day) than 50 mg 3 times Hepatic impairment (patients with Child- 50 mg 3 times daily daily, at weekly 250 mg 3 times Pugh 7-9) per week intervals daily (150 mg per day) (750 mg per day) Hepatic impairment 200 mg 3 times (patients with Child- 50 mg 3 times daily daily Pugh >10) per week (600 mg per day) Deleted: / (150 mg per day) CONCLUSIONS AND RECOMMENDATIONS: The Office of Clinical Pharmacology/Division of Clinical Pharmacology 1 (OCP/DCP- 1) has reviewed the Sponsor’s complete response for the NDA 22-345, including the labeling, and finds it acceptable from an OCP perspective provided that the Sponsor agrees with the Phase IV commitment (PMR). In addition, agreement on the labeling language should be reached between the Sponsor and the Agency. PHASE IV RECOMMENDATIONS: The office of Clinical Pharmacology requests the following PMR: A study in humans for the evaluation of the acetyl metabolite of ezogabine (NAMR) as an inhibitor for P-glycoprotein (P-gp) using digoxin as a probe substrate 5 Reference ID: 2956199 Ta-Chen Wu, Ph.D.