CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 22-253 & 22-254
`
`MEDICAL REVIEW! S!
`
`

`

`CLINICAL REVIEW
`
`
`Application Type 22253, 22254 4.44»
`Submission Number 0
`
`12(4)
`
`-
`
`Letter Date
`_
`PDUFA GoalDate
`
`9/28/07
`10/28/08 (following extension)
`
`Reviewer Name Norman Hershkowitz, MD, PhD
`Review Completion Date
`10/28/08
`
`Established Name Lacosamide
`
`(Proposed) Trade Name Vimpat
`'
`Therapeutic Class Anticonvulsant
`Applicant Schwarz Biosciences Inc. (UCB)
`
`Priority Designation
`
`S
`
`Formulation
`
`1) Tablets 50,100 150, 200, 250 and 300 mg
`(22253)
`2)1V solution (22254)
`
`”(4)
`
`11(4)
`
`”
`
`
`‘ mg BID
`100, 200
`Sponsor’s Dosing Regimen
`‘ Indication Epilepsy of Partial Onset
`Intended Population Adjunctive Treatment >16 years
`
`M4)
`
`'
`
`

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`Clinical Review
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`{Insert Reviewer Name}
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`{Insert Product Trade and Generic Name}
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`
`
`Table of Contents
`
`1 EXECUTIVE SUMMARY
`
`..........................................................................................4
`
`INTRODUCTION .......................................................................................................................................................... 4
`BACKGROUND ...........................................................................................................................................................4
`CLINICAL/STATISTICAL- EFFICACY ........................................................................................................................ 4
`
`SAFETY ..................................................................................................................................................................... 10
`BASED UPON THIS INFORMTION, BOTH DR VILLABLA AND YASUDA BELIEVE THAT THIS SYNDROME SHOULD BE
`
`DESCRIBED IN THE WARNINGS SECTION. THIS REVIWER AGREES. ’ K—x
`,___ ................................................................................................................................................................ 18
`RECOMMENDATIONS/RISK BENEFIT ASSESSMENT .................................................................................................. 18
`
`2 INTRODUCTION AND BACKGROUND..........................................................................................................20
`
`2.1 PRODUCT INFORMATION ................................................................................................................................... 20
`2.2 CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS .................................................................................. 20
`2.3 AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ...................................................... 20
`2.4 IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS .......................................................... 20
`2.5 PRESUBMISSION REGULATORY ACTIVITY ......................................................................................................... 20
`2.6 OTHER RELEVANT BACKGROUND INFORMATION ............................................................................................. 21
`
`3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES ..........................................................21
`
`3.1 CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ..............................i.....................................................21
`3.2 ANIMAL PHARMACOLOGY/TOXICOLOGY .......................................................................................................... 21
`
`4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY ..........................................................22
`4.1 SOURCES OF CLINICALDATA ............................................................. 22
`4.2 TABLES OF CLINICAL STUDIES .................................................................................................................... 22
`
`4.3 REVIEW STRATEGY ....................... L ...................................................................................................................23
`4.4 DATA QUALITY AND INTEGRITY ....................................................................................................................... 23
`4.5 COMPLIANCE WITH GOOD CLINICAL PRACTICES .............................................................................................. 24
`
`.
`
`4.6 FINANCIAL DISCLOSURES ................................................................................................................................. 24
`5 CLINICAL PHARMACOLOGY.........................................................................................................................24
`
`6 INTEGRATED REVIEW OF EFFICACY .........................................................................................................27
`
`6.1 INDICATION .......................................................................................................................................................27
`6.1.1 Methods .................................................................................................................................................... 27
`
`6.1.2 General Discussion of Endpoints ............................................................................................................. 28
`6.1.3 Study Design ............................................................................................................................................ 31
`6.1.4 Efficacy Findings ..................................................................................................................................... 36
`6.1.5 Clinical Microbiology......................................................... ..................................................................... 64
`6.1.6 Efficacy Conclusions ............................................................................................................................... 64
`
`7 INTEGRATED REVIEW OFSAFETY.........67
`
`8 ADDITIONAL CLINICAL ISSUES .................................................................................................................... 67
`
`8.1 DOSING REGIMEN AND ADMINISTRATION ......................................................................................................... 67
`8.2 DRUG-DRUG INTERACTIONS ................................................................................................................... 67
`
`
`8.3 SPECIAL POPULATIONS ........................................................................................................................... 67 y
`8.4 PEDIATRICS ....................................................................................................................................................... 68
`8.5 ADVISORY COMMITTEE MEETING ..................................................................................................................... 68
`
`8.6 LITERATURE REVIEW ................................................................................................................................. 68
`
`8.7 POSTMARKETING RISK MANAGEMENTPLAN ........._.................................... 68
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`

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`Clinical Review
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`8.8 OTHER RELEVANT MATERIALS ......................................................................................................................... 69
`
`9 OVERALL ASSESSMENT ..................................................................................................................................70
`
`9.1 CONCLUSIONS ................................................................................................................................................... 70
`9.2 RECOMMENDATION ON REGULATORY ACTION ................................................................................................. 70
`
`V
`9.3 RECOMMENDATION ON POSTMARKETING ACTIONS ....................................
`............................................ 70
`9.3.1 Risk Management Activity ......... -. .......................................................................................................... 70
`9.3.2 Required Phase 4 Commitments
`............................... 71
`9.3.3 Other Phase 4 Requests ...................................................................................................................... 71
`9.4 LABELING REVIEW ...................................................................................................................................... 71
`9.5. COMMENTS TO APPLICANT ...................................................................................
`
`
`
`
`
`
`REFERENCES ..........................................................................................................................................................72
`
`WARS THIS WAY
`ON ORIGINAL
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`Clinical Review
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`1 EXECUTIVE SUMMARY
`
`The CDTL acted as the primary efficacy reviwer. Therefore, the CDTL review is being
`reprinted, in part, below so as to serve as the Executive summary.
`
`Introduction
`
`Lacosamide has been developed for two separate indications, partial onset seizures and pain
`associated with diabetic peripheral neuropathy (DPN). This CDTL Division of Neurology
`Prodcuts (DNP) review will concentrate on efficacy results in partial onset seizures. That for
`DPN will be reviewed by Division of Anesthesia, Analgesia and Rheumatologic Products
`(DAARP). Safety data in this application has been reviewed by both division, and while this
`review will concentrate on safety in epilepsy, all data will be discussed. Because of specific
`interest in a potential cardiac signal the Division of Cardiovascular and Renal Products (DCRP)
`was asked to comment not only on the formal QT study but issues of PR prolongation and
`general cardiac safety.
`
`Background
`
`According to the Sponsor Lacosamide, (R)-2-acetamid0—N-benzyl-3-meth0xypropionamide, is a
`member of a series of functional amino acids. From a mechanistic perspective lacosamide
`appears to act as a sodium channel blocker, an action shared by a number other anticonvulsants
`including phenytoin, carbamazepine, oxcarbazepine and Iamictal. The Sponsor also notes that
`lacosamide’s anticonvulsant activity may also be related to its ability to bind to collapsin
`response mediator protein-2 (CRMP-Z), a phosphoprotein which is mainly expressed in the
`nervous system and is involved in neuronal differentiation and control of axonal outgrowth. This
`reviwer believes that this latter mechanism is highly speculative.
`
`Clinical/Statistical- Efficacy
`
`The clinical efficacy review was performed by this CDTL, Dr. Norman Hershkowitz.
`
`

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`Clinical Review
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`{Insert Reviewer Name}
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`The Sponsor submitted 3 adequate and well controlled trials for review. Supportive studies were
`also included. The adequate well controlled trial consists of a phase 2b, dose finding study
`(SP667) and two phase 3 trials (SP754 and SP755). All three trials were of similar design (see
`below). The table below presents a summary of dose, time and numbers of patients studied in
`these protocols.
`
`Number of
`sub§ects
`randomized to
`receive LCRP
`
`299mgf'day: If}?
`_
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`603mgfday: 166
`
`430mg§da3¥ 304
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`.
`r,
`3
`606mgzda} ' 97
`
`3133311111111
`durafian of
`treatment!“
`
`Number (if
`sabjects
`razidnmized
`to. receive
`
`placebo“
`
`'21 weeks
`
`
`
`Trial namberfC’liniml {levelegmezzt
`'
`phasefi‘riai design
`
`S?66?.é?iiase 2fnmlticenter.. double-
`blind: windowed, placebm—controfied,
`ymfiei—group trial to investigate the
`efficacy and safety ofLCM (230, 49a
`and fiOOmg‘day)
`‘
`
`S?7543Phase 3imulticenteg double—
`mind, randomized, placebo—cummiieda
`pamfiei—gmup mm to investigate the
`efficacy and safety ofLCM (400 and
`600mgi‘day)
`'
`
`S?755!‘Phase 3f‘multice1iter,double—
`blind, randomized. placebo-committed;
`parallel-gong) trial to max—estigate the
`efficacy and safety ofLCM (200 and
`400111951513!)
`
`.ZOOnigtfdaY:
`
`A
`
`'
`
`i
`
`I8 weeks
`
`400mgday:
`
`200mg1day
`490mgfday
`600n1gi‘day
`Total: 944
`
`LC1M=iac>osamide
`
`:1
`
`b
`
`Because of audit findings suggesiizm; neucmnplianoe with the SPéfi? protocol, at} 3 msdomized and
`treated subjects at Site 12 were remarried from the. Safety Set (SS). As a result, 413 subjects were
`included in the 33.
`All 3 trials had a 12—week Maintenance Phase.
`
`The Sponsor describes 4 additional trials as supportive for the claim of efficacy. All supportive
`trials were uncontrolled and open-label studies whose data principally contributed to the safety
`database.
`
`As noted above all three studies were of a similar design. They were all multi-institutional,
`double-blind, placebo-control, parallel cohort, adjunctive treatment studies in adults (>16 years
`old) with partial epilepsy (simple partial, complex partial and partial secondarily generalized)
`Trials were rather similar in design. ‘ The schedule of evaluations was similar across studies.
`
`5
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`Initial screening was performed on the first day of the baseline period. Seizure diaries were
`provided at this time and patients were instructed in their use. Patients then entered an 8 week
`baseline phase. They were randomized following this period if they continued to fulfill
`inclusion/exclusion criteria (there was a requirement for a minimal seizure frequency during this
`period). Inclusion/exclusion criteria were relatively routine for this class of study. Patients .
`entered the treatment phase following randomization which consisted of a titration and a
`maintenance period. The titration period in SP 667 and SP754 were of 6 weeks duration and that
`of SP 755 were of 4 weeks in duration. All titrations proceeded at the rate of 100 mg qD (in a
`BID divided dose) every week. All doses were administered in an evenly divided BID regimen.
`Subjects who could not tolerate their final dose were permitted one back step of 100 mg/day
`during the titration period. The titration period was followed by a 12 week maintenance period
`in all studies. No back titration was permitted during this period. After the study was completed
`the patients were given a choice to continue on lacosamide in an open label study at a dose of
`200 mg/day. If they so decided, they would undergo a blind transition period where they were
`titrated to a dose of 200 mg/day. If they declined they would undergo a down-titration that
`would proceed at a rate of 200 mg/day every week.
`'
`
`The primary endpoint required by the FDA and EMEA where different, but were based upon the
`standards typically used for those agencies. These different primary endpoints were agreed upon
`by the FDA in an end of phase 2 meeting. The FDA assigned endpoint was the change in partial
`seizure frequency per 28 days from baseline to the maintenance period. Seizure frequency (SF)
`was calculated by the formula: SF = (Number of Seizures) x (28 / D), where, D is the number of
`days. The manner that baseline seizure frequency was calculated was different between the
`initial dose ranging study, SP667 and the two phase 3 studies, SP754 and SP755. These
`differences were protocol driven. Thus, for SP667 baseline values were based upon the complete
`8 week baseline period, but for SP754 and SP755 baseline value was based upon the last 56 days
`of the baseline period. For patients who discontinued during maintenance phase an LOCF
`frequency value was calculated. If the patient dropped out prior to entering the maintenance
`period an LOCF value for the titration period was calculated.
`
`Statistical analysis of the seizure frequency change was performed on the log-transformed
`seizure frequency1 based on an ANCOVA model with terms for treatment and pooled site. Log-
`transforrned average seizure frequency during the Baseline Phase was used as the covariate. This
`maneuver is rather commonly used in these studies to normalize such data. The seizure
`frequency between treatment and placebo was compared using LS means. Percentage reduction
`over placebo was calculated by: 100 x (I - exp[LSM Treatment — LSM Placebo]), where LSM is
`the least squares mean from the analysis. This analysis was previously described in the Sponsor’s
`statistical analysis plans. The log transformation allows a normalization of data. Criteria for
`statistical significance were P 5 0.05.
`
`The primary outcome described above and its method of analysis is similar to those used for the
`approval of a number of drugs. The single difference is the fact that only the maintenance period
`as opposed to the full treatment (titration plus maintenance period) was used to calculate post-
`
`1 Log transformation was based upon the formula ln(x+1), where x is equal to the seizure frequency.
`
`_ 6
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`treatment seizures. More commonly the titration and maintenance are included in this
`calculation. Off note, this analysis was performed as a secondary endpoint analysis.
`
`A number of secondary analyses were preformed including, but not limited to: 50 percent
`responder to Maintenance Phases (the EMEA primary endpoint), change in partial seizure
`frequency per 28 days from Baseline to the Treatment Phase (ie, Titration + Maintenance Phases:
`a more typical for the primary endpoint as noted above), other responder rates(375%, 250% and
`325%), Proportion of seizure-free days during the Maintenance Phase for subjects who entered
`the Maintenance Phase, proportion of subjects who achieved “seizure-free status” during the
`Maintenance Phase for subjects who completed the Maintenance Phase, Response to treatment
`by seizure type, Clinical Global Impression of Change, Quality of Life in Epilepsy-31.
`
`All 3 studies underwent changes in sample size during their implementation. One had a decrease
`in sample size because of unexpectedly fewer dropouts and 2 had an increase in sample size
`becasue a repeat calculation indicated that the original determination of standard deviation and
`effect size, based upon another anticonvulsant study, was incorrect. These changes were made
`without unblinding and, according to the statistics reviewer, Dr. Massie, are justified.
`
`Drop out rate during the trial differed slightly between placebo and the 200 mg/day dose, with
`the ranges in trials being 11%t014% and 17 to 21% for placebo and lacosamide (200 mg/day),
`respectively. That for the 400 mg dose showed a larger difference with 11% to 14% versus 21 to
`26% for placebo versus drug, respectively. High drop out rates where observed for the 600
`mg/day with a range of 11 to 13% versus 33% to42% for placebo and drug, respectively. Most
`drop outs in the drug treatment groups resulted from adverse events (see safety).
`
`Subject demographics were comparable across treatment groups. The mean age amongst all
`studies was approximately 40 years old. Most patients were categorized as Caucasian with
`“black” making up only 2 to 6 percent of the studied population. Seizure types were also well
`distributed across treatment groups in all studies. Complex partial and partial secondary
`generalized were more common then simple partial seizures. The most common concomitant
`AED were carbamazepine (35.2% subjects), followed by lamotrigine (31.2%) and levetiracetam
`(29.0% subjects). The majority of patients were on 2 concomitant medications.
`
`The results of the primary endpoint (percent change from baseline to maintenance) over placebo
`is presented for all three trials in the table below. The percent reduction from placebo is based
`upon logarithmically transformed data, but is actually very close to arithmetic percent changes.
`From these data it is apparent that both the-400 and 600 mg daily dose resulted in a significant
`reduction in seizures from placebo. This was also the conclusion of the Pharmaco—metrics
`reviewer, by Dr. Zhu, who noted that in a nonlinear regression least squares modeling response
`curve started to flatten out beyond the median exposure of 400 mg dose. From the data below,
`and as per Dr Zhu’s analysis, there is no obvious additional therapeutic benefit observed for the
`600 mg/day as compared to 400 mg/day.
`In the 2 studies that examined the 200 mg/day dose a
`therapeutic trend was noted. This effect, however, was statistically significant for only one
`study. This reviewer believes that the 200 mg dose is therapeutic in some patients but may on
`average have a smaller effect resulting in an inconsistent statistical finding between both studies.
`
`7
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`Clinical Review
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`”A: reductian aver
`phoebe
`
`P—vmine
`
`Tfiai-‘Compmison of
`LISA-1 to placebo
`3113613?
`
`
`LCM Zflfimyday {23:1 03*)
`(—3.2, 2-9.4}
`
`m 405%139'6333' {N=1 or}
`£0023“
`(1 3.3, 422 =
`
`{6-0, 34.1)
`LCM 600111g’day»m=105}
`
`513254
`
`LCM 400mgday {@2201}
`.-
`.
`.
`0.8973“
`
`959% (:3 far 9%“:- 1‘efitxtfion
`over pincebo
`
`
`
`mm 5001113]day(N=973
`
`a _
`
`G.00fi1.**
`
`LCM 'Eflmlgfday fN=I so}
`
`LCM zinesng-‘aay (16:53}
`
`As noted above, the change in frequency from baseline to maintenance phase is not a typical
`endpoint. The more conventional endpoint of change from baseline to the experimental period
`(titration + maintenance) was examined as a secondary endpoint. Data from this analysis is
`presented below, and differs little from the primary endpoint. This serves as an excellent
`sensitivity analysis to the Sponsor’s endpoint.
`
`Tfiaiifflbmgafisen 9f
`LCM to placebo
`
`‘34: reduction over
`giacebo
`
`953% CI far We redaction
`ever Mambo
`
`LCM 259mgday {N=IO?)
`
`mmm}
`
`momww
`
`_
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`

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`Clinical Review
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`{Insert Reviewer Name}
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`
`The statistical significance of secondary endpoint, 50% responder rate (the EMEA primary
`analysis), exhibited results identical, in terms of which doses were statically significant from
`placebo, to the primary endpoints in the FDA analysis. Other secondary endpoints, dealing with
`mimerical alterations is seizure rates exhibited statistical significant effects as compared to
`placebo or trended in the correct direction. The Global evaluations trended toward improvement
`in the 400 and 600mg doses. Effects of quality of life measures were small and inconsistent.
`
`Another secondary endpoint was the reduction in seizures by seizure type (i.e. simple partial,
`complex partial and partial secondarily generalized). These data were only presented using
`descriptive statistics. There was likely insufficient power to draw definitive conclusions. In
`general both complex partial seizures and partial secondarily generalized all trended in a
`direction that suggested a therapeutic effect. The effect on simple partial was more inconsistent.
`N0 definitive trend was observed, with some studies showing decreases and others increases in
`seizure activity of drug over placebo. Nothing can be definitively drawn from these data as
`these seizures were the least frequently observed and the data would be prone to a sampling
`error.
`
`Dr Massie, the statistical reviewer, confirmed the Sponsor’s analysis for all performed studies.
`Dr Massie also noted that “overall, there was no compelling evidence that the treatment effect
`varied by gender.” He also determined that there was no obvious age dependency for the age
`range'studied (16 to 71 years of age). Considering the limitation of the small size of the non-
`Caucasian sample size, it was concluded that no obvious racial differences in effect was
`observed.
`
`This reviwer concludes that both the 200, 400 mg/day dose (divided bid) impart a therapeutic
`effect in adjunctive treatment of partial seizures. The 600mg/day dose does not appear, on
`average, to be superior to the 400 mg dose. The 200 mg dose may, on average, appears to have a
`smaller therapeutic benefit. However, on an individual basis, dosing will have to be adjusted not
`only based upon therapeutic benefit but also on tolerability. As will be discussed in the safety
`section, the 600 mg dose was poorly tolerated.
`
`The Sponsor intends to market =2 formulations of lacosamide: tablets, intravenous solution
`
`All pivotal studies were performed using a tablet formulation. Conclusions for
`efficacy for other formulations are based upon studies demonstrating equivalent bioavailability
`between those formulations and the tablet formulation. ’f—\
`N .Bioequivalence was also demonstrated with the1V infusion
`solution when such infusions were performed over 30 and 60 minutes. Shorter infusions resulted
`in higher Cmax values1n the formal bioequivalence studies (see Pharmacokinetic section above).
`
`“(4)
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`Safety
`
`I1(4)
`
`Two separate major safety reviews were perfomed because of the two independent proposed
`indications: one by Dr. Villalba, for its anticonvulsant indication, and the other by Dr
`Pokrovnichka, for the neuropathic pain indication.
`In addition cardiology was consulted, not to
`only comment on QT studies, but also on other cardiac issues describedbelow. A CSS review is
`also included with scheduling recommendations (see below). Although the Sponsor has
`simultaneously submitted an application to the European Union for approval, there is no foreign
`marketing experience.
`
`Dr Villalba principally reviewed phase 1 to phase 3 studies relevant for the epilepsy indication.
`Dr Vilalba also reviewed safety data from the studies using X iv as well as the tablet
`formualtions. Dr Pokrovnichka’s review concentrated on the tablet as it applied to the indication
`for diabetic neuropathic pain (DNP). The application includes a total of 4012 unique adult
`subjects exposed to LCM (including all routes of administration, all indications and healthy
`volunteers). Of these, 1338 subjects were in the partial—onset seizure studies (1327 subjects from
`studies with the oral tablet) and 2001 subjects in the neuropathic pain studies. The exposures in
`the epilepsy studies where of sufficient dosage and duration and met ICH guidelines. The
`database included both double-blinded placebo-controlled and open label studies. Of the subjects
`with partial—onset seizures exposed to oral LCM, 199 subjects also received IV LCM in Phase
`2/3 trials. Intravenous studies were generally shorter in duration and either open label or were
`designed for comparison to the tablet formulation. Assuming similar PK and no obvious local
`issues of irritation, while these studies use a much smaller database, they should be considered
`sufficient for a determination of additional risks over the oral formulations.
`
`In her review, Dr. Villalba distinguishes two phase 2/3 safety pools: EP SI which includes
`patients from al/J’p/aceéo—co/z/m/lm,’ dazzé/e—é/J'Izdedstudies and EP 82 which included all
`patients receiving drug product in all/phase 2/3 studies. These will be referred to below.
`
`Deaths
`
`No deaths were observed in phase I trials. A total of 9 deaths were observed in the epilepsy
`phase 2/3 studies. Eight of these nine occurred during open label studies. No deaths were
`observed in the placebo group. This leaves a comparison of 1 in drug Vs 0 in placebo in the EP
`81 population. It should be remembered that the placebo population was third the size of those
`who received drug in the EP SI population. These numbers are insufficient to draw any
`conclusions regarding an excess of drug—induced deaths. Four deaths were believed to be result
`of Sudden Unexpected Death in Epilepsy (SUDEP). Calculations by Dr. Villalba revealed no
`excess over that which would be expected in the studied population. On death, in a patient with
`a history of depression, was attributed to a completed suicide. None of the other deaths followed
`a particular pattern that can be easily attributed to a common cause.
`
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`There were a total of 15 deaths in patients on lacosamide in the DNP population. Four of these
`(4/1023) were in the controlled studies with none (0/291) in the placebo group. Of the 15 total
`deaths a majority (8) were cardiac-related (ventricular fibrillation, myocardial infarction, heart
`failure (n=2), myocarditis, cardiac arrest (n=2) and sudden death). Such a number is not
`unexpected for a patient population with diabetes and with many patients also having a history of
`hypertension, coronary artery disease, cerebrovascular disease, and/or peripheral vascular
`disease. One of the cardiac deaths was noted to include myocarditis/toxic hepatitis which
`occurred following completion of LCM treatment. This case may represent a suspected case of
`multiorgan hypersensitivity and will be discussed below. Three of the cardiac deaths however
`were observed in the placebo control studies, which may be suggestive of a potential cardiac
`related signal. However, the numbers of patients exposed in the placebo population is
`substantially lower then that in the drug population. These data however must be viewed against
`the background of other cardiac events, which will be discussed below. All but two of the
`remainder of deaths (5) was from a variety of cancers. No one type stood out. One case of a
`completed suicide was observed. Suicide and suicide ideation will be discussed below.
`
`Other Serious Adverse Events
`
`Comparison by Dr Villalba of rates of serious adverse events in the EP 81 epilepsy population
`revealed a higher rate amongst patients on drug then on placebo: :i.e. 6.5% and 3.8%,
`respectively. No obvious dose response was observed for these grouped rates. The most
`frequent reported serious adverse events, classified by system organ class (SOC), were Nervous
`Systems Disorders (1.6% in placebo and 2.1% in lacosamide in the EP 8] pool). The most
`frequent single preferred term was “convulsions” with 0.8 in placebo and 0.8 in the lacosamide
`group. While it may be unexpected that these rates are the same, when you lump all other
`epilepsy preferred terms (e.g. epilepsy, complex partial seizures, etc) you observe a comparison
`of 1.7% Vs 1.3%, in placebo and drug. Other, non-convulsive serious CNS adverse events
`observed which were more common in drug as compared to placebo groups, were dizziness,
`nystagmus, coordination abnormal, loss of consciousness and tremor. No placebo patients
`exhibited these vents. Except for dizziness and nystagmus which were observed in 0.3% and
`0.2% of patients, respectively, all events occurred in only 0.1% of patients (1 patients).
`Although the numbers of some of these events are low, many of these events are common with
`other anticonvulsants, with CNS adverse events limiting the dose that can be used. These are
`very common adverse events reactions associated with this class of anticonvulsants.
`
`The next most frequent SAEs in the EP 81 population for patients with epilepsy were in the
`Psychiatric disorders SOC (0.7% for LCM and 0 for placebo-treated patients). Psychiatric
`events included preferred terms such as hallucinations, epileptic psychosis, psychotic disorders,
`completed suicide (see above), suicide attempt and insomnia. As Dr Villalba points out, the risk
`of such events are commonly seen in patients with epilepsy and although occurred in small
`numbers were only observed in patients receiving lacosamide. Dr. Villalba consequently
`reviewed each case, many of which an alternative explanation could be found (e.g. previous
`history of similar behavior). Dr Villalba suggested that the low numbers and perhaps other
`explainable cases undermine a casual attribution to drug use. This CDTL agrees.
`
`11
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`

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`Clinical Review
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`{Insert Reviewer Name}
`{Insert Application and Submission Number}
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`{Insert Product Trade and Generic Name}
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`The next most common SAEs in the EP S1 population for patients with epilepsy included GI
`disorders systems (0 6% for LCM and 0.3% for placebo--treated patients, respectively) and
`infections (0.5% for LCM and 0.3% for placebo-treated. patients, respectively). These events
`were not thought to be related to treatment
`
`Examination of SAEs in the EP S2 pool for the epilepsy population did not reveal much
`additional information. A high number of injuries from fracture were noted (16 patients) and
`. were possibly thought to be related to dizziness and ataxia, which appear to be drug related.
`
`Serious adverse events in the DPN controlled population were similar to that reported for the
`epilepsy population: i.e. 6.6% (68/1023) of subjects who received lacosamide an