CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 22-253 & 22—254
`
`SUMMARY REVIEW
`
`

`

`' Deputy Office Director Decisional Memo
`
` Date October 28, 2008
`
`
`
`From
`Ellis F. Unger, M.D., Deputy Director (acting), ODEl
`
`
`Subject
`1 Deputy Office Director Decisional Memo
`
`NDA/BLA #
`22-253, 22-254, ' §=~
`‘
`(1(4)
`
`
`
`
`Supplement #
`000
`.
`
`
`Applicant Name
`Schwarz Biosciences
`
`Date of Submission A
`September 28, 2007
`
`
`
`PDUFA Goal Date
`i October 28, 2008 (extended from July 28, 2008)
` Proprietary Name /
`
`
`-
`
`Vi‘mpat
`
`Lacosamide
`Established (USAlfl) Name
`
`
`Dosage Forms / Strength
`Tablets 50-, 100—, 150-, and ZOO-mg; 200 mg/ZOmL
`
`
`single—use vial for intravenous use
`
`
`Proposed Indication(s)
`_ 1.
`For the treatment of epilepsy as adjunctive therapy
`
`
`
`in subjects with partial onset seizures aged 16
`
`years and older (tablets)
`'
`
`....when oral administration is temporarily not
`2.
`
`feasible (200 mg/mL IV)
`
`
`
`A rovalfor22—253,22-254' N'
`
`
`
`
`
`
`
`Microbiology Review
`
`Material Reviewed/Consulted ‘
`OND Action Pack_age, including:
`
`Norman Hershkowitz
`Medical Officer Review
`
` Tristan Massie
` Statistical Review
`
` Safety Review
`Lourdes Villalba, Sally U. Yasuda (sumrvisoryi
`
`Pharmacology Toxicology Review
`BeLinda A. Hayes, Ed Fisher, Lois M. Freed
`(sumisgy), Paul C. Brown tertiary}
`
`CMC Review/O'BP Review
`Wendy 1. Wilson, Prufull Shiroman, Blair Fraser
`
`(su ervisoryi
`
`Vinayak B. Pawar Clinical Pharmacology Review Veneeta Tandon, Lei Zhang, Emmanuel Fadiran, and
`
`Hao Zhu
` DMEPA
` Loretta Holmes
`DSI
`
` Shgyl Gunther
` CDTL Review
`
`Norman Hershkowitz
`
` OSE/DRISK
`Sharon R. Mills
`
` OSE/ Division of Medication Errors Judy Park
`Cardiac safety
` Stephen M. Grant
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE=Office of Surveillance and Epidemiology
`DMETS=Division of Medication Errors and Technical Support
`DSI=Division of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DSRCS=Division of Surveillance, Research, and Communication Support
`CDTL=Cross—Discipline Team Leader
`
`

`

`I concur with Dr. Russell Katz, Director, Division of Neurology Products, in his
`recommendation to approve Vimpat (lacosamide) tablets for adjunctive treatment of partial
`seizures in adult patients with epilepsy, and to approve Lacosamide Injection for the same
`indication when oral administration is temporarily not feasible.
`
`There were no notable disagreements or issues between disciplines (microbiology, CMC,
`nonclinical pharmacology/toxicology, clinical pharmacology, clinical, biostatistical) or within
`review discipline hierarchies (primary, secondary, tertiary reviewers).
`
`The evidence of effectiveness and safety was based on studies of the oral tablet form (NDA
`22—253). The NDAs for the
`*—'——‘
`intravenous injection were supported by
`bioequivalence to the tablet.
`"’—
`,
`
`
`at
`
`13(4)
`
`Initial review of the NDA raised concern regarding a multiorgan hypersensitivity syndrome,
`and the Division asked the sponsor to submit more detailed analyses of this issue. They
`submitted their analysis on 7/ 16/08, resulting in a 3-month extension of the PDUFA goal date.
`The sponsor also submitted NDA """ for the use of lacosamide for the treatment of the
`pain of diabetic peripheral neuropathy. That application was reviewed by the Division of
`
`Analgesic, Anesthetic, and Rheumatology Products (DAARP), and not approved
`
`
`Effectiveness: The applicant established lacosamide’s effectiveness as adjunctive therapy in
`partial—onset seizures (with or without secondary generalization) in three 12-week,
`randomized, double-blind, placebo—controlled, multicenter trials in adult patients (studies 667,
`I 754, and 755). The studies were similar in their designs and analytic plans.
`
`Study 667 compared doses of 200—, 400-, and 600—mg/day with placebo. Study 754 compared
`doses of 400— and 600-mg/day with placebo. Study 755 compared doses of 200- and 400—
`mg/day with placebo. All three studies included an 8—week baseline period to establish seizure
`frequency prior to randomization, and ensure a frequency of at least 4/week with no seizure-
`free period exceeding 21 days, despite use of 1 to 3 concomitant antiepileptic drugs. The
`baseline period was followed by a 6—week titration phase (only 4 weeks long in study 755).
`Subjects randomized to lacosamide were begun at a dose of 100 mg/day (50 mg given twice
`daily), and increased weekly in 100 mg/day increments to the target dose. All 3 trials included
`a 12-week maintenance phase, during which patients were to remain on a stable dose of
`lacosamide.
`
`The primary outcome measure was reduction from baseline in 4 week seizure frequency
`during the maintenance phase, analyzed by an ANCOVA with terms for treatment and region,
`based on log—transformed seizure frequency, with log-transformed average baseline seizure
`frequency as the covariate. Testing was to be hierarchical, with the highest dose tested first,
`followed by progressively lower doses. The sponsor’s results are shown in Table 1.
`
`

`

`Table 1: Basic Features and Efficacy Endpoints — Studies 667, 754, 755
`
`Australia
`
`Location
`
`Daily dose
`
`placebo
`
`400 mg
`600 mg
`placebo
`
`200 mg
`400 mg
`placebo
`
`Europe,
`
`755
`
`.
`o
`A reduction
`vs. placebo
`
`14.6%
`28.4%
`21.3%
`
`21.6%
`24.6%
`
`14.4%
`15.0%
`
`95% Cl
`
`(~32, 29.4)
`(11.3, 42.2)
`(6.0, 34.1)
`
`(6.3, 34.5)
`(7.8, 38.3)
`
`0.101
`0.0023
`0.0084
`
`0.0078
`0.0061
`
`0.0223
`0.0325
`
`(2.2, 25.1)
`(1.4, 26.8)
`
`For the 3 studies, subjects had a mean duration of epilepsy of 24 years and a median baseline
`seizure frequency ranging from 10—17 per 28 days. Eighty-four percent (84%) of subjects
`were taking 2 to 3 concomitant antiepileptic drugs, with or without concurrent vagal nerve
`stimulation.
`
`All 3 studies showed a fairly robust treatment effect that survived sensitivity analyses and
`different imputation paradigms for missing data. The results were also positive if seizures that
`occurred during the Titration Phase were considered in the analyses. Study 667 (but not 75 5)
`provided evidence in favor of greater efficacy of the 400-mg daily dose versus the 200—mg
`daily dose; however, both studies that included a 600—mg daily dose (667 and 754) failed to
`show that the 600—mg daily dose was more efficacious than the 400—mg daily dose. In all 3
`studies, there was a clear dose response for adverse events, as well as for discontinuations for
`adverse events.W '
`‘
`Re“.
`
`0(4)
`
`Safety: I agree with the Division’s conclusions regarding safety of lacosamide, with one
`slight exception. In the controlled studies in the epilepsy patient population, 2 lacosamide-
`treated subjects and l placebo—treated subject experienced syncope. The Division had a
`tendency to consider these 3 events in isolation, and declare that there was no signal for
`syncope in the epilepsy patient population. However, a total of 36 lacosamide—treated subjects
`experienced syncope in phase 2 and 3 studies in all indications, compared to only 2 placebo—
`treated subjects. In open-label epilepsy studies; an additional 8 subjects experienced an
`episode of syncope; 2 had received 400 mg/day, and the remainder had received 2 500
`mg/day. In Phase 1 studies, 4 subjects (all on lacosamide) experienced syncope. Thus, it is
`appropriate that the labeling include a warning/precaution for syncope. Although the risk may
`be lower in patients with epilepsy than in patients with diabetic neuropathy (the latter may
`have dysautonomia and cardiovascular disease, and have concomitant use of multiple
`cardiovascular medications), the risk should not be minimized in the epilepsy population.
`
`

`

`The sponsor has agreed to conduct an in vitro postmarketing study to determine which
`enzymes may be involved in the metabolism of lacosamide in addition to CYP2C19.
`
`Abuse and Dependence
`
`According to Dr. Bonson of CSS, in a human abuse study in subjects with a history of abuse of
`CNS active agents, 200-800 mg lacosamide produced subjective responses on visual analogue
`scales of drug liking that were different from placebo and similar (at the 800 mg dose) to
`alprazolam, a Schedule IV drug. Further, there were reports of euphoria in Phase 1 studies in
`healthy volunteers, as well as a high rate of “feeling drunk” in another Phase 1 study in healthy
`individuals. For these reasons, CSS has recommended that lacosamide be scheduled in
`Schedule IV of the Controlled Substances Act.
`
`As noted by Dr. Katz, “. . .the sponsor continues to disagree with CSS’s recommendation that
`lacosamide be placed in Schedule IV of the CSA. The sponsor has, in effect, appealed this
`recommendation, and has had a telephone conference with Dr. Doug Throckmorton, Deputy
`Director of CDER, and staff of DNP and CSS to discuss this. Subsequent to this conference,
`the sponsor has submitted additional data requested by Dr. Throckmorton, who will be
`reviewing it. Clearly, a decision about scheduling will not have been made by the PDUFA date
`(today). Nonetheless, we recommend that these applications be approved today, and we have
`come to an agreement with the sponsor on language for labeling describing the data addressing
`abuse potential. It is important to point out that, by signing FDA form 356H, the sponsor has
`agreed to not market the product until a final decision on scheduling has been made.” The
`Approval letter will remind the sponsor of their commitment in this matter.
`
`NDA 22-254
`
`\=— for use of
`I also agree with the DivisiOn’s recommendation to approve
`lacosamide intravenous injection for the treatment of partial seizures in adults with epilepsy,
`based on a finding of bioequivalence between a 200-mg dose of the infusion given as a 30 or
`60 minute infusion and 2 X lOO—mg tablets in 27 healthy volunteers (study 658).
`
`The safety of the IV formulation was demonstrated in approximately 200 subjects who
`received intravenous infusions of lacosamide as replacement for their oral doses (same dosing
`regimen and daily dose as their oral dose) for 2-5 days. In study 757, 160 subjects received 2
`5 days of IV lacosamide infused over 10 (n=20), 15 (n=100), or 30 (n=40) minutes. All
`subjects received 2200 mg/day, and 65 subjects received daily doses of 2400 mg given over 15
`minutes. A total of 32 subjects received doses of 2 400 mg/day given over 30 minutes. No
`new or concerning adverse events were observed.
`
`l1(4)
`
`.————-
`
`/
`
`//
`
`

`

`Pharmacology/Toxicology
`
`There are no pharmacology issues that would preclude approval. However, adverse effects on
`neurodevelopment observed in a juvenile rat study, as well as a suggestion of effects on
`learning and memory in the offspring in the pre—and post-natal development rat study, argue
`for further evaluation of this finding in a non-clinical study. All agree that this can be
`performed post-marketing.
`
`Conclusions and Recommendations
`
`I concur with the Division’s recommendation to approve NDAs 22—253 and 22—254, with
`attached labeling. The sponsor has submitted adequate evidence of safety and substantial
`evidence of effectiveness for the use of lacosamide oral tablets as adjunctive treatment for
`partial seizures in adults with epilepsy. They have also demonstrated bioequivalence of the
`intravenous solution of lacosamide to lacosamide oral tablets, when given as either a 30 or 60
`minute infusion. There is some evidence of dose response between 200 and 400 mg/day, but
`no appreciable increment in effectiveness with 600 mg/day, despite a considerable increase in
`adverse events. Therefore, the recommended dose range will be 200—400 mg/day, given in a
`BID regimen. Under these circumstances, it is appropriate to display the adverse events in the
`600-mg treatment group in labeling, and this is planned.
`‘
`
`Labeling will include the new class warning regarding an increased risk of suicidal thoughts
`and behaviors (as recommended by the PCNS Advisory Committee). Labeling will also
`include prominent language regarding dizziness and ataxia, PR prolongation, and syncope, as
`particular issues of concern. Labeling will also include a new class Medication Guide.
`
`There will be Phase 4 commitments for the sponsor to study brain changes in developing rats,
`with drug given throughout the period corresponding to the relevant period in human
`development, as well as an in vitro study to determine which enzymes, in addition to
`CYP2C19, may be involved in the metabolism of lacosamide. Furthermore, the Division will
`require that the sponsor perform adequate trials in pediatric patients with partial seizures from
`the ages of 1 month to 16 years of age as a Post Marketing Requirement (as with other AEDs
`initially approved in adults).
`
`/
`
`/
`
`7,
`
`/
`
`/
`
`/
`
`11(4)
`
`11(4)
`
`11(4)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Ellis Unger
`. 10/28/2008 06:12:15 PM
`MEDICAL OFFICER
`
`

`

`MEMORANDUM
`
`DATE:
`
`October 28, 2008
`
`FROM:
`
`Director
`Division of Neurology Products/HFD-120
`
`“(4)
`
`TO:
`
`File, NDA 22—253, 22-254
`
`”unfi—
`
`SUBJECT: Recommendation for action on NDAs 253, 22-254,_ ~——— , for the
`use of VlMPAT (lacosamide) tablets, solution, and injection, respectively, as
`adjunctive treatment for partial seizures in adult patients with epilepsy.
`
`M4)
`
`NDAs 22-253, 22-254, am i, for the use of VlMPAT (lacosamide) tablets,
`solution, and injection, respectively, as adjunctive treatment for partial seizures in
`adult patients with epilepsy, were submitted by Schwarz Biosciences on 9/28/07.
`Essentially all of the safety and effectiveness data were generated with the tablet
`dosage form (NDA 22-253), with the NDAs for the
`Qua-ma
`intravenous
`injection relying on bioequivalence to the tablet formulation.
`'
`
`33(4)
`
`NDA 22-253 contains reports of three adequate and well-controlled studies
`(Studies 667, 754, and 755) in adult patients with partial seizures in which
`lacosamide was given as adjunctive therapy.
`In addition, the requisite safety,
`CMC, and non-clinical data were submitted. Because initial review of the
`applicatiOn revealed the capacity of lacosamide to cause a multi—organ
`hypersensitivity syndrome that the sponsor had not adequately investigated, we
`asked the sponsor to submit more detailed analyses of this issue. This analysis
`was submitted on 7/16/08, and resulted in an extension of the PDUFA goal date.
`At the same time that them NDAs referred to here were submitted, the
`sponsor also submitted NDA Nfor the use of lacosamide in the treatment
`of the pain of diabetic peripheral neuropathy, to the Division of Analgesic,
`Anesthetic, and Rheumatology Products. That application was Not Approved,
`~—__~>_M
`
`m4)
`
`These NDAs have been reviewed by Dr. Lourdes Villalba, safety reviewer, Dr.
`Sally Yasuda, Safety Team Leader, Dr. Tristan Massie, statistician, Drs. Vaneeta
`Tandon, Lei Zhang, Emmanuel Fadiran, and Hao Zhu, Office of Clinical
`Pharmacology, Drs. BeLinda Hayes and Ed FiSher, pharmacologists, Dr. Lois
`Freed, Pharmacology Team Leader, Dr. Paul Brown, ODE Associate Director for
`Pharmacology and Toxicology, Drs. Wendy Wilson and Prufull Shiroman,
`chemists, Dr. Stephen Grant, cardiology reviewer, Dr. Katherine Bonson,
`Controlled Substance Staff, Dr. Ling Chen, statistician, Dr. Judy Park, Division of
`Medication Errors, Dr. Sheryl Gunther, Division of Scientific investigations, and
`Dr. Norman Hershkowitz, Neurology Team Leader. The review team
`recommends that lacosamide oral tablets and intravenous injection be approved
`for use as adjunctive treatment for partial seizures in adults with epilepsy.
`
`

`

`6(4) '
`
`In this memo, I will briefly review the relevant effectiveness and safety data
`submitted in support of the epilepsy indication, and offer the division’s
`recommendation for action on these r“— NDAs.
`
`5(4)
`
`EFFECTIVENESS
`
`As noted above, the sponsor submitted reports of three adequate and well-
`controlled trials in support of the proposed claim for the use of lacosamide as
`adjunctive treatment for partial seizures in adults with epilepsy.. I will briefly
`review the results of these trials.
`
`Study 667
`
`This was a randomized, multi-center (US and Europe), double-blind, parallel
`group trial in which patients being treated with 1 or 2 anti-epileptic drugs (AEDs)
`were randomized to receive either lacosamide 200 mg/day, 400 mg/day, 600
`mg/day, or placebo, given Q 12 Hours. After an 8 week Baseline Phase, in
`which patients were required to have an average of at least 4 seizures/4 weeks,
`patients were entered into a 6 week titration phase, then a 12 week Maintenance
`Phase. Patients entering an open-label extension then entered a 2 week
`Transition Phase; those choosing not to continue were withdrawn from drug over
`3 weeks.
`
`The primary outcomemeasure was Reduction From Baseline in 4 Week Seizure
`Frequency During the Maintenance Phase, analyzed by an ANCOVA with terms
`for treatment and region, based on log transformed seizure frequency, with log-
`transformed average baseline seizure frequency as the covariate. Testing was
`to be hierarchical, with the highest dose tested first and mid—and low-doses
`tested sequentially.
`
`Secondary outcome measures were proportion of responders (those with at least
`a 50% decrease in seizure frequency compared to baseline), reduction in seizure
`frequency for the entire treatment phase, seizure-free status, Clinical Global
`impression of Change, and many others.
`
`Results
`
`A total of 421 patients were randomized, and a total of 418 had at least one post-
`baseline efficacy evaluation. A total of 347 patients completed titration, 321
`(77%) completed maintenance, and 312 (75%) completed the entire trial.
`Discontinuations due to adverse events were clearly dose-related. The following
`percentage of discontinuations for adverse events by dose are described below:
`
`,
`
`

`

`Percent Discontinuations for Adverse Events by Dose
`
`Placebo
`
`200 mg/day
`400 mg/day
`600 mg/day
`
`5%
`
`15%
`19%
`30%
`
`The following results on the primary outcome measure, derived by Dr. Massie,
`are described:
`
`Median Percent Reduction in Seizure Frequency Compared to Placebo
`
`Dose
`
`200 mg/day
`400 mg/day
`600 mg/day
`
`N
`
`107
`107
`105
`
`P-value vs Pbo
`
`-14.8%
`-27.9%
`-21.5%
`
`0.14
`0.003
`0.026
`
`In general, the results were comparable across multiple analyses using different
`imputation schemes for missing data.
`If all seizures were counted, including
`those that occurred during the Titration Phase, the corresponding percent
`changes from baseline compared to placebo were about 7%,'20%, and 28% for
`the 200, 400, and 600 mg/day doses, respectively. The differences in proportion
`of responders compared to placebo were 12%, 19%, and 16% for the 200, 400,
`and 600 mg/day doses, respectively.
`
`Study 754
`
`This was of similar design as Study 667, except there were only 3 groups
`(placebo, 400, and 600 mg/day) and the study was performed entirely in the US.
`
`Results
`
`A total of 405 patients were randomized, and all received at least one dose and
`had at least one effectiveness assessment. Discontinuations due to adverse
`events were again dose related (5%, 18%, and 27% for placebo, 400, and 600
`mg/day groups, respectively).
`
`The results of the analyses of the primary outcome, performed by Dr. Massie, are
`given below:
`
`

`

`Median Percent Reduction in Seizure Frequency Compared to Placebo
`
`Dose
`
`400 mg/day
`600 mg/day
`
`N
`
`201
`97
`
`P:value vs Pbo
`
`—21.2%
`-24.8%
`
`0.011
`0.009
`
`In general, the results were similar regardless of imputation methods used for
`missing data.
`If all seizures are included (not just those during Maintenance), the
`corresponding reductions from baseline compared to placebo are 12.8% and
`11.7% for the 400 and 600 mg/day groups, respectively. The differences in
`responder rate compared to placebo were 21% and 23% for the 400 and 600
`mg/day groups, respectively.
`
`Study 755
`
`This was a study of similar design as the two previously described studies,
`except there were 3 arms (placebo, 200 mg/day, and 400 mg/day), the study was
`performed in Europe and Australia, and there was a 4 week (as opposed to a 6
`week) TitrationPhase.
`
`Results
`
`A total of 485 patients were randomized, and all 485 received at least one dose
`and had at least one effectiveness evaluation. Discontinu'ations due to adverse
`events were dose related, with 5.5%, 6%, and 16% discontinuing for adverse
`events in the placebo, 200, and 400 mg/day groups, respectively.
`
`The following analyses, performed by Dr. Massie, are presented:
`
`Median Percent Reduction in Seizure Frequency Compared to Placebo
`
`Dose
`
`200 mg/day
`400 mg/day
`
`N
`
`160
`158
`
`P-value vs Pbo
`
`-1 3.6%
`—27.3%
`
`0.05
`0.027
`
`In general, the results were similar regardless of imputation methods used for
`missing data.
`If all seizures are included (not just those during Maintenance), the
`corresponding reductions from baseline compared toplacebo are 11.4% and
`15% for the 200 and 400 mg/day groups, respectively. The differences in
`responder rate compared to placebo were 9% and 15% for the 400 and 600
`mg/day groups, respectively.
`
`

`

`SAFETY
`
`A total of 944 patients were randomized to lacosamide oral tablets in controlled
`trials of patients with epilepsy. A total of 1327 patients with epilepsy were
`exposed to lacosamide in controlled and uncontrolled trials.
`In addition, a total of
`644 healthy volunteers received at least one dose of an oral formulation of
`lacosamide in 21 Phase 1 studies (including pharmacokinetic, abuse liability, QT,
`drug interaction, and special population studies).
`
`In epilepsy studies, a total of 1000 patients received lacosamide for at least 6
`months (2163 patient—years), and 590 patients received lacosamide for at least 2
`years (1704 patient-years).
`'
`
`’A total of 133 patients received at least 400 mg/day for 6 months to 1 year. A
`total of 334 patients received at least 400 mg/day for 1—2 years.
`
`Further, a total of 2001 patients with neuropathic conditions (1939 with painful
`diabetic neuropathy) were exposed to lacosamide. This memo will largely be
`restricted to a description of the safety in the epilepsy population, but, as with Dr.
`Villalba’s review, I will also highlight those findings from the diabetic population
`where they differ from the findings in the epilepsy population.
`
`Deaths
`
`There was one death in a patient treated with lacosamide in controlled trials in
`epilepsy (a 63 year old man with a history of depression who committed suicide
`upon learning his wife was diagnosed with cancer; he had received 68 days of
`treatment and it was unclear if he had received drug in the preceding 3 weeks),
`and no deaths in placebo treated patients. There weree8 deaths in open-label
`treatment, 4 of which were consistent with Sudden Unexplained Death in
`Epilepsy (SUDEP). As noted by Dr. Villalba, this yields a SUDEP rate of .002
`deaths/patient—year, a rate consistent with that with other AEDs. None of the
`other deaths were reasonably attributable to drug (see Dr. Villalba’s review,
`. Table 6, pages 23-25).
`
`In the diabetic population, there were 4 deaths in controlled trials (out of 1023
`lacosamide treated patients), and 11 additional deaths in open-label treatment,
`and no deaths in placebo-treated patients. A total of 8 deaths were related to
`cardiovascular events (3 in controlled trials; v. fib, Ml, heart failure, myocarditis,
`cardiac arrest, and sudden death). All of these patients had pre-existing
`cardiovascular disease. Thelother deaths were unlikely related to drug
`(including 5 cancers, all of different type).
`
`The mortality in all controlled trials (regardless of indication) was 0.3% in
`lacosamide-treated patients (5/1967) and 0% in placebo-treated patients.
`
`

`

`Serious Adverse Events
`
`In epilepsy controlled trials, the rate of SAEs was 6.5% in lacosamide— and 3.8%
`in placebo-treated patients. There was no dose—response for SAEs.
`
`The most common SAEs were Nervous System disorders (2.1% vs 1.6% in
`placebo), Psychiatric disorders (0.7% vs 0% in placebo), and Gastrointestinal
`disorders (0.6% vs 0.3% in placebo).
`In the Nervous System category, seizures
`of various type were the most frequently reported, but not at a rate greater than
`in the placebo group. The most frequent SAE in the Nervous System category
`was Dizziness, in 3/203 patients treated with 600 mg/day, compared to 0/364
`placebo treated patients.
`
`In the Psychiatric disorders group, there was no SAE that occurred in more than
`one patient, except Psychotic Disorder, which occurred in 2/471 patients treated
`with lacosamide 400 mg/day, compared to 0/364 placebo-treated patients.
`In
`only one of these patients was the psychosis considered treatment related (52
`year old man with a history of depression, delusional disorder, panic attacks, and
`psychotic disorder [all poorly documented], who behaved “strangely" after 11
`days at 400 mg/day). Twenty days after treatment discontinuation, the behaviors
`were not resolved.
`'
`
`No GI SAEs were of concern.
`
`In open-label treatment, no additional particularly important events were
`considered to have been related to treatment, save for the following.
`
`A 30 year old man experienced several episodes of dizziness %-1 hour after
`various lacosamide doses (400-1000 mg/day). Twelve days after discontinuing
`treatment, he developed nausea, abdominal discomfort, fatigue, and brown urine.
`Three days after this, his AST was 1550 U/L, ALT 422 U/L, gamma—GT 982 U/L,
`proteinuria and casts. Bilirubin was not measured at that time, but several days
`later was normal, when the AST and ALT were markedly improved. Tests for
`viral hepatitis were normal.
`
`There was a patient with hallucinations in the epilepsy trials, but that patient was
`also taking recreational psychoactive drugs (amphetamine, marijuana). Another
`patient who received 600 mg/day for 2 days (he had been titrated to this dose) in
`a study of an oral capsule developed visual hallucinations. He was treated with
`IV lorazepam, his dose was dropped to 400 mg/day, and he recovered.
`
`In the diabetic population, most of the SAEs were Cardiac disorders (angina,
`coronary artery disease, a. rib, a. flutter., bradycardia). Although the frequency
`of cardiac SAEs were the same between drug and placebo (ZS-2.9%), most-of
`the conduction/rhythm abnormalities were in the drug-treated group. Of
`particular concern was the frequency of syncope in this population (7.3% on drug
`
`

`

`vs 2.4% in placebo-treated patients). A total of 0.5% (5/1023) lacosamide-
`treated patients discontinued treatment in controlled trials compared to 0 placebo
`patients due to syncope. Most of these cases were not monitored with EKG; in
`the few that were, those with apparent cardiac etiology were seen at a dose of
`600 mg/day.
`
`Discontinuations due to Adverse Events
`
`A total of 17% of lacosamide-treated patients discontinued controlled trials in
`epilepsy, compared to 5% of placebo—treated patients. These were clearly dose-
`related, as seen below:
`
`Placebo
`
`200 mg/day
`400 mg/day
`600 mg/day
`
`4.9%
`
`8.1%
`17.2%
`28.6%
`
`Almost all of the events reported by System Organ Class (SOC) that resulted in
`treatment discontinuation were dose related (see Dr. Villalba’s Table 19, pages
`47-8). The most common SOCs in which discontinuations occurred were
`Nervous System (9.9% vs 2.5% in placebo), Gl (3.2% vs 0.8%), Eye Disorders
`(3% vs 0.3%), General (1.7% vs 0.3%), Psychiatric (1.6% vs 0%), and Ear and
`Labyrinth Disorders (1.4% vs 0%), and almost all of these were dose-related.
`
`The following table displays those events that resulted in treatment—
`discontinuation, were dose related, and for which the frequency in the 600
`mg/day dose was greater than 1%:
`
`Event
`
`Dizziness
`Coordination
`
`Abn’l (Ataxia)
`Nausea
`Vomiting
`Blurred Vision
`Tremor
`Nystagmus
`Diplopia
`Asthenia
`Fatigue
`
`Pbo
`
`.6%
`
`0%
`.3%
`.8%
`0%
`0%
`0%
`.3%
`0%
`.3%
`
`200 mg/d
`
`400 mg/d
`
`600 mg/d
`
`0.4%
`
`4.2%
`
`17.2%
`
`'
`
`0.4%
`0.4%
`0.4%
`0.4%
`0%
`0%
`1.5%
`0%
`0%
`
`1.3%
`1.7%
`2.3%
`0.6%
`0.6%
`0.2%
`2.1%
`0%
`0.7%
`
`5.4%
`3.9%
`3.0%
`3.0%
`2.5%
`2.5%
`2.0%
`2.0%
`1.5%
`
`Additional patients had their close of lacosamide decreased due to adverse
`events (see Dr. Villalba’s Table 27, page 58). Similar events as those resulting in
`
`

`

`treatment—discontinuation in the controlled trials in epilepsy also resulted in
`treatment discontinuation in the open-label epilepsy studies (see Dr. Villalba’s
`Table 28, page 59 and Table 29, page 61).
`
`Common Adverse Events
`
`In controlled trials in epilepsy, a total of 81% of lacosamide-treated patients
`experienced at least one adverse event compared to 65% of placebo-treated
`patients. Overall adverse events were dose related; those adverse events
`previously seen to be dose related and considered as serious or that led to
`discontinuation and described above were also dose related when the total
`frequency were considered (see Dr. Villalba’s Table 58, page 108).
`
`In the diabetic population, the most common adverse events were also in the
`Nervous System, with the most common being Dizziness, occurring at a
`frequency of 83% in the 600 mg/day group.
`
`Laboratory Measures '
`
`There were no systematic changes in mean hematologic parameters or routine
`chemistries, including liver function tests. There were no systematicIncreases in
`the proportion of patients developing clinically important changesIn hematologic
`parameters, or in routine clinical chemistries.
`
`Vital Signs
`
`There were no systematic changes in mean blood pressure or pulse rate during
`the controlled trials in epilepsy. There was a slight increase in the proportion of
`patients who met outlier criteria at least once-for changes in blood pressure at
`the 600 mg/day dose compared to placebo as below:
`
`SBP increase of at least 20 mm Hg
`Pbo
`22.5%
`
`600 mm Hg 29.1%
`
`DBP Increase of at least 10 mm Hg DBP Increase of at least 20
`39.2%
`7.8%
`Pbo
`600 mm Hg 48.8%
`12.3%
`
`Most of these changes occurred once (see Dr. Villalba’s Table 69, page 125 for
`further details)
`
`EKG
`
`There was a dose related increase in mean PR interval in the controlled trials in
`
`epilepsy, as follows:
`
`

`

`APPEARS THIS WAY
`0N ORIGINAL
`
`Mean Change From Baseline in PR Interval (msec)
`
`Placebo
`200 mg/day
`400 mg/day
`600 mg/day
`
`-0.3
`1.4
`4.4
`6.6
`
`A similar pattern of increase in mean PR interval'was seen in Study 640, a
`thorough QT study. In that study, the maximum mean changes in PR interval on
`Day 6 were seen at 1 hour post-dose, and were 6.3, 13.6, and 18.2 msec in the
`placebo, 400, and 800 mg/day groups, respectively.
`In addition, at Tmax on Day
`6, there was a mean shortening of the QT interval of 9.4 msec compared to
`placebo at the 400 mg dose, and of 7.4 msec at the 800 mg dose. There were
`no important mean changes in other EKG parameters in either the controlled
`trials or in Study 640.
`
`There was a slight increase in the proportion of patients treated with Iacosamide
`that had at least one documented episode of PR increase of greater than 200 ms
`(8.8%) compared to placebo (4.5%), but this was not dose related. There was
`also a slight increase in the proportion of patients who had at least one episode
`of QRS duration greater than 120 ms on Iacosamide (2.6% and 3.5% on 400 and
`600 mg/day, respectively) compared to placebo (1 .4%).
`
`In Study 640, the following percent of patients had the described increase in PR
`interval in msec on Day 6:
`
`Dose
`
`~
`
`At least 200
`
`At least 220
`
`At least 250
`
`Placebo
`400 mg/day
`800 mg/day
`
`‘
`
`0
`1.8%
`13.5%
`
`O
`1.8%
`5.8%
`
`'
`
`0
`O
`1.9%
`
`There were no other important changes in EKG parameters seen in Study 640.
`
`In two of the controlled trials in epilepsy (Studies 744 and 745), a common
`central EKG reader was used.
`In these studies 'combined, the percentage of
`patients with a broad QRS was 3% in the placebo group and 12% in the 600
`mg/day group.
`
`

`

`A thorough QT study (Study 640) was perfdrmed at doses of placebo, 400 and
`800 mg/day.
`In this study, there were mean changes as follows at Day 6 (end of
`treatment):
`
`Mean Changes From Baseline at Day 6
`
`Placebo
`(N=55)
`
`400 mg/day 800 mg/day
`(N=57)
`(N=56)
`
`SBP (mm Hg)
`DBP (mm Hg)
`Pulse (BPM)
`
`-2.5
`2.0
`-6
`
`1.9
`3.9
`-1
`
`8.6
`10.3
`2.7
`
`There were no systematic changes in the proportion of patients who met criteria
`for orthostatic blood pressure or pulse changes in this study.
`
`Adverse Events of Special Interest
`
`Syncope
`
`There were a total of 36 lacosamide-treated patients who experienced an
`episode of syncope in Phase 2/3 studies in all indications, compared to 2
`, placebo-treated patients.
`in the epilepsy controlled studies, 2 lacosamide and 1
`placebo-treated patient experience syncope.
`In open-label epilepsy studies, an
`additional 8 patients had an episode of syncope; 2 were at 400 mg/day, and the
`rest were receiving at least 500 mg/day.
`In Phase 1 studies, 4 subjects (all on
`lacosamide) experienced syncope.
`-
`
`In the diabetes controlled trials, 13 lacosamide-treated patients experienced
`syncope compared to 0 placebo-treated patients; 11 were receiving 600 mg/day.
`Thirteen more patients experienced syncope in the open-label expe